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Rapid Response Report: Systematic Review and Meta-Analysis

Pharmacological and Non-pharmacological CADTH Therapies for Adults with Attention-Deficit/Hyperactivity Disorder: Systematic Review and Meta-analysis of Clinical Evidence

September 2011

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Cite as: Nuwwareh, S, Cimon, K, Ford, C and Weiss, M. Pharmacological and Non- pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder: Systematic Review and Meta-analysis of Clinical Evidence [Internet] Ottawa: Canadian Agency for Drugs and Technologies in Health; 2011 (Rapid Response Report: Systematic Review). [cited 2011-09-21]. Available from: http://www.cadth.ca/media/pdf/htis/sept-2011/RE0026_ADHD_in%20adults_e.pdf

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Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder: Systematic Review and Meta-analysis of Clinical Evidence

Samer Nuwwareh, BDS, MSc1 Karen Cimon, MLT1 Caitlyn Ford, BA (Hons.), MLIS1 Dr. Margaret Weiss, MD, PhD, FRCP(c)2

September 2011

1Canadian Agency for Drugs and Technologies in Health (CADTH), Ottawa, Ontario 2 Children‘s and Women‘s Health Centre, Vancouver, British Columbia

Health technology assessment agencies face the challenge of providing quality assessments of medical technologies in a timely manner to support decision-making. Ideally, all important deliberations would be supported by comprehensive health technology assessment reports, but the urgency of some decisions often requires a more immediate response.

The Rapid Response Service provides Canadian health care decision-makers with health technology assessment information, based on the best available evidence, in a quick and efficient manner. Inquiries related to the assessment of health care technologies (drugs, devices, diagnostic tests, and surgical procedures) are accepted by the service. Information provided by Rapid Response Service is tailored to meet the needs of decision-makers, taking into account the urgency, importance, and potential impact of the request.

Consultations with the requestor of this Rapid Response assessment indicated that a review of the literature would be beneficial. The research question and selection criteria were developed in consultation with the requestor. The literature search was carried out by an information specialist using a standardized search strategy. The review of evidence was conducted by one internal reviewer. The draft report was internally reviewed and externally peer-reviewed by two or more peer reviewers. All comments were reviewed internally to ensure that they were addressed appropriately.

Reviewers These individuals kindly provided comments on this report:

AG Ahmed, MBBS, MSc, MPsycMed, LLM, MRCPsych, FRCPC Clinical Director, South East Forensic Services, Royal Ottawa Health Care Group Department of Psychiatry, Faculty of Medicine, University of Ottawa Ottawa ON

Cynthia Slade BSc (Hons), MD Psychiatrist, St. John‘s NL

Dr. Drew Kingston, Ph.D Psychologist (Supervised Practice Integrated Forensic Program, Royal Ottawa Health Care Group Ottawa ON

This report is a review of existing public literature, studies, materials, and other information and documentation (collectively the “source documentation”) that are available to CADTH. The accuracy of the contents of the source documentation on which this report is based is not warranted, assured, or represented in any way by CADTH, and CADTH does not assume responsibility for the quality, propriety, inaccuracies, or reasonableness of any statements, information, or conclusions contained in the source documentation.

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Pharmacological and Non-pharmacological Therapies for Adults with i Attention-Deficit/Hyperactivity Disorder

misuse) of any information, statements, or conclusions contained in or implied by the information in this document or in any of the source documentation. CADTH takes sole responsibility for the final form and content of this report subject to the limitations noted above. The statements, conclusions, and views expressed herein do not necessarily represent the view of Health Canada or any Canadian provincial or territorial government. Production of this report is made possible by financial contributions from Health Canada and the governments of Alberta, British Columbia, Manitoba, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Prince Edward Island, Saskatchewan and Yukon. Copyright: Copyright @ CADTH (September 2011). You are permitted to make copies of this document for non-commercial purposes provided it is not modified when reproduced and appropriate credit is given to CADTH.

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Industry: The following manufacturers were provided with an opportunity to comment on an earlier version of this report Paladin Labs, Janssen Ortho, Purdue Pharma Canada, Sandoz Canada, Shire Canada Inc., Novartis, Eli Lilly. All comments that were received were considered when preparing the final report.

ii Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

ACRONYMS AND ABBREVIATIONS AAQoL Adult ADHD Quality of Life Measure ADHD attention-deficit/hyperactivity disorder ADHD-RS-IV ADHD Rating Scale, Version IV AIM-A ADHD Impact Module for Adults AISRS Adult ADHD Investigator Symptom Rating Scale ATX atomoxetine BAI Beck Anxiety Inventory BDI-II Beck Depression Inventory CAARS-Inv:SV Conners Adult ADHD Rating Scale-Investigator Rated: Screening Version CAARS-O Conners Adult ADHD Rating Scale-Observer CBT cognitive behavioural therapy CGI-I Clinical Global Impression-Improvement scale CGI-S Clinical Global Impression-Severity scale CI confidence interval CT cognitive therapy DEX dextroamphetamineS DSM-IV Diagnostic and Statistical Manual of Mental Disorders – 4th edition DSS Driving Safety Score DWR delayed word recall ELS Emotional Liability Scale EWPS Endicott Work Productivity Scale GAF Global Assessment of Functioning scale HAM-A Hamilton Anxiety Rating Scale HAM-D Hamilton Depression Rating Scale HTA health technology assessment IWR immediate word recall LDX lisdexamfetamine dimesylate LSAS Liebowitz Social Anxiety Scale MAS-XR mixed amphetamine salts – extended release MLR-MPH multilayer-release methylphenidate MPH methylphenidate OR odds ratio OROS-MPH osmotic release oral system-methylphenidate PERMP Permanent Product Measure of Performance PSQI Pittsburgh Sleep Quality Index Q-LES-Q Quality of Life Enjoyment and Satisfaction Questionnaire RCT randomized controlled trial RSEI Rosenberg Self Esteem Inventory RVIP rapid visual information processing SD standard deviation SDS Sheehan Disability Scale SSRT stop-signal reaction time SWM spatial working memory TB MAS-ER treble-bead mixed amphetamine salts – extended release TEAE treatment-emergent adverse events

Pharmacological and Non-pharmacological Therapies for Adults with iii Attention-Deficit/Hyperactivity Disorder

TABLE OF CONTENTS

ACRONYMS AND ABBREVIATIONS ...... III EXECUTIVE SUMMARY ...... 1 1 CONTEXT AND POLICY ISSUES ...... 4 2 RESEARCH QUESTIONS ...... 4 3 KEY MESSAGE ...... 4 4 METHODS ...... 5 4.1 Literature search strategy ...... 5 4.2 Selection criteria and method...... 5 4.3 Exclusion criteria ...... 7 4.4 Data extraction strategy and critical appraisal of individual trials ...... 7 4.5 Data analysis methods...... 7 5 RESULTS ...... 8 5.1 Quantity of research available ...... 8 5.2 Outcome measures used in included trials ...... 8 5.3 Clinical efficacy of stimulant and non-stimulant therapies for adults with ADHD ...... 9 6 DISCUSSION ...... 33 6.1 Summary of Evidence ...... 33 7 CONCLUSIONS AND IMPLICATIONS FOR DECISION- OR POLICY-MAKING ...... 35 8 REFERENCES: ...... 36

APPENDIX 1: Literature Search Strategy ...... 42 APPENDIX 2: Selection of Included Trials...... 52 APPENDIX 3: Included Trials ...... 53 APPENDIX 4: Excluded Studies ...... 58 APPENDIX 5: Description of Outcome Measures ...... 68 APPENDIX 6: Trial Characteristics ...... 72 APPENDIX 7: Patient Characteristics ...... 87 APPENDIX 8: Summary of Trial Results ...... 93 APPENDIX 9: Psychotherapeutic Interventions for the Treatment of ADHD in Adults .. 114

iv Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

TITLE: Pharmacological and Non- a. What is the clinical efficacy of pharmacological Therapies for Adults psychological therapies or combination with Attention-Deficit/Hyperactivity therapy with pharmacological and Disorder: Systematic Review and Meta- psychological treatments in the adult analysis of Clinical Evidence prison population with attention- deficit/hyperactivity disorder? DATE: September 2011 EXECUTIVE SUMMARY Methods A peer-reviewed literature search was conducted using the following bibliographic databases: Context and Policy Issues MEDLINE, Embase, PsycINFO, The Cochrane Attention-deficit/hyperactivity disorder (ADHD) Library (2011, Issue 2), and PubMed. Grey is a chronic biobehavioural disorder that is literature (literature that is not commercially characterized by hyperactivity, impulsivity, published) was identified by searching relevant and/or inattention. The results of a survey done sections of the Grey Matters checklist by the World Mental Health Survey Initiative at (http://www.cadth.ca/index.php/en/cadth/produc the World Health Organization showed that an ts/grey-matters). Methodological filters were average of 3.5% of employed adults between the occasionally applied to limit retrieval to study ages of 18 years to 44 years old were deemed to design (see literature search portion of the have ADHD.1 A higher prevalence of ADHD methods section for full details). Where (40%) was reported among adult male prisoners possible, retrieval was limited to the human in Sweden.2 Stimulant medications may be population. The search was also limited to subject to abuse and a source of potential profit English language documents published between in prisons. In addition, the safety of patients with January 1, 2006 and March 10, 2011. Regular ADHD, who may be pressured or harmed to alerts were established to update the search until relinquish medication to other inmates, may be July 27, 2011. compromised.3 Two reviewers independently screened the titles This systematic review will be used to inform and abstracts of the retrieved publications and the development of clinical practice guidelines independently evaluated the full-text on pharmacological and psychological publications for final article selection. treatments in adults with ADHD, including the Randomized controlled trials were eligible for prison population. inclusion if they involved adult patients with ADHD (18 years or older), compared Research Questions pharmacological treatment with placebo or compared psychotherapy with supportive 1) What is the clinical efficacy of stimulant and therapy, and reported outcomes that were related non-stimulant therapies for adults with to patient safety or clinical efficacy. This report attention-deficit/hyperactivity disorder in the was peer-reviewed by clinical experts. general population? a. What is the clinical efficacy of Summary of Findings stimulant and non-stimulant therapies in Thirty-three randomized controlled trials were the adult prison population with included in this review. Five trials evaluated the attention-deficit/hyperactivity disorder? 4-8 efficacy of amphetamine-based medications, 2) What is the clinical efficacy of 15 trials assessed the efficacy of psychological therapies or combination methylphenidate (MPH)-based drugs,9-23 eight therapy with pharmacological and trials evaluated the efficacy of atomoxetine psychological treatments for adults with (ATX)-based medications,24-31 and four trials attention-deficit/hyperactivity disorder in the assessed the efficacy of psychotherapy.32-35 One general population? trial evaluated the efficacy of both amphetamine

Pharmacological and Non-pharmacological Therapies for Adults with 1 Attention-Deficit/Hyperactivity Disorder

and ATX medication in two separate cohorts.36 trial,35 which showed a statistically significant No trials on ADHD therapy efficacy specific to reduction of ADHD symptoms compared with the adult prison population were identified. In supportive therapy, as measured using CAARS- addition, the results from trials on the efficacy of O. Vitra et al.39 showed that the number of combined psychological and pharmacological responders, as measured by means of CGI-I, was therapies were not identified. numerically higher among patients who were treated with hypnotherapy compared with the ADHD symptom reduction was associated with control group (the control group did not receive all evaluated therapies. The effect of any active treatment), and fewer responders amphetamine-based medications on ADHD were found with cognitive treatment compared symptoms was evaluated in six trials by means with the same control group. The differences in of two outcome measures (ADHD-RS-IV both cases were not statistically significant. [ADHD Rating Scale, Version IV] and CGI-I [Clinical Global Impression-Improvement Quality of life was assessed in five scale]).4-8,36 Compared with placebo, the results trials;27,28,32,38,39 three trials assessed the effect of from both measures showed greater ATX using the AAQoL (Adult ADHD Quality improvement in ADHD symptoms associated of Life scale),27,28,38 one trial evaluated the effect with the use of amphetamine-based medications. of dialectical behavioural therapy using the Fifteen trials assessed the effect of MPH general well-being questionnaire,32 and one trial medications on ADHD symptoms using six assessed cognitive behavioural therapy, outcome measures (ADHD-RS-IV, AISRS cognitive therapy, and hypnotherapy by means [Adult ADHD Investigator Symptom rating of the Q-LES-Q (Quality of Life Enjoyment and Scale], CAARS-O [Connors Adult ADHD Satisfaction Questionnaire).39 The interventions Rating Scale-Observer], CGI-I, CGI-S [Clinical that were studied all showed greater than Global Impression-Severity] scale, and average improvement in the quality of life WRAADDS [Wender-Reimherr ADHD measures compared with placebo or supportive Scale]).9-23 The findings from these trials showed therapy, but the improvement did not reach that MPH was associated with greater statistical significance in three trials.27,28,39 A improvement in ADHD symptoms when systematic review40 that evaluated the impact of measured using ADHD-RS-IV, AISRS, CGI-S, ADHD medications on quality of life echoed the and WRAADDS. Of the ten trials that used the findings of this review; for example, few trials CGI-I measure;9,13,15,18-23,37 two 15,23 showed evaluated quality of life as part of their protocol greater improvement associated with placebo, and, when evaluated, the assessment was done in and one trial showed a similar association when the short period of clinical trials, which might symptoms were measured by means of CAARS- not reflect the long-term benefits given the O.11 Atomoxetine, when compared with placebo, chronic nature of ADHD. was associated with a greater reduction in ADHD symptoms as measured using AISRS, The effects of ADHD therapies on the ADHD-RS-IV, CAARS-Inv:SV (Conners Adult depression and anxiety associated with ADHD ADHD Rating Scale-Investigator Rated: were evaluated in one amphetamine trial,8 two Screening Version), CGI-I, and MPH trials,11,22 and one psychotherapy trial.35 WRAADDS.24,26-30,36,38 Of the six trials that used The results from these studies did not provide the CGI-S scale,24,26-29,38 two reported a greater evidence of important benefits on depression or than average improvement with the placebo anxiety. Function and cognitive skills were group.26,28 However, these differences were not evaluated in three amphetamine trials,4,8,36 two statistically significant. Studies of psychological MPH trials,10,19 and one ATX trial.28 interventions provided evidence on the efficacy Methylphenidate was associated with consistent of cognitive behavioural therapy in reducing and statistically significant improvement of ADHD symptoms as measured using the function as measured using SDS (Sheehan ADHD-RS-IV,34 CGI-I,39 and CGI-S scales.34 Disablitiy Scale) 10 and GAF (Global Meta-cognitive therapy was evaluated in one Assessment of Functioning) scale.19

2 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Conclusions and Implications for Decision- or Policy-Making The available evidence suggests that amphetamine, MPH, ATX, cognitive behavioural therapy, and meta-cognitive therapy are associated with greater ADHD symptom reduction compared with placebo or supportive therapy. The evidence also suggests that the use of MPH is associated with better functioning and cognitive skills than placebo. Large, well- designed trials that specifically address the treatment of ADHD in adults are needed to accurately assess the impacts on quality of life and ADHD-associated morbidities.

Pharmacological and Non-pharmacological Therapies for Adults with 3 Attention-Deficit/Hyperactivity Disorder

1 CONTEXT AND common in this population.2 Stimulant medications may be subject to abuse and a POLICY ISSUES source of potential profit in prisons. In addition, the safety of patients with ADHD who may be Attention-deficit/hyperactivity disorder (ADHD) pressured or harmed to relinquish medication to 3 is a chronic biobehavioural disorder that is other inmates may be compromised. characterized by hyperactivity, impulsivity, and/or inattention. The symptoms usually 2 RESEARCH manifest in childhood and continue into adulthood for many patients with ADHD.41 QUESTIONS ADHD may lead to academic, emotional, and social impairment.41 ADHD is diagnosed 1) What is the clinical efficacy of stimulant and according to the International Classification of non-stimulant therapies for adults with Mental and Behavioural Disorders –10th attention-deficit/hyperactivity disorder in the revision and the Diagnostic and Statistical general population? Manual of Mental Disorders – 4th edition (DSM-IV). Therapy options include a) What is the clinical efficacy of stimulant pharmacological treatments such as stimulants, and non-stimulant therapies in the adult psychological treatments including behavioural prison population with attention- therapy, and changes to daily lifestyle deficit/hyperactivity disorder? activities.42,43 2) What is the clinical efficacy of psychological therapies or combination therapy with The prevalence of ADHD in the general 2,44 pharmacological and psychological population is approximately 3% to 4%. The treatments for adults with attention- results from the World Mental Health Survey deficit/hyperactivity disorder in the general Initiative by the World Health Organization population? showed that an average of 3.5% of employed adults between 18 years and 44 years of age a) What is the clinical efficacy of were thought to have ADHD according to the 1 psychological therapies or combination DSM-IV criteria. The survey sample included therapy in the adult prison population 7,705 respondents in 10 countries. ADHD was with attention-deficit/hyperactivity more common among males than females, and disorder? less common among professionals compared with those in other occupations, such as white collar technical and blue collar employees.1 3 KEY MESSAGE

This systematic review will be used to inform The available evidence suggests that the development of clinical practice guidelines amphetamine, methylphenidate (MPH), on pharmacological and psychological atomoxetine (ATX), cognitive behavioural treatments in adults. An analysis on the adult therapy, and meta-cognitive therapy are prison population with ADHD will be conducted associated with greater ADHD symptom based on the available clinical evidence. In the reduction compared with placebo or supportive adult prison population, the prevalence of therapy. ADHD appears to be higher. A 2010 trial conducted in a high-security prison in Sweden estimated that 40% of adult male prisoners are affected by ADHD.2 Furthermore, the authors indicated that coexisting disorders — such as substance use disorder, autism spectrum disorder, and personality disorder — are

4 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

4 METHODS 10, 2011. Regular alerts were established to update the search until July 27, 2011. Conference abstracts were excluded from the 4.1 Literature search strategy search results. See Appendix 1 for the detailed search strategy. The literature search was performed by an information specialist using a peer-reviewed Grey literature (literature that is not search strategy. commercially published) was identified by searching relevant sections of the Grey Matters Published literature was identified by searching checklist the following bibliographic databases: (http://www.cadth.ca/index.php/en/cadth/produc MEDLINE with In-process records and daily ts/grey-matters). Google and other Internet updates via Ovid; Embase via Ovid; PsycINFO search engines were used to search for additional via Ovid; The Cochrane Library (2011, Issue 2) materials. These searches were supplemented by via Wiley; and PubMed. The search strategy reviewing the bibliographies of key papers, the comprised controlled vocabulary, such as the included studies and previous systematic National Library of Medicine‘s MeSH (Medical reviews, and through contacts with appropriate Subject Headings), and keywords. The main experts and industry. search concepts were pharmacological and psychological therapies and ADHD in adults. 4.2 Selection criteria and To address the research questions on the clinical method efficacy of pharmacological treatments for ADHD in adults, methodological filters were Two reviewers (SN and KC) independently applied to limit retrieval to health technology screened citations and selected trials relevant to assessments, systematic reviews, meta-analyses, the research questions on pharmacological and and randomized controlled trials (RCTs) for psychological treatments in adults with ADHD. pharmacological interventions. Non-randomized The decision to order an article in full text for trials were also searched for the research further examination was based on the screening question on the clinical efficacy of non- of the title of each citation and its abstract, when pharmacological interventions. The results and available. In cases of insufficient information, conclusions of previous health technology the article was ordered for more information. assessments, systematic reviews, and meta- Two reviewers (SN and KC) selected the final analyses will be compared with those found in articles for inclusion based on an examination of this review and presented in the discussion the full-text publications. A trial was included section. In addressing the research questions on for review based on the selection criteria that the psychological and pharmacological were established before the research was started treatments for ADHD in adults in the prison (Table 1). Any disagreement between reviewers population, no filters were applied to limit the was discussed until consensus was reached. The retrieval by trial type. Where possible, retrieval trial selection process is presented in a flow was limited to the human population. The search chart based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses was also limited to English language documents 45 published between January 1, 2006 and March (PRISMA) statement (Appendix 2).

Pharmacological and Non-pharmacological Therapies for Adults with 5 Attention-Deficit/Hyperactivity Disorder

Table 1: Trial Selection Criteria Population Adult population (men and women), 18 years and older and diagnosed with ADHD Adult prison population (men and women), 18 years and older with ADHD Intervention Pharmacological therapies – Stimulants (drugs that excite or speed up the central nervous system)46 □ Immediate release (short-acting, three times per day dose schedule): o MPH hydrochloride (Brand name: Ritalin, Metadate, Methylin) o dextroamphetamine sulfate (Brand name: Dexedrine) o mixed amphetamine salts (Brand name: Adderall) □ Intermediate release (intermediate-acting, twice-daily dose schedule): o MPH hydrochloride (Brand name: Ritalin SR, Ritalin LR, Metadate ER, Metadate CD, Methylin ER, Focalin, and Focalin XR) o dextroamphetamine sulfate (Brand name: Dexedrine) □ Extended release (long-acting, once-daily dose schedule): o MPH hydrochloride (Brand name: Biphentin, Concerta) o mixed amphetamine salts (Brand name: Adderall XR) o lisdexamfetamine dimesylate (Brand name: Vyvanse) Non-stimulants o atomoxetine (Brand name: Strattera) o tricyclic antidepressants . desipramine hydrochloride (Brand name: Norpramin) . imipramine hydrochloride (Brand name: Tofranil) . amitriptyline hydrochloride (Brand name: Elavil) . nortriptyline hydrochloride (Brand name: Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren and Nortrilen) o bupropion (Brand name: Wellbutrin) o guanfacine XR (Brand name: Intuniv) Psychological therapies – Behavioural therapy Cognitive behavioural therapy Interpersonal psychotherapy Comparator Placebo for pharmacological therapies, or supportive therapy for psychotherapy (that controls for non-specific therapeutic effects of a group intervention) Outcomes Primary outcomes o Change in severity of ADHD symptoms assessed using a standardized instrument and rated by a trial investigator or an independent observer Secondary outcomes o Cognitive and adaptive skills and functional outcomes assessed by an investigator or self-rated o Quality of life and psychiatric morbidity assessed by an investigator or self- rated o Serious adverse events and treatment-emergent adverse events Trial design RCTs ADHD = attention-deficit/hyperactivity disorder; MPH = methylphenidate; RCTs = randomized controlled trials.

6 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

4.3 Exclusion criteria The data synthesis of individual trials was based on differences of means between the compared In addition to those reports not meeting the groups and associated 95% confidence intervals selection criteria, duplicate publications, (CI) for continuous measures and odds ratios preliminary reports of data that are presented in (OR) and 95% CI for dichotomous outcomes. If full, and studies that have been superseded by the mean difference was not reported in the more recently published trials by the same group included articles, it was calculated by the were also excluded, unless they provided reviewers and then entered into a random effects additional data. generic variance approach to meta-analysis. Data summarizing mean within-group changes 4.4 Data extraction strategy from baseline to follow-up (with corresponding and critical appraisal of measures of uncertainty), or variations of these individual trials changes, were collected from all included trials for all continuous outcome measures that were Before the research was started, two reviewers of interest. Where the standard deviations of (SN and KC) piloted the data extraction and change scores in all intervention arms of a trial quality assessment forms on a small number of were not reported, the application of an included trials. The same reviewers then approach discussed by Abrams et al.48 and independently extracted the clinical efficacy data Follman et al.49 and used to impute standard for each included article, using the finalized data deviations based on empirical estimation of extraction and quality assessment forms. The correlation was planned. For an informed Scottish Intercollegiate Guidelines Network selection of a correlation value, sufficient SIGN 5047 quality assessment tool for RCTs was baseline and follow-up data for the studies were used to critically appraise the included trials. required and, at a minimum, there needed to be a The internal trial validity was assessed based on small number of other trials that had complete the adequacy of randomization, allocation information on means and standard deviations at concealment, degree of blinding, and use of an baseline, follow-up, and for the difference intention-to-treat approach to analysis. Any between baseline and follow-up. In cases where disagreements in the assessment of these data there was a lack of trials from which the were resolved through discussion until correlations of baseline with final values can be consensus was reached. estimated, we assumed a moderate correlation of 0.25. 4.5 Data analysis methods A formal meta-analysis was conducted for It was expected that there would be various outcomes that were evaluated using the same outcome measures used in ADHD trials. The measure in two or more studies. Statistical 2 measures were categorized in this review under heterogeneity was assessed by means of the I five types of outcomes: change in the severity of test, which determines the proportion of 50 ADHD symptoms, improvement in cognitive variability due to heterogeneity. The chi- skills and function, improvement in quality of squared test was used to confirm the results of life, improvement in ADHD-associated the analysis of statistical heterogeneity. A P- morbidities, and adverse events. For the change value of < 0.1 for the chi-square test was in severity of ADHD symptoms outcomes, only indicative of important statistical heterogeneity. measures that were rated by the trial investigator In cases where this was observed, possible or an independent observer (no patient-reported explanations have been suggested based on outcomes) were included in this review to avoid characteristics of the patients, interventions, or studies with an internal validity that could be other relevant study traits. If one trial was found threatened by evaluation bias. For the other to report a certain outcome, results were then outcome types, self-reported measures were described using a narrative approach. included.

Pharmacological and Non-pharmacological Therapies for Adults with 7 Attention-Deficit/Hyperactivity Disorder

5 RESULTS conclusions of these reports will be compared with those found in this review and presented in the discussion section. 5.1 Quantity of research available 5.2 Outcome measures used The electronic literature search and updates in included trials yielded 1,957 citations. Upon screening the titles Various measures were used in the included and abstracts, 1,804 citations were excluded, and trials to assess each of the five outcome types in 153 potentially relevant articles were retrieved this review. Different trials used different for full-text review. An additional three measures for the same outcome. Six measures potentially relevant reports were identified were used to evaluate the change in ADHD through grey literature and hand-searching. Of symptoms, including the ADHD Rating Scale: the 156 potentially relevant reports, 110 reports Interviewer or Observer, Version IV (ADHD- did not meet the inclusion criteria. Thus, 46 RS-IV), Adult ADHD Investigator Symptom articles presenting data from 33 clinical trials Rating Scale (AISRS), Conners Adult ADHD were included in this review. The trial selection Rating Scale - Observer version and Investigator process appears in a PRISMA flowchart survey version (CAARS:O/Inv:SV), Clinical (Appendix 2). Included and excluded trials are Global Impression-Improvement Scale (CGI-I), listed in Appendices 3 and 4, respectively. Clinical Global Impression-Severity (CGI-S) scale, and Wender-Reimherr Adult Attention

Of the 46 publications that are included in this Deficit Disorder Scale (WRAADDS). Quality of review, 10 articles reported the results of six life was evaluated using the ADHD impact trials evaluating the efficacy of amphetamine- based medications,4-8,36,51-54 22 articles reported module for adults (AIM-A), the Adult ADHD the results from 15 trials evaluating the efficacy Quality of Life Measure (AAQoL) and Quality of methylphenidate (MPH)-based drugs,9-23,37,55- of Life Enjoyment and Satisfaction 60 10 articles reported the results from nine trials Questionnaire (Q-LES-Q). ADHD-associated evaluating the efficacy of ATX-based morbidities were evaluated using the Beck medications,24-31,36,38 and five articles reported Anxiety Inventory (BAI), Beck Depression the results from four trials evaluating the Inventory (BDI-II), Emotional Liability Scale efficacy of psychotherapy.32-35,39 One trial (ELS), Hamilton Anxiety Rating Scale (Ham- evaluated the efficacy of both amphetamine and A), Hamilton Depression Rating Scale (Ham-D), ATX medication in two separate cohorts.36 The Liebowitz Social Anxiety Scale (LSAS), trial characteristics, critical appraisal, and data Pittsburgh Sleep Quality Index (PSQI) and analysis and synthesis of the selected trials are Rosenberg Self Esteem Inventory (RSEI). presented by research question. This Twelve measures were used to evaluate the presentation was chosen to give a change in function and cognitive skills, comprehensive analysis of each therapy and including the Driving Safety Score (DSS), facilitate the comparison between therapies. delayed word recall (DWR), Endicott Work Productivity Scale (EWPS), Global Assessment No RCTs on ADHD therapy efficacy specific to of Functioning scale (GAF), immediate word the adult prison population were identified recall (IWR), Permanent Product Measure of during the literature search. In addition, the Performance-Attempted questions (PERMP-A), results from RCTs on the efficacy of combined Permanent Product Measure of Performance- psychological and pharmacological therapies Correctly Answered (PERMP-C), Permanent were not identified. One health technology Product Measure of Performance-Attempted + assessment (HTA) and five systematic reviews Correctly Answered Questions (PERMP-total), on pharmacological and non-pharmacological rapid visual information processing (RVIP), treatments in adults with ADHD were identified Sheehan Disability Scale (SDS), spatial working in the literature search. The results and memory, and stop-signal reaction time (SSRT).

8 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

A description of each measure appears in and the remaining trials included a majority of Appendix 5. patients with combined subtype, and few or no patients with hyperactive subtype.4,6-8,53,54 The Adverse events were evaluated by examining the employment status was not reported in any trial. number of serious adverse events, total number The use of a previous ADHD medication was of adverse events, and number of patients with at reported in two trials,6,7,53,54 ranging from least one adverse event. The treatment-emergent 13.3%7 to 26.6%6,53,54 of the trial population. adverse events that were most frequently Patients‘ comorbidities at baseline were not reported in the trials (and which are presented in reported in any of the included trials. The patient this review) include nausea, dry mouth, characteristics appear in Appendix 7 Table A5. decreased appetite, headache, and fatigue. Interventions and comparators

Wigal et al.4 enrolled patients during an open- 5.3 Clinical efficacy of label dose optimization period (four weeks) with stimulant and non- 30 mg/day LDX to 70 mg/day LDX, before entering a two-week randomized, double blind, stimulant therapies for 36 adults with ADHD placebo-controlled crossover phase. Kay et al. conducted a crossover RCT that compared the Two stimulant drugs (amphetamine and MPH) effect of 50 mg/day MAS-XR with that of placebo on simulated driving performance in and one non-stimulant drug (ATX) were 5,51,52 included in this review. young adults. Adler et al. conducted a parallel groups RCT where patients were a) Amphetamine enrolled for up to four weeks in a washout Ten articles reported the results from six RCTs period before being randomized into one of the on the clinical efficacy of amphetamine for the four trial arms: 30 mg/day LDX, 50 mg/day treatment of ADHD in adults.4-8,36,51-54 LDX, 70 mg/day LDX, or placebo. The outcomes were assessed after four weeks of Trial characteristics treatment. Spencer et al.6,53,54 conducted a seven- Five RCTs, which were conducted in the United week dose-optimization, parallel-group RCT States, evaluated the efficacy of mixed comparing the efficacy of six optimized doses of amphetamine salts – extended release (MAS- MAS-XR (12.5 mg/day to 75 mg/day) with that XR),6,7,36,53,54 triple-beads extended release (TB of placebo. Weisler et al.7 compared dose- MAS-ER),6,7,36,53,54 and lisdexamfetamine escalation MAS-XR (20 mg/day, 40 mg/day, dimesylate (LDX).4,5,51,52 One RCT, conducted and 60 mg/day) with placebo in a four-week, in Canada and the United States, evaluated the parallel-group RCT. In a 20-week, parallel- efficacy of dextroamphetamine (DEX).8 All group RCT, Weiss and Hechtman8 compared the trials were funded by industry.4-8,24,36,51-54 Two efficacy of optimized dextroamphetamine trials used a crossover design,4,36 and the (DEX) up to 20 mg twice a day with that of remainder were parallel-group RCTs.5-8,24,51-54 placebo. All treatments, except DEX, were Two trials evaluated the efficacy of three fixed administered once daily. doses of LDX5,51,52 and MAS-XR;7 all other 4,6,8,36,53,54 Outcomes trials used a titrated dose. Patients with substance abuse disorders were excluded in all All trials evaluated change in ADHD symptoms 4-8,24,36,51-54 based on ADHD-RS-IV, and the change in trials. The treatment duration varied 4- 4 8 general level of impairment based on CGI-I. from two weeks to 20 weeks. The trial 8,36,51-54 characteristics appear in Appendix 6 Table A1. Function and cognitive outcomes were measured using DSS,36 PERMP,4 and GAF.8 Patient characteristics ADHD-associated morbidity was measured The mean ages of the included populations using the Hamilton Depression (HAM-D) and ranged from 22.3 years36 to 39.9 years.7 Two Hamilton Anxiety (HAM-A) rating scales,8 and trials did not report the ADHD subtype,5,36,51,52

Pharmacological and Non-pharmacological Therapies for Adults with 9 Attention-Deficit/Hyperactivity Disorder

PSQI.51 Quality of life was measured using the AIMA in one trial.6,53,54 Critical appraisal of individual trials

The critical appraisal of trials evaluating amphetamine-based medications in the treatment of ADHD in adults appears in Table 2.

Table 2: Critical Appraisal of Trials Evaluating Amphetamine-Based Medications in the Treatment of ADHD in Adults Key Areas of Concern Trial Description Regarding Risk of Bias • Allocation concealment • Concealment method not reported in trial article Wigal et al. 20104 • Adequate blinding • Not reported if patients and investigators were kept blinded about treatment allocation • Allocation concealment • Concealment method not reported in trial article Kay et al. 200936 • Adequate blinding • Not reported how patients and investigators were kept blinded from treatment allocation Adler et al. • Randomized assignment • Sequence generation method not reported in trial articles, and could 2008, 2009, not be assessed for adequacy 20095,51,52 Spencer et al. • Allocation concealment • Allocation concealment method not reported in trial articles 2008,6,53 Brown and • Unequal patient • Patients who had been titrated to a dose of 62.5 mg or 75 mg had a 54 Landgraf 2010 treatment midweek visit to clinic to assess vital signs; other patients did not • Allocation concealment • Allocation concealment method not reported in trial article

• Adequate blinding • Not reported if patients and investigators were kept blinded from Weisler et al. treatment allocation 20067

• Trial site effect • Results from different sites where trial was conducted were not compared in trial article • Allocation concealment • Allocation concealment method not reported in trial article

Weiss and • Adequate blinding • Not reported if patients and investigators were kept blinded from Hechtman treatment allocation 8 2006 • Trial site effect • Results from different sites where trial was conducted not compared in trial article

Attention-deficit/hyperactivity disorder Data analyses and synthesis symptoms This section summarizes the effects of Symptom reduction, as measured using ADHD- amphetamine-based medications on ADHD RS-IV, was superior in the amphetamine group. symptoms, quality of life, ADHD-associated The mean difference varied from −10.4 (95% CI morbidities, and function and cognitive skills. 5 8 −14.5 to −6.3) to −2.7 (95% CI −9.2 to 3.8) ; The adverse events associated with lower mean difference values indicate greater amphetamine-based medications are also improvement in the treatment group compared summarized. The results are summarized in with placebo. These differences did not reach Appendix 8 Table A9.

10 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

statistical significance in two trials.6,8 One trial A meta-analysis of ADHD-RS-IV scores reported results by comparing the response rates obtained from the included trials (Figure 1) between groups, finding that the MAS-XR group showed that the use of amphetamines was had 13.3% (P = 0.0004) more patients with a associated with greater symptom reduction; the score reduction of 30 points or more from pooled mean score reduction was −9.06 (95% CI baseline compared with the placebo group.36 A −10.37 to −7.76). Statistically significant dose response effect was seen in two trials heterogeneity was found between trials. Possible evaluating three doses of LDX in one trial,5,51,52 explanations of this heterogeneity could include and MAS-XR in the other.7 The associated mean the fact that four different amphetamine differences between 30 mg/day LDX, 50 mg/day formulations were evaluated; LDX formulation LDX, 70 mg/day LDX, and placebo were −8.0 was associated with the highest effect size (95% CI −12.1 to −3.9), −9.2 (95% CI −13.2 to followed by treble-bead mixed amphetamine −5.1), and −10.4 (95% CI −14.5 to −6.3), salts-extended release (TB MAS-ER), MAS, and respectively. A similar dose response effect was finally DEX. Another explanation could be the associated with MAS-XR; the mean differences differences in medication daily doses. LDX in ADHD-RS-IV score of 20 mg/day MAS-XR, optimal dose titration, which was used by Wigal 40 mg/day MAS-XR, and 60 mg/day MAS-XR et al.,4 was associated with the highest mean compared with placebo were −6.6 (95% CI difference, thus greatest symptom reduction, −11.0 to −2.3), −7.2 (95% CI −11.5 to −2.8), followed by the LDX daily fixed dose of 70 mg, and −7.8 (95% CI −12.2 to −3.4), respectively. 50 mg and 30 mg. Despite the presence of These results show that greater ADHD symptom statistical heterogeneity, the direction of effect reduction was associated with higher doses of was consistent across trials, and only the LDX and higher doses of MAS-XR. magnitude of change on the ADHD-RS-IV scale would be affected by excluding the extreme results.

Figure 1: Efficacy of Amphetamine Compared with Efficacy of Placebo in Reducing ADHD-RS-IV Scores*

ADHD-RS-IV = Attention-Deficit/Hyperactivity Disorder Rating Scale, Version IV; CI = confidence interval; SE = standard error. * Kay et al.36 did not report data suitable for pooling, and results were not included in the forest plot

Pharmacological and Non-pharmacological Therapies for Adults with 11 Attention-Deficit/Hyperactivity Disorder

The number of clinical responders, defined on escalating LDX dose. One trial5,51,52 evaluated the CGI-I scale as having ―very much improved‖ the responder rate associated with 30 mg/day or ―much improved‖ (achievement of CGI-I LDX, 50 mg/day LDX, and 70 mg/day LDX scores of 1 or 2 points, respectively), were found compared with placebo; the associated ORs to be statistically significantly greater in the were 3.3 (95% CI 1.7 to 6.4), 4.1 (95% CI 2.1 to amphetamine group relative to placebo, with 7.9), and 3.8 (95% CI 1.9 to 7.3), respectively. ORs ranging from 2.8 (95% CI 1.3 to 5.8)7 to 10.9 (95% CI 5.9 to 20.0);4 here a higher OR A meta-analysis that compared the CGI-I means more responders in the treatment group. response status of amphetamine with that of Dose effect was shown with MAS-XR in one placebo (Figure 2) found that amphetamines trial;7,8 the associated ORs assessing the relative were associated with a greater number of ADHD frequency of clinical response of 20 mg/day patients achieving a CGI-I score of 2 or less; the MAS-XR, 40 mg/day MAS-XR, and 60 mg/day pooled estimate was OR 4.24 (95% CI 3.20 to MAS-XR compared with placebo were 2.8 (95% 5.62). Statistical heterogeneity was not identified CI 1.3 to 5.8), 3.5 (95% CI 1.7 to 7.5), and 3.9 as a problem in this analysis. (95% CI 1.8 to 8.3), respectively. The frequency of clinical response was associated with

Figure 2: Odd Ratios Comparing Efficacy of Amphetamine with Efficacy of Placebo in Reducing ADHD Symptoms as Measured by Number of Responders on CGI-I Scale*

CGI-I = Clinical Global Impression Improvement scale; CI = confidence interval; ER = extended release; LDX = lisdexamfetamine dimesylate; MAS = mixed amphetamine salts; TB MAS ER= treble bead mixed amphetamine salts- extended release. * Kay et al.36 did not report data suitable for pooling, and results were not included in this forest plot.

12 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Quality of Life with placebo, with a mean difference between groups in a PERMP total score of 23.4 (95% CI One trial6,53,54 evaluated the impact of using TB 15.6 to 31.2); here, a higher mean difference MAS-ER on the quality of life of patients with indicates that patients on LDX had more ADHD, using the AIM-A scale, and reported questions attempted and correctly answered. that patients in the amphetamine group had a statistically significantly larger score change One trial, which consisted of two cohorts, compared with the placebo group to address the evaluated the effect on the cognitive skills of question ―How would you rate the overall patients with ADHD of using MAS-XR as quality of your life right now?‖ The mean assessed based on the DSS scale.36 The results difference was 0.6 (95% CI 0.01 to 1.2), from both cohorts showed reductions on the indicating that the treatment was associated with DSS scale, but one cohort was associated with a higher scoring in response to the question than statistically significant difference compared with placebo. However, patients in both groups had placebo. The mean difference of change between lower scores after treatment with the question groups in cohort I was −0.59 (P = 0.014), and ―How much do you agree with this statement: the mean difference in cohort II was −0.0395 (P ‗Over the past few weeks, I‘ve had more good = 0.293); lower DSS scores indicate better days than bad days‘?‖ The mean difference was driving performance.36 −0.4 (95% CI −0.8 to −0.01). This result indicates that patients in the placebo group gave Weiss and Hechtman8 reported the effect of higher mean scores in response to the question DEX on function, as measured based on the than the treatment group. GAF score. The results showed that patients Attention-deficit/hyperactivity disorder- who used DEX had a higher GAF score (better associated morbidities performance) than those in the placebo group. One trial evaluated the efficacy of using DEX on Although the use of DEX was associated with a psychiatric morbidity based on the HAM-A and statistically significantly higher GAF score HAM-D scales.8 Patients in the amphetamine (Fisher test P value of 0.037), the difference in group showed a lower reduction of anxiety and mean change between groups was not depression scores than patients in the placebo statistically significant on the intention to treat analysis. The mean difference was 1.1 (95% CI group, but the difference between groups was 8 not statistically significant. The mean difference −6.7 to 8.9). between treatment and placebo was 1.5 (95% Adverse events CI −3.0 to 6.0) on the HAM-A scale, and 1.6 Spencer et al.6 reported one serious adverse (95% CI −2.3 to 5.5) on the HAM-D scale (the event (possible transient ischemic attack) that positive mean difference indicates that the was related to the trial treatment. After placebo group had better results for anxiety and 8 hospitalization, the patient was diagnosed with depression control). Tourette‘s syndrome with vocal tic.

5,14,51 Adler et al. evaluated the effect on sleep of Five trials4-7,36 reported total treatment-emergent using LDX based on the PSQI scale. The mean adverse events (TEAEs). In four trials, the change showed some evidence of greater amphetamine-based treatment was associated improvement of sleep among patients using with statistically significantly higher rates of LDX; however, the difference did not achieve events; ORs ranged from 2.2 (95% CI 1.2 to statistical significance (−0.3 [95% CI −0.9 to 4.3)5 to 5.6 (95% CI 1.4 to 22.0).36 Wigal et al.4 0.3]). reported a numerically higher rate of TEAEs in Function and cognitive skills the placebo group compared with the LDX Wigal et al.4 evaluated the effect on performance group. The associated OR was 0.7 (95% CI 0.4 5 of using LDX based on the PERMP scale. They to 1.2). Adler et al. reported 22 severe TEAEs showed that using LDX was associated with in the LDX group compared with three severe higher improvement in performance compared adverse events in the placebo group. The report

Pharmacological and Non-pharmacological Therapies for Adults with 13 Attention-Deficit/Hyperactivity Disorder

did not provide details on these cases. The patients.23 The trial characteristics appear in TEAE rate was associated with amphetamine Appendix 6 Table A2. dose. Adler et al.5 reported TEAEs after the use Patient characteristics of 30 mg/day LDX, 50 mg/day LDX, and 70 mg/day LDX, and the associated ORs compared The mean ages of the included population with placebo were 2.2 (95% CI 1.2 to 4.3), 2.4 groups ranged from 30.6 years20,59 to 40.0 (95% CI 1.2 to 4.7), and 3.7 (95% CI 1.8 to 7.4), years.23 ADHD subtype was reported in five respectively. trials,12,15-17,19,55,57,58 indicating that most patients were combined subtype, and few or no patients The most frequently reported adverse events were hyperactive subtype. Employment status included anxiety (associated ORs ranged from was reported in three trials,11,18,23 and ranged 2.0 [95% CI 0.4 to 11.3]7 to 10.5 [95% CI 0.6 to from 16.7% employment11 to 89% 182.8]5); decreased appetite (ORs ranged from employment.23 Previous ADHD medication was 2.1 [95% CI 0.4 to 11.5]4 to 24.4 [95% CI 3.3 to reported in four trials described in a total of six 183.1]5); dry mouth (ORs ranged from 0.4 [95% articles,12,14,15,19,37,55 and ranged from 21.8%19 to CI 0.0 to 3.5]4 to 24.1 [95% CI 5.4 to 107.2]7); 100%12,55 of the trial population. Patients‘ fatigue (ORs ranged from 0.1 [95% CI 0.0 to comorbidities at baseline were reported in two 0.5]4 to 0.9 [95% CI 0.2 to 3.8]5); and headache trials. The numbers of patients with anxiety (ORs ranged from 0.7 [95% CI 0.1 to 4.1]4 to disorder ranged from 10 (9.9%)17 to 26 (49%).18 2.9 [95% CI 1.2 to 7.4]7). The patient characteristics appear in Appendix 7 Table A6. b) Methylphenidate Interventions and comparators Twenty-two articles reported results from 15 RCTs on the clinical efficacy of using MPH for All trials except one12,55 used a titrated dose of the treatment of ADHD in adults.9-23,37,55-60 MPH with varying maximum doses of 40 mg/day to 120 mg/day. Verster et al.12,55 used Trial characteristics one fixed dose of 10 mg to 30 mg. All trials The efficacy of MPH was evaluated in nine compared MPH with placebo. trials from the US,9,13,15,16,18-20,22,23,56,59,60 two trials from Germany,10,14,37 one trial from Outcomes 11 12,55 Sweden, one trial from the Netherlands, The efficacy measures of change in ADHD 17,58 one trial from Europe, and one trial from symptoms were most commonly evaluated using 21 Canada. Eleven trials received industry AISRS,13,15,22,56,60 ADHD-RS-IV,19,20,59 10,11,13-17,19-22,37,56-60 funding. Four trials were CAARS,11,17,21,57,58 CGI-I,9,13-15,18-23,37,56,60 CGI- 12,20,21,55,59 crossover RCTs, and the remainder S,16,17,19 and WRAADDS.9,10,14,20,37,59 ADHD- were parallel-group RCTs. Substance or alcohol associated morbidities were measured using dependence was an exclusion criterion if BDI-II and BAI,11 ELS scale,37 HAM-A and 12,21,55 patients had a history of dependence or HAM-D scales.22 Function and cognitive skills dependence within the preceding six were evaluated using IWR and DWR,12 GAF,19 10,13-15,17,19,22,37,56-58,60 months. In three trials, the and SDS.10 The quality of life was not evaluated exclusion criteria did not specify substance or in the included studies. alcohol dependence.9,16,20,59 Three trials included only patients who had substance use disorder: Critical appraisal of individual trials amphetamine dependence,11 cocaine The critical appraisal of trials evaluating MPH- dependence,18 and methadone-maintained based medications in the treatment of ADHD in adults appears in Table 3.

14 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table 3: Critical Appraisal of Trials Evaluating MPH-based Medications in the Treatment of ADHD in Adults First Author Publication Risk of Bias Description Year • Allocation concealment • Concealment method not reported in trial article Wender et al. 20119 • Adequate blinding • Not reported if patients and investigators were kept blinded to treatment allocation Retz et al. • Adequate blinding • Not reported if patients and investigators were kept blinded to 201010 treatment allocation • Randomized assignment • Sequence generation method not reported in trial article and could not be assessed for adequacy

Konstenius et 11 • Allocation concealment • Concealment method not reported in trial article al. 2010

• Adequate blinding • Not reported if patients and investigators were kept blinded to treatment allocation • Randomized assignment • Sequence generation method not reported in trial articles, and could not be assessed for adequacy Verster et al. 2008 and • Allocation concealment • Concealment method not reported in trial articles 201012,55 • Adequate blinding • Reported in trial that blinding had been breached by patients experienced with treatment • Randomized assignment • Sequence generation method not reported in trial articles, and could not be assessed for adequacy

Biederman et • Allocation concealment • Concealment method not reported in trial articles al. 2010 and 201113,56 • Adequate blinding • Reported in trial that blinding had been breached by patients experienced with treatment

• Outcome measurements • Assessment of ADHD symptoms relied on self-report • Randomized assignment • Sequence generation method not reported in trial articles, and could not be assessed for adequacy

• Allocation concealment • Concealment method not reported in trial articles

Rosler et al. • Adequate blinding • Not reported how patients and investigators were kept blinded to 2009 and 14,37 treatment allocation 2010

• Trial site effect • Results from different sites where trial was conducted were not compared in trial articles

• Outcome measures • ELS used in this trial is a self-reported measure Adler et al. • Sample bias (enrichment • Known non-responders to MPH excluded from trial 200915 design) • Randomized assignment • Sequence generation method not reported in trial article, and could not be assessed for adequacy

Chronis- • Allocation concealment • Concealment method not reported in trial article Tuscano et al. 16 2008 • Adequate blinding • Trial had treatment discontinuation design, which could allow patients experienced to treatment to be aware if they were being actively medicated or not Medori et al. • Randomized assignment • Sequence generation method not reported in trial articles, and 2008,17 could not be assessed for adequacy Buitelaar et al. 2011,57 • Allocation concealment • Concealment method not reported in trial articles Rösler et al. • Adequate blinding • Not reported if patients and investigators were kept blinded to

Pharmacological and Non-pharmacological Therapies for Adults with 15 Attention-Deficit/Hyperactivity Disorder

First Author Publication Risk of Bias Description Year 201158 treatment allocation • Randomized assignment • Sequence generation method not reported in trial article, and could not be assessed for adequacy

• Allocation concealment • Concealment method not reported in trial article Levin et al. 18 2007 • Adequate blinding • Not reported if patients and investigators were kept blinded to treatment allocation

• Unequal patient treatment • Patients in placebo arm were given folic acid supplement • Randomized assignment • Sequence generation method not reported in trial article, and could not be assessed for adequacy

Spencer et al. 19 • Allocation concealment • Concealment method not reported in trial article 2007

• Adequate blinding • Not reported if patients and investigators were kept blind to treatment allocation Reimherr et • Allocation concealment • Concealment method not reported in trial articles al. 2007,20 Robison et al. • Adequate blinding • Not reported if patients and investigators were kept blinded to 201059 treatment allocation • Allocation concealment • Concealment method not reported in trial article

Jain et al. • Adequate blinding • Not reported if patients and investigators were kept blinded to 200721 treatment allocation • Appropriateness of statistical analysis • Trial article reported only per protocol analyses • Randomized assignment Sequence generation method not reported in trial articles, and could not be assessed for adequacy

• Allocation concealment • Concealment method not reported in trial articles Biederman et al. 2006 and 22,60 • Adequate blinding • Not reported if patients and investigators were kept blinded to 2007 treatment allocation

• Outcome measures • Diagnosis and assessment of ADHD outcomes were evaluated by means of self-reported measures • Randomized assignment • Sequence generation method not reported in trial article and could not be assessed for adequacy

• Allocation concealment • Concealment method not reported in trial article Levin et al. 200623 • Adequate blinding • Not reported if patients and investigators were kept blinded to treatment allocation

• Unequal patient treatment • Patients in placebo arm were given folic acid supplement; impact on outcomes not evaluated ADHD = attention-deficit/ hyperactivity disorder; ELS = Emotional Liability Scale; MPH = methylphenidate.

16 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Data analyses and synthesis (95% CI −13.6 to 2.0), −5.5 (95% CI −13.3 to 2.3), and −9.0 (95% CI −18.4 to 0.4), This section summarizes the effects of MPH- respectively. Although the results were not based medications on ADHD symptoms, quality statistically significant for the three doses, a of life, psychiatric morbidities, function, and greater average symptom reduction was cognitive skills; and the adverse events that are associated with the highest dose of 40 mg per associated with MPH-based medications. The day. results are summarized in Appendix 8 Table

A10. A meta-analysis of ADHD-RS-IV (Figure 3) Attention-deficit/hyperactivity disorder found that MPH was associated with greater symptoms symptom reduction compared with placebo. The Two trials evaluated the effect of using pooled overall mean score reduction was extended-release MPH on the reduction of estimated to be −7.71 (95% CI −11.55 to −3.87). ADHD symptoms as measured by means of the The measures of heterogeneity did not suggest ADHD-RS-IV.19,20 Inter-group differences in that statistically significant heterogeneity was mean symptom reduction ranged from −5.5 present. Although all results were in the 19 direction that favoured active therapy, only the (95% CI −13.3 to 2.3) to −9.9 (95% CI −16.4 20 to −3.4)20 across studies; here, a lower mean results from Reimherr et al.‘s trial were difference indicates higher improvement in the statistically significant. The results from this treatment group compared with placebo. The trial accounted for 35% of the overall effect, dose-effect relationship was evaluated in one showing that the optimal daily dose of osmotic trial19 comparing extended-release MPH daily release oral system-methylphenidate (OROS- doses of 20 mg, 30 mg, and 40 mg with placebo. MPH) was associated with the greatest ADHD- The inter-group differences in mean symptom RS-IV score reduction compared with MPH reduction compared with placebo were −5.8 fixed doses.

Figure 3: Comparing Efficacy of MPH with Efficacy of Placebo in Reduction of ADHD-RS-IV Scores

ADHD = attention-deficit/hyperactivity disorder; ADHD-RS-IV = ADHD Rating Scale, Version IV; MPH = methylphenidate; OROS-MPH = osmotic release oral system-methylphenidate; SE = standard error.

The reduction in the score on the AISRS scale (95% CI −6.7 to −0.9); here, negative results was used to evaluate improvement of ADHD indicate greater improvement in the treatment symptoms in three trials.13,15,22 The results were group compared with placebo. In the third trial,22 reported in terms of the number of responders results were reported only in the statistical who had more than 30% score reduction in one significance of the responder rate, indicating that trial.13 The associated OR was 2.8 (95% CI 1.7 a greater proportion of MPH patients had 30% to 4.9) in favour of the active therapy. One trial15 and 50% reduction in AISRS scores; the reported results in mean score reduction. The associated P value was less than 0.001 for both associated inter-group mean difference was −3.8 levels of response.

Pharmacological and Non-pharmacological Therapies for Adults with 17 Attention-Deficit/Hyperactivity Disorder

Clinical responders to treatment, as measured A meta-analysis that compared the CGI-I results using the CGI-I scale, were defined as patients of using MPH with placebo (Figure 4) found who had a score of less than 3: ―very much that MPH was associated with a greater number improved‖ or ―much improved.‖ The frequency of patients with ADHD achieving a CGI-I score of responders in MPH groups compared with the of 2 or less. The observed pooled estimate was placebo group as measured using ORs varied OR 2.38 (95% CI 1.39 to 4.08). Statistically from OR 0.36 (95% CI 0.1 to 1.1)23 to 10.3 significant heterogeneity was found across trials (95% CI 5.5 to 19.5);9 here, an OR of more than based on the observed values of I2 and the 1 means a higher rate of responders in the associated chi-squared test, which could be treatment group. One trial19 evaluated the dose- explained by the different formulation of MPHs effect relation that compared extended-release and by different dosing regimen. Levin et al.23 MPH daily doses of 20 mg, 30 mg, and 40 mg provided an extreme result favouring placebo with placebo; the associated ORs of response over the optimal dose of sustained release MPH. were 2.5 (95% CI 1.1 to 5.6), 1.6 (95% CI 0.7 to This could be explained by the fact that this 3.7), and 3.9 (95% CI 1.5 to 7.9), respectively. study included opiate- dependent patients who One trial37 reported the effect of intermediate were treated actively with methadone. However, release MPH in mean score change, as measured the exclusion of Levin et al.‘s trial from the using CGI-I. The associated inter-group mean meta-analysis did not reduce the P value of the difference was 0.40 (95% CI −2.0 to 2.8), chi-square test for heterogeneity below the meaning that greater improvement was noted in chosen value of 0.1. This only occurred after the placebo group, although this difference was Wender et al.‘s study9 (which showed the largest not statistically significant. OR in favour of MPH) was also excluded. Removing either trial separately or both of them simultaneously did not affect the statistical significance of the pooled effect size.

Figure 4: ORs Comparing Efficacy of MPH with Efficacy of Placebo in Reducing ADHD Symptoms as Measured by the Number of Responders on the CGI-I Scale*

ADHD = attention-deficit/hyperactivity disorder; CGI-I = Clinical Global Impression-Improvement scale; CI = confidence interval; M- H: Mantel-Haenszel; MPH = methylphenidate; OR = odds ratio; OROS-MPH = osmotic release oral system-methylphenidate; SR- MPH = sustained release MPH. * Adler et al,15 Jain et al,21 and Biederman et al22,60 did not report data suitable for pooling and the results were not included in the forest plot

18 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Three trials evaluated the improvement in (95% CI 1.4 to 6.7), 2.2 (95% CI 1.0 to 4.8), and ADHD symptoms using the CGI-S scale.16,17,19 2.6 (95% CI 1.2 to 5.7), respectively. Two trials reported an improvement in mean A meta-analysis of CGI-S mean difference score difference.16,17 The associated inter-group scores from two trials16,17 (Figure 5) showed that mean difference ranged from −0.4 (95% CI −0.8 the use of OROS-MPH was associated with to −0.0)17 for the extended-release MPH daily greater ADHD symptom control. The pooled doses of 18 mg and 36 mg to −0.9 (95% CI mean difference was −0.51 (95% CI −0.71 to −16.4 to −3.4)16 for the maximal effective −0.31). The optimal dose regimen was extended-release dose of MPH. Clinical associated with the greatest effect size, followed responders were defined in one trial19 as patients by the daily doses of 72 mg, 36 mg, and 18 mg. who had a decline in CGI-S score at the final The I2 and chi-square quantities did not suggest visit (the amount of decrease was unspecified). the presence of important statistical The associated ORs of responders for the three heterogeneity. extended-release MPH doses of 20 mg, 30 mg, and 40 mg compared with placebo were 3.1

Figure 5: Efficacy of MPH Compared with Placebo in Reducing CGI-S Scores*

CI = confidence interval; CGI-S = Clinical Global Impression-Severity scale; MPH = methylphenidate; OROS-MPH = osmotic release oral system-methylphenidate; SE = standard error. * Spencer et al19 did not report data suitable for pooling and the results were not included in the forest plot.

The Connors Adult ADHD Rating Scale- −0.1), −3.9 (95% CI −6.6 to −1.2), and −6.1 Observer (CAARS-O) was used in three trials to (95% CI −9.0 to −3.2), respectively; here, a evaluate ADHD symptom reduction in mean lower mean difference indicates that the use of score difference.11,17,21 The associated inter- MPH was associated with a greater reduction in group difference ranged across studies from symptoms. −4.3 (95% CI −10.4 to 1.8)21 with extended- release MPH, to 0.1 (95% CI −10.3 to 10.5)11 A meta-analysis of CAARS-O mean difference with intermediate- release MPH dose; here, scores (Figure 6) showed that the use of MPH positive results mean that greater improvement was associated with greater ADHD symptom was found in the placebo group. The dose effect control compared with placebo. The pooled was evaluated in one trial that compared the mean difference was −4.21 (95% CI −5.79 to mean differences associated with extended- −2.63). The I2 and chi-squared quantities did not release MPH daily doses of 18 mg, 36 mg, and suggest the presence of important statistical 72 mg with placebo. The associated inter-group heterogeneity. mean differences were −3.0 (95% CI −5.9 to

Pharmacological and Non-pharmacological Therapies for Adults with 19 Attention-Deficit/Hyperactivity Disorder

Figure 6: Efficacy of MPH Compared with Efficacy of Placebo in Reducing CAARS-O Scores

CAARS-O = Connors Adult ADHD Rating Scale-Observer; CI = confidence interval; MLR = multilayer release; MPH = methylphenidate; OROS = osmotic release oral system ; SE = standard error.

Symptom reduction was evaluated using the differences (Figure 7) showed that MPH was WRAADDS scale in four trials.9,10,20,37 associated with greater symptom reduction Statistically significantly higher mean reductions compared with placebo. The pooled mean were reported in the MPH group in all four difference was −7.40 (95% CI −9.01 to −5.79). trials. The associated inter-group differences The I2 and chi-square quantities did not suggest varied across studies from −8.0 (95% CI −10.2 the presence of important statistical to −5.8)9 to −6.5 (95% CI −9.8 to −3.2).20 A heterogeneity. meta-analysis of WRAADDS mean score

Figure 7: Efficacy of MPH Compared with Efficacy of Placebo in Reducing WRAADDS Scores*

CI = confidence interval; ER = extended release; MPH = methylphenidate; OROS = osmotic release oral system ; SE = standard error; WRAADDS = Wender-Reimherr Adult Attention Deficit Disorder Scale. * Rosler et al. 200914,37 reported results in effect size and P value; for this reason, their study was not included in the forest plot.

19 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Quality of life mg) compared with placebo. The associated inter-group mean differences were not reported. Quality of life was not assessed in the included trials evaluating MPH-based drugs. Adverse events Attention-deficit/hyperactivity disorder- One cerebrovascular accident was reported as a associated morbidities serious adverse event associated with the use of extended-release MPH.17 Two trials reported the The efficacy of using MPH in reducing anxiety number of patients with at least one adverse was evaluated in two trials, using the BAI 11 22 event and showed that the use of MPH was scale and the HAM-A scale. Both scales associated with a higher rate of adverse showed higher score reduction among patients in events.15,17 Higher adverse event rates were the placebo groups based on reported point associated with higher MPH doses. The group estimates, although inter-group differences were titrated up to 108 mg/day MPH was associated not statistically significant. The estimates were 15 11 with an OR of 3.1 (95% CI 1.6 to 5.9), and the 2.9 (95% CI −1.4 to 7.2) and 0.3 (95% CI −1.1 22 group titrated up to 72 mg/day was associated to 1.7), respectively. with an OR of 1.8 (95% CI 1.1 to 3.0).17 The

most frequently reported adverse events The reduction of depression was evaluated in 11 included nausea, (associated ORs ranged from two trials, using the BDI-II scale and the 20 22 2.2 [95% CI 0.4 to 12.1] to 9.4 [95% CI 0.5 to HAM-D scale. One trial reported statistically 176.0]9); dry mouth (ORs ranged from 2.2 [95% significantly greater reductions in depression CI 1.3 to 3.9]37 to 7.2 [95% CI 2.6 to among patients using MPH compared with 22,60 11 20.4] );decreased appetite (ORs ranged from placebo (inter-group mean difference −6.5 1.7 [95% CI 0.7 to 4.4]19 to 63.8 [95% CI 3.1 to [95% CI −13.0 to −0.03]). The other trial 20,59 22 1277.6] ); and headache (ORs ranged from showed similar reductions for both trial arms 0.6 [95% CI 0.2 to 2.4]20,59 to 4.2 [95% CI 0.5 (inter-group mean difference 0.0 [95% CI −1.6 to 39.3]).18 to 1.6]).

c) Atomoxetine One trial evaluated the effect of using intermediate MPH on emotional liability by Ten articles reported results from nine RCTs on means of a reduction in ELS score. The inter- the clinical efficacy of using ATX for the group mean difference was −1.1 (95% CI −2.3 treatment of ADHD in adults.24-31,36,38 to 0.1);37 here, a negative score indicates that a Trial characteristics greater improvement was associated with the treatment group. The efficacy of using ATX was evaluated in seven US trials,24-28,30,36,38 one trial conducted in Function and cognitive skills Canada and in the United States,29 and one Retz et al.10 evaluated functional disability using United Kingdom trial.31 All but one31 trial were the SDS and reported a statistically significantly funded by industry. Three trials were crossover greater reduction in disability associated with RCTs30,31,36 and six were parallel-group RCTs.24- using intermediate-release MPH compared with 29,38 Substance or alcohol dependence was an placebo. The trial reported a moderate effect size exclusion criterion if the patients had a history of 0.4 (P = 0.017). Verster et al.12 evaluated of dependence,27,28 current substance changes in cognitive skills by means of a word dependence,30 or dependence within the recall test and found no differences for preceding six months.36 In one trial, the immediate word recall and for delayed word exclusion criteria did not specify substance or recall. The corresponding inter-group mean alcohol dependence.31 The study population in differences were not reported. Spencer et al.19 one trial was restricted to patients with an reported statistically significant improvement of alcohol use disorder.11 The trial characteristics function based on GAF scores for each of three appear in Appendix 6 Table A3. daily fixed doses of MPH (20 mg, 30 mg, and 40

Pharmacological and Non-pharmacological Therapies for Adults with 21 Attention-Deficit/Hyperactivity Disorder

Patient characteristics compared the efficacy of ATX (up to 100 mg/day) with that of placebo. One trial31 The mean ages of the included populations 36 27 compared the efficacy of a single 60 mg dose of ranged from 22.3 years to 38 years. The ATX with placebo. Four trials evaluated a long- ADHD subtype was reported in most 28,29,31,36 24,25,27-29,31,38 acting formulation of ATX, one trial trials. Most patients had a combined evaluated an intermediate- release ATX dose,27 subtype and few or no patients had a hyperactive and one trial did not report the daily schedule of subtype. Employment status was reported by 29 28 ATX treatment. two trials, ranging from 61% to 100% employed subjects. The use of a previous Outcomes ADHD medication was reported in three 25,28,31,38 28 31 Two trials evaluated the change in ADHD trials, ranging from 20.4% to 55% of 30,36 symptoms using ADHD-RS-IV, and four the trial population. Patients‘ comorbidities at trials used the Connors Adult ADHD Rating baseline were reported in two trials.26,27 One 26 Scale-Investigator Rated: Screening Version trial reported the mean score of depression and 24,25,28,38 (CAARS-Inv:SV). One trial measured anxiety as measured using HAM-D and HAM- the change in general level of impairment using A, respectively. The mean HAM-D scores were 36 the CGI-I scale, and six trials measured 5.4 (SD 3.1) for the treatment group and 6.6 (SD 24,26-29,38 symptom severity using the CGI-S scale. 3.7) for the placebo group. The mean HAM-A One trial evaluated a change in ADHD scores for the treatment and placebo groups were 26 symptoms using WRAADDS. Quality of life 7.4 (SD 4.5) and 9.1 (SD 5.9), respectively. One 27,28,38 was measured in three trials using the trial reported the percentage of included patients 27 AAQoL scale. One trial evaluated social with depression and anxiety disorder (23.3% and anxiety using the LSAS. Function and cognitive 86.9%, respectively).18 The patient measures were reported in one trial using characteristics appear in Appendix 7 Table A7. 28 EWPS, and in a second trial using various Interventions and comparators measures.31 Two trials conducted crossover RCTs to Critical appraisal of individual trials evaluate the effects of using ATX 80 mg/day,36 A critical appraisal of trials that evaluated ATX- and ATX 0.6 mg/kg to 1.2 mg/kg30 on driving based medications for the treatment of ADHD in performance, compared with placebo. Six adults appears in Table 4. trials24-29,38 were parallel-group RCTs that

Table 4: Critical Appraisal of Trials Evaluating ATX-based Medications in Treatment of ADHD in Adults First Author, Publication Risk of Bias Description Year • Sample bias • Selection of a more motivated and less impaired patient population Young et al. 24 in order to have family involvement to evaluate secondary family 2011 functioning measures Brown et al. • Outcome measurement • Trial used one self-report scale to assess impairments of executive 2011,38 Adler functions; relation between self-report data and other clinical et al. 200925 measures not evaluated • Randomized assignment • Sequence generation method not reported in trial article and could not be assessed for adequacy

Rae-Clark et 26 • Allocation concealment • Concealment method not reported in trial article al. 2010

• Incomplete outcome data • Trial had poor retention rate and modified ITT definition, including only patients who had at least one post-treatment assessment Kay et al. • Allocation concealment • Concealment method not reported in trial article 200936

22 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

First Author, Publication Risk of Bias Description Year • Adequate blinding • Not reported how patients and investigators were kept blinded to treatment allocation • Sample bias • Trial design included 2-week placebo lead-in phase before Adler et al. randomization to evaluate patient‟s response to placebo; patients who 200927 achieved >25% decrease of social anxiety symptoms were excluded from randomized phase • Allocation concealment • Concealment method not reported in trial article Adler et al. 200828 • Trial had a high attrition rate, which was attributed, by the trial article • Incomplete outcome data author, to relaxed entry criteria • Allocation concealment • Concealment method not reported in trial article Wilens et al. 200829 • Adequate blinding • Not reported how patients and investigators were kept blinded to treatment allocation • Allocation concealment • Concealment method not reported in trial article Barkley et al. 200730 • Outcome measurement • Efficacy was measured using a virtual reality simulator; its sensitivity to medication effects was not assessed • Randomized assignment • Sequence generation method not reported in trial article and could not be assessed for adequacy

Chamberlain et 31 • Allocation concealment • Concealment method not reported in trial article al. 2007

• Adequate blinding • Not reported how patients and investigators were kept blinded to treatment allocation ATX = atomoxetine; ITT = intention to treat.

Data analyses and synthesis for the relative frequency of responders was 1.8 (95% CI 0.2 to 15.4) in cohort II favouring ATX This section summarizes the effects of ATX- over placebo, but the difference did not reach based medications on ADHD symptoms, quality statistical significance.36 of life, psychiatric morbidities, function, and cognitive skills; and the adverse events Three trials reported ADHD symptom reduction associated with ATX-based medications. The in terms of AISRS mean reduction.24,29,38 The results are summarized in Appendix 8 Table associated inter-group mean difference ranged A11. from −3.6 (95% CI −6.0 to −1.3)38 to −5.7 Attention-deficit/hyperactivity disorder (95% CI −7.9 to −3.5)24 across trials; here, a symptoms negative mean difference value indicates that the The ADHD-RS-IV scale was used in two ATX treatment group had a greater ADHD trials.30,36 In one trial,30 it was associated with a symptom reduction than the placebo group. A statistically non-significant inter-group mean meta-analysis of AISRS mean score differences difference30 of −4.7 (95% CI −14.3 to 4.9); here, (Figure 8) showed that ATX was associated with a negative mean difference value indicates that greater symptom reduction; the pooled mean difference score was −4.83 (95% CI −6.29 to the ATX group had a greater reduction in the 2 ADHD-RS-IV score. The responder rate, which −3.37). The I and chi-square quantities did not was reported in the other trial, was defined as suggest the presence of important statistical the rate of patients who had a score reduction of heterogeneity. 30% or more from baseline. The associated OR

Pharmacological and Non-pharmacological Therapies for Adults with 23 Attention-Deficit/Hyperactivity Disorder

Figure 8: Efficacy of ATX Compared with Efficacy of Placebo in Reducing AISRS Scores

ADHD = attention-deficit/hyperactivity disorder; AISRS = Adult ADHD Investigator Symptom Rating Scale; ATX = atomoxetine; CI = confidence interval; SE = standard error.

The improvement of ADHD symptoms was control compared with placebo; the pooled mean evaluated using CAARS-Inv:SV in four difference was −3.71 (95% CI −6.02 to −1.40). trials.24,25,27,28,38 Three trials reported statistically Statistically significant heterogeneity was found significantly greater improvement in the ATX between trials as indicated by the associated I2 group; the inter-group mean difference varied value and chi-square test. A possible explanation from −2.2 (95% CI −3.6 to −0.8)25 to −6 (95% of this heterogeneity could be that Young et al.24 CI −8.0 to −4.0) 24 across trials. One trial used a once daily optimal dosage, and Adler et reported a mean change of −0.1 with no al.25,27 used a twice daily regimen that could confidence interval.28 A meta-analysis of affect patients‘ compliance. However, this CAARS-Inv:SV scores (Figure 9) showed that heterogeneity did not affect the direction of ATX was associated with greater symptom effect.

Figure 9: Efficacy of ATX Compared with Efficacy of Placebo in Reducing CAARS-Inv:SV Scores*

ATX = atomoxetine; CAARS-Inv:SV = Conners Adult ADHD Rating Scale-Investigator Rated: Screening Version; CI = confidence interval; SE = standard error. * Adler et al. 200828 did not report SE nor suitable data to estimate its value.

24 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

One trial reported results of treatment symptom reduction in the ATX group,29 responders as measured using the CGI-I.36 reporting an inter-group mean difference of −0.3 Responders were defined as patients who had a (95% CI −0.7 to 0.1). Two trials reported greater score of ―very much improved‖ or ―much symptoms reduction in the placebo group;26,28 improved‖, and the associated OR of responders the associated inter-group mean differences were was 1.0 (95% CI 0.05 to 19.4) in cohort II.36 0.7 (95% CI 0.1 to 1.3) in one trial26 and 0.1 (P = 0.456, 95% CI not reported) in the other.28 A Improvement measured using the CGI-S scale meta-analysis of CGI-S scores (Figure 10) was reported in six trials.24,25,26,27,29,38,61 Three showed that ATX was superior to placebo in trials reported statistically significantly greater reducing CGI-S score; the pooled mean improvement in the ATX group; the associated difference was −0.33 (95% CI −0.45 to −0.21). inter-group mean difference varied from −0.5 The I2 and chi-square scores did not suggest the (95% CI −0.7 to −0.3)24 to −0.2 (95% CI −0.4 to presence of important statistical heterogeneity. 0.0)27 across trials. One trial did not find greater

Figure 10: Efficacy of ATX Compared with Efficacy of Placebo in Reducing CGI-S Scores*

ATX = atomoxetine; CGI-S = Clinical Global Impression-Severity scale; CI = confidence interval; SE = standard error. * Adler et al. 200828 did not report SE nor suitable data to estimate its value

Rae-Clark et al.26 reported a numerically higher positive mean difference values indicate greater WRAADDS score reduction in the ATX group. improvement associated with the ATX group However, the associated inter-group mean than the placebo group. One trial reported difference did not reach statistical significance: numerically greater improvement in the ATX MD −4.0 (95% CI −10.1 to 2.1). group; however, this difference did not achieve statistical significance.28 Only the associated Quality of life inter-group mean difference of 2.7 was reported, Three trials evaluated the effect of using ATX without the corresponding confidence interval. on quality of life as measured by means of the A meta-analysis of AAQoL scores (Figure 11) 25 27,28,38 AAQoL scale. The use of ATX titrated showed that ATX was associated with greater up to 100 mg/day was associated with enhancement of quality of life compared with statistically significantly greater improvement of placebo; the pooled mean difference was 4.21 25 27,38 the quality of life in two trials. The (95% CI 1.95 to 6.47). associated inter-group mean difference was 4.5 (95% CI 1.6 to 7.4) in one trial25 and 3.8 (95% CI 0.3 to 7.3) in the other trial;27 here greater

Pharmacological and Non-pharmacological Therapies for Adults with 25 Attention-Deficit/Hyperactivity Disorder

Figure 11: Efficacy of ATX Compared with Efficacy of Placebo in Enhancing Quality of Life*

ATX = atomoxetine; CI = confidence interval; SE = standard error. * Adler et al. 200828 did not report SE nor suitable data to estimate its value

−0.3 to 0.1) and −3.8 (95% CI −12.6 to 5.0), Attention-deficit/hyperactivity disorder- respectively. associated morbidities 28 Adverse events Adler et al. evaluated the effect of using ATX on social anxiety measured by means of LSAS, One trial reported one case of atrial fibrillation and reported statistically significant greater as a serious adverse event related to the treatment.24 Two trials reported the number of reduction in anxiety score in the ATX group 26,27 compared with placebo; the associated inter- patients with at least one adverse event. group mean difference was −8.5 (95% CI −13.4 Of the two trials that reported higher rates of to −3.6). adverse events in the ATX group, one trial was associated with a statistically significant Function and cognitive skills difference (OR 1.7 [95% CI 1.0 to 2.8]).27 The Adler et al.28 evaluated the effect of using ATX most frequently reported adverse events were on productivity and impairment as measured by nausea (associated ORs ranged from 2.3 [95% 27 29 means of the EWPS scale. The trial reported a CI 1.2 to 4.7] to 7.3 [95% CI 3.0 to 18.2] ); numerically larger reduction in impairment score dry mouth (ORs ranged from 1.0 [95% CI 0.2 to 26 24 in the ATX group compared with placebo; 4.3] to 7.1 [95% CI 3.7 to 13.8] ); decreased however, this difference did not reach statistical appetite (ORs ranged from 1.9 [95% CI 0.9 to 27 29 significance. The associated inter-group mean 4.0] to 8.0 [95% CI 1.8 to 37.0] ); headache 24 difference was −0.6 (95% CI −4.1 to 2.9). (ORs ranged from 0.8 [95% CI 0.5 to 1.2] to 27 1.5 [95% CI 0.9 to 2.6] ); and fatigue (ORs 27 Chamberlain et al.31 evaluated the effect of using ranged from 1.1 [95% CI 0.5 to 2.4] to 5.9 29 ATX on driving skills as measured by means of [95% CI 1.2 to 27.9] ). a virtual reality simulator. The trial found d) Psychotherapy statistically significant improvement of the results of stop-signal testing in the ATX group Five articles reported the results from four compared with placebo. The associated inter- clinical trials on the comparative clinical group mean difference was −49.3 (95% CI efficacy of five psychotherapy interventions: dialectical behaviour therapy,32 cognitive −90.9 to −7.8). The results of rapid visual 33,34,39 information processing and special working behavioural therapy (CBT), cognitive therapy (CT),33,39 hypnotherapy,33,39 and meta- memory showed that ATX was associated with 35 numerically greater improvements compared cognitive therapy. with placebo; however, these differences did not reach statistical significance. The associated inter-group mean differences were −0.1 (95% CI

26 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Trial characteristics 0%33 to 62%.32 The patient characteristics appear in Appendix 7 Table A8. The clinical efficacy of psychotherapy was evaluated in four RCTs that were published in 2010 and 2011.32-35,39 One trial was conducted in Interventions and comparators 32 Sweden, two trials were conducted in the 32 Hirvikoski et al. compared dialectical United States34,35 and one trial was conducted in 33,39 behaviour therapy to loosely structured Finland. The trial duration varied from 12 33,39 discussion sessions. Virta et al. compared the weeks33,39 to 14 treatment sessions with 12- efficacy of CBT, CT, and hypnotherapy with month follow-up.32 Active substance abuse was 33-35 that of control therapy; the control therapy was an exclusion criterion in three trials, and one 34 not detailed. Safren et al. compared the trial allowed patients with documented lifetime efficacy of CBT with that of relaxation therapy substance abuse to participate, but the current 32 combined with education support. Solanto et dependence status was unspecified. The trial 35 al. compared the efficacy of meta-cognitive characteristics appear in Appendix 6 Table A4. therapy with that of supportive psychotherapy. Patient characteristics Each psychotherapy method and its control are described in Appendix 9. The mean ages of the compared populations ranged from 32 years33,39 to 45 years.35 Outcomes Concomitant ADHD medications were allowed The change in ADHD symptoms was measured in all included trials. ADHD subtype was 34 35 using ADHD-RS-IV and CAARS-O, and the reported in one trial with 33% patients with change in the general level of impairment was combined ADHD, and the remaining 33,39 measured using the CGI-I scale in one trial participants classified as patients with inattentive 34 and the CGI-S scale in another trial. The ADHD.35 Patients‘ comorbidities were reported quality of life was measured using the Q-LES-Q in terms of the number of patients who had 33,39 general subscale. ADHD-associated depression disorder in one trial.33 The morbidities were assessed using the BDI-II, percentage of patients with depression varied 35 32 HAM-A, and RSEI scales. Hirvikoski et al. among the trial‘s four arms, from 11% in the reported the results from using the BDI-II scale cognitive training group to 60% in the cognitive in graphs only; therefore, these results could not behavioural therapy group. The number of be reported in this review. patients with anxiety disorders was reported in three trials;13,32,35 the associated percentage of Critical appraisal of individual trials patients varied from 11%33 to 56%.35 Personality 13,32,35 A critical appraisal of trials that evaluated disorder was reported in three trials; the psychotherapies in the treatment of ADHD in associated percentage of patients varied from adults appears in Table 5.

Table 5: Critical Appraisal of Trials Evaluating Psychotherapies in Treatment of ADHD in Adults First Author, Publication Risk of Bias Description Year • Trial not blinded • Intervention cannot be blinded; no information provided on attempts to minimize this risk by blinding the assessment and analysis Hirvikoski et al. 201132 • Equal treatment • Patients randomized to the DBT-based skills training group had 14 therapeutic sessions; patients in the control group were expected to come to as many sessions as possible. • Trial not blinded • Intervention cannot be blinded; no information provided on attempts to Virta et al. minimize this risk by blinding the assessment and analysis 201033,39 • Allocation • No mention about randomization sequence generation, nor how allocation

Pharmacological and Non-pharmacological Therapies for Adults with 27 Attention-Deficit/Hyperactivity Disorder

First Author, Publication Risk of Bias Description Year concealment concealment was done

• Equal treatment • Patients from four arms of trial used their ADHD medications; effect of this treatment was not considered in analysis. No evidence that all treatment arms had equal effect of concomitant therapies. A potential bias could be found if one arm had more efficacious concomitant therapy than other arms • Trial not blinded • Intervention cannot be blinded; trial protocol minimized this risk of bias by having a blinded assessment conducted using recordings from evaluation sessions

Safren et al. 34 • Equal treatment • Patients from four arms of trial used their ADHD medications; the effect of 2010 this treatment was not considered in analysis. No evidence that all treatment arms had equal effect of concomitant therapies. A potential bias could be found if one arm had more efficacious concomitant therapy than other arms • Trial not blinded • Intervention cannot be blinded; trial protocol minimized this risk of bias by Solanto et al. 35 having a blinded assessment conducted using recordings from evaluation 2010 sessions ADHD = attention-deficit/hyperactivity disorder; DBT = dialectical behaviour therapy.

had scores ―very much improved,‖ ―much Data analyses and synthesis improved,‖ or ―improved.‖ The cognitive This section summarizes the effects of behavioural therapy group and the hypnotherapy psychotherapy on ADHD symptoms, quality of group had higher rates of treatment responders life, psychiatric morbidities, function, and compared with the control group; the associated cognitive skills. The results are summarized in ORs were 5.4 (95% CI 0.8 to 36.9) and 4.7 (95% Appendix 8 Table A12. CI 0.7 to 32.7), respectively. The cognitive training group was associated with a lower rate of treatment responders compared with the Attention-deficit/hyperactivity disorder control group: OR 0.7 (95% CI 0.1 to 5.3). symptoms Safren at al.34 evaluated the effectiveness of Quality of life cognitive behavioural therapy in the reduction of Virta et al.33 evaluated the impact of using three ADHD symptoms using ADHD-RS-IV and psychotherapies on the quality of life as CGI-S. The trial reported statistically measured by means of the Q-LES-Q scale. The significantly greater improvement in the therapy trial reported that the three psychotherapies were group compared with the control group. The associated with numerically greater associated inter-group mean differences were improvement in the quality of life of adults with −5.8 (95% CI −10.3 to −1.3) and −0.6 (95% CI ADHD; however, this difference did not reach −0.99 to −0.21) on the ADHD-RS-IV and CGI-S statistical significance. The inter-group mean scales, respectively. differences were −0.4 (95% CI −16.5 to 15.7), −0.1 (95% CI −16.8 to 16.6), and −2.4 (95% CI Solanto et al.35 evaluated the efficacy of meta- −20.0 to 15.2), respectively. Hirvikoski et al.32 cognitive training in the reduction of ADHD evaluated the effect of dialectical behavioural symptoms using the CAARS-O scale. The trial therapy on the general well-being of patients reported an inter-group mean difference of with ADHD and reported that there was −4.8 (95% CI −8.7 to −0.88), indicating greater statistically significant improvement in improvement in the therapy group. association with the psychological intervention compared with placebo (P < 0.05; the results Virta et al.33 used CGI-I to measure treatment were not reported). responders, who were defined as patients who

28 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder- change in the placebo group. The results of associated morbidities using RSEI showed equal change in both 35 groups; the inter-group mean difference was 0 Solanto et al. evaluated the efficacy of meta- (95% CI −1.8 to 1.8). cognitive training on depression, measured using BDI-II, and self-esteem, measured using RSEI. Summary of clinical efficacy of attention- The trial reported a numerically lower deficit/hyperactivity disorder in adult improvement in depression in the meta-cognitive therapies therapy group compared with the control group, Table 6 summarizes the objectives and although this difference did not reach statistical conclusions of clinical trials evaluating the significance. The associated inter-group mean clinical efficacy of ADHD therapies in adult difference was 0.5 (95% CI −2.2 to 3.2), where a patients. positive mean difference indicates greater

Table 6: Clinical Efficacy of Included Studies First Author, Treatment Objectives and Authors’ Conclusions Publication Year Hirvikoski et al. DBT compared with loosely “To evaluate the feasibility, acceptability, and efficacy of a 201132 structured discussion group dialectical behavioral therapy-based method developed in Germany, in a Swedish outpatient psychiatric context.” (p.176)

“The treatment was feasible in an outpatient psychiatric context, well tolerated, and significantly reduced ADHD symptoms in on-treatment individuals who remained stable regarding medication status.” (p.175) Virta et al. CBT compared with CT “To preliminarily examine the feasibility and efficacy of short 201033,39 compared with hypnotherapy term individual CBT, CT in adults with ADHD and their impact compared with control on ADHD symptoms, mood quality of life, and cognitive performance.” (p.444)

“[CBT and CT] were found to be quite acceptable and tolerable.” (p.450) Safren et al. CBT versus relaxation with “To test cognitive behavioural therapy of ADHD in adults 201034 educational support treated with medication but who still have clinically significant symptoms.” (p.875)

“Among adults with persistent ADHD symptoms treated with medication, the use of cognitive behavioural therapy compared with relaxation with education support resulted in improved ADHD symptoms, which were maintained at 12 months.” (p.875) Solanto et al. MCT compared with “[To investigate] the efficacy of a 12-week manualized meta- 201035 supportive psychotherapy cognitive therapy group intervention designed to enhance time management, organization, and planning in adults with ADHD.” (p.958)

“Meta-cognitive therapy yielded significantly greater improvements in dimensional and categorical estimates of severity of ADHD symptoms compared with supportive therapy.” (p.958) Kay et al. 200936 MAS XR (titrated to 50 “To assess the effect of an extended-release formulation of mg/day) compared with ATX MAS, MAS XR, and ATX on simulated driving performance in (titrated to 80 mg/day) young adults with ADHD.” (p.317)

“MAS XR in young adults with ADHD yields significant improvements in simulated driving performance and ADHD symptoms.” (p.316)

Pharmacological and Non-pharmacological Therapies for Adults with 29 Attention-Deficit/Hyperactivity Disorder

First Author, Treatment Objectives and Authors’ Conclusions Publication Year Spencer et al.6,53 Triple bead MAS-ER (titrated “To evaluate the efficacy and safety of triple-bead MAS in 2008, Brown and to optimal dose 12.5 to 75 adults with ADHD.” (p.1,439) Landgraf 201054 mg/day) compared with placebo “Triple-bead MAS was significantly more effective than placebo in treating adult ADHD.” (p.1,437) Weisler et al., MAS XR (escalating dose 20 “To assess the efficacy, safety, and duration of action of MAS 20067 mg/day, 40 mg/day, or 60 XR in adults with ADHD, combined type.” (p.625) mg/day) compared with placebo “Results suggest that MAS XR is safe and effective in adults with ADHD, and controlled ADHD symptoms for up to 12 hours.” (p.626) Weiss and Dextroamphetamine “To determine the effect of psychotherapy, Hechtman 20068 (10 mg/day to 40 mg/day) and dextroamphetamine, and/or paroxetine on ADHD in adults.” paroxetine (20 mg/day to (p.611) 40 mgday), both titrated to optimal dose over 4 weeks, or “ADHD symptoms improved with dextroamphetamine… dextroamphetamine Patients who received both dextroamphetamine and (10 mg/day to 40 mg/day) or paroxetine had more severe adverse events but did not show paroxetine (20 mg/day to 40 greater improvement overall than patients treated with one mgday), both titrated to medication.” (p.611) optimal dose over 4 weeks, compared with placebo; all groups had problem-focused therapy Wigal et al. 20114 LDX (30 mg/day titrated to “To evaluate the efficacy of LDX compared with placebo in maximum of 70 mg/day) adults with ADHD in the simulated AWE setting, and to assess compared with placebo the duration of effect in a highly structured, controlled environment from 2 to 14 hours postdose.” (p.2)

“LDX significantly improved PERMP scores vs placebo and maintained improvement throughout the day from the first (2 hours) to last (14 hours) postdose time point vs placebo in adults with ADHD.” (p.1) Adler et al. 2008, LDX 30 g/day, LDX 50 mg/day “To evaluate the efficacy and safety of 30, 50, and 70 mg/day and 20095,51,52 (forced dose), LDX 70 mg/day lisdexamfetamine dimesylate compared with placebo in adults (forced dose) compared with with ADHD.” (p.1,364) placebo “All 3 lisdexamfetamine doses were significantly more effective than placebo in the treatment of adults with ADHD, with improvements noted within one week. “ (p.1,364) Young et al. Atomoxetine 60 mg to “This study in adults with ADHD examined the effect of ATX 201124 100 mg/day compared with dosed once daily over 12 weeks and 24 weeks on ADHD, placebo depressive, and anxiety symptoms.” (p.52)

“ATX demonstrated significant improvement in ADHD symptoms at 12 and 24 weeks over PBO.” (p.51) Brown et al. Atomoxetine up to 100 mg/day “To assess the effect of ATX on ADHD-related executive 2011,38 Adler et compared with placebo functions over a 6-month period using the BADDS for Adults.” al. 200925 (p.130)

“Once-daily ATX can improve executive function impairments in adults with ADHD as assessed by the BADDS.” (p.130) Rae-Clark et al. Atomoxetine up to 100 mg/day “[To evaluate] the effects of ATX on the symptoms of ADHD 201026 compared with placebo and marijuana use in marijuana-dependent adults.” (p.481)

“Results suggest that ATX may improve some ADHD symptoms but does not reduce marijuana use in this population.” (p.481)

30 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

First Author, Treatment Objectives and Authors’ Conclusions Publication Year Adler et al. Atomoxetine (up to “To evaluate the effect of ATX on ADHD and comorbid social 200927 100 mg/day) compared with anxiety disorder in adults.” (p.212) placebo “ATX monotherapy effectively improved symptoms of ADHD and comorbid social anxiety disorder in adults and was well tolerated.” (p.212-3) Adler et al. Atomoxetine (up to “[To examine] functional outcomes following 6-month treatment 200828 100 mg/day; one dose, or with ATX or placebo.” (p.720) divided if not tolerated) compared with placebo “Following 6-month treatment with ATX, adults with ADHD showed significantly greater improvement in functioning on disease-specific measures of quality of life than patients treated with placebo.” (p.720) Wilens et al. Atomoxetine (25 mg/day to “To determine if ATX was superior to placebo in improving 200829 100 mg/day) compared with ADHD and alcohol use in recently abstinent adults with ADHD placebo and comorbid alcohol use disorder.” (p.145)

“ATX in adults with ADHD and comorbid alcohol use disorder demonstrates clinically significant ADHD improvement and inconsistent effects on drinking behaviour.” (p.145) Barkley et al. Atomoxetine (0.6 mg/kg to “[To examine] the value of ATX for improving the driving 200730 1.2 mg/kg) compared with performance of adults with ADHD.” (p.306) placebo “The authors find a mixed pattern of results such that ATX warrants further study for its effects on driving in this high-risk population.” (p.306) Chamberlain et Atomoxetine 60 mg “To evaluate the cognitive effects of acute ATX treatment in al. 200731 adults with ADHD.” (p.978)

“ATX improved inhibitory control.” (p.977) Wender et al. MPH 10 mg 3 times a day up “To determine the effects of long-term MPH treatment on 20119 to 60 mg/day compared with symptom severity and social adjustment in adult ADHD.” (p.36) placebo “ADHD adults, who responded to MPH in a short-term, placebo-controlled trial, responded to long-term treatment with marked improvement in ADHD symptoms and psychosocial functioning.” (p.36) Retz et al. 201010 MPH-ER 40 mg/day, “To test the efficacy and safety of an extended-release 60 mg/day, 80 mg/day, formulation of MPH.” (p.1) 120 mg/day twice a day (maximum 1 mg/kg/day) “This clinical trial demonstrated statistically significant and compared with placebo clinical relevant effects of MPH ER in adults with ADHD for several self- and investigator-rated ADHD psychopathology and also functional efficacy measures.” (p.1) Konstenius et al. OROS-MPH 18 mg titrated up “To test the feasibility of using MPH pharmacotherapy in adults 201011 to 72 mg twice a day with amphetamine dependence and ADHD.” (p.130) compared with placebo; both groups participated in a “Both the groups significantly reduced their self-rated ADHD weekly skills training symptoms. No difference was found between the two groups programme with regards to craving for amphetamine or in retention in treatment.” (p.130) Verster et al. MPH (10 mg to 30 mg) “To examine the effects of MPH on memory functioning of 2010, 200812,55 compared with placebo adults with ADHD.” (p.277)

“MPH improves declarative memory functioning in patients with ADHD.” (p.277) Biederman et al. OROS-MP 36 mg titrated up to “To evaluate the long-term efficacy, tolerability, and safety of 2010, 201113,56 1.3 mg/kg compared with OROS-MPH in the treatment of adults with ADHD. “ (p.549)

Pharmacological and Non-pharmacological Therapies for Adults with 31 Attention-Deficit/Hyperactivity Disorder

First Author, Treatment Objectives and Authors’ Conclusions Publication Year placebo “Results… suggest that OROS-MPH was effective in reducing symptoms of ADHD and generally well tolerated for more than 34 weeks of treatment.” (p.552) Rosler et al. MPH-ER 10 mg titrated up to “To assess the medium- to long-term effects of extended 2010,37 Rosler et 60 mg/day twice a day release MPH on emotional symptoms and other al. 200914 compared with placebo psychopathology frequently seen in ADHD patients.” (p.709)

“MPH-ER appears to be an efficacious treatment for emotional symptoms with ADHD. Also obsessive-compulsive symptoms and problems with self-concept were affected positively.” (p.709) Adler et al. OROS-MPH dose-escalation “To assess the efficacy and safety of OROS MPH in the 200915 36 mg/day, 54 mg/day, management of ADHD in adults.” (p.239) 72 mg/day, 90 mg/day, or 108 mg/day compared with “OROS MPH is effective and well tolerated in the management placebo of ADHD in adults.” (p.239) Chronis-Tuscano OROS-MPH maximal effective “To examine the efficacy of OROS MPH for ADHD symptoms et al. 200816 dose obtained in titration and parenting behaviours in mothers with ADHD who had phase compared with placebo children with ADHD.” (p.1,938)

“OROS MPH was well tolerated and was associated with significant improvement in maternal ADHD symptoms and parenting. Variable effects on parenting suggest that behavioural interventions may be necessary to address impairments in parenting among adults with ADHD.” (p.1,938) Medori et al. PR-OROS-MPH 18 mg, “To evaluate efficacy and safety of MPH treatment [in adults 2008,17 Buitelaar 36 mg, or 72 mg compared with ADHD].” (p.981) et al. 2011,57 with placebo Rösler et al. “Prolonged-release MPH is an effective treatment of ADHD in 201158 adults.” (p.981) Levin et al. SR-MPH 18 mg, 36 mg, or “To compare the efficacy of sustained-release MPH to placebo 200718 72 mg compared with placebo in treating adult ADHD symptoms in current cocaine dependent treatment seekers.” (p.20)

“Results… do not suggest that sustained-release MPH produced a greater reduction in ADHD symptoms compared with placebo.” (p.26) “This trial provides some evidence that improvement in ADHD symptoms (clinician rated) among those patients receiving MPH was associated with a reduction in cocaine use.” (p.20) Spencer et al. D-MPH-ER 20 mg, 30 mg, or “[To evaluate] the efficacy of extended-release 200719 40 mg every day compared dexmethylphenidate in adults with ADHD.” (p.1380) with placebo “Once-daily d-MPH-ER at 20 mg, 30 mg, or 40 mg is a safe and effective treatment for adults with ADHD.” (p.1380) Reimherr et al. OROS-MPH 18 mg titrated up “To assess the efficacy of OROS MPH upon adult ADHD as 2007,20 to 90 mg/day compared with measured by the WRAADDS, the ADHD-RS-IV, and CGI-I.” Robison et al. placebo (p.94) 201059 “OROS MPH proved effective in treating adult ADHD.” (p.93) Jain et al. 200721 MLR-MPH 10 mg/day, “To evaluate the efficacy and safety of a new biphasic 15 mg/day, 20 mg/day, multilayer-release MPH formulation in adults with ADHD.” 30 mg/day, 40 mg/day, (p.268) 50 mg/day, 60 mg/day, or 80 mg/day every day “Once-daily MLR MPH produces significant improvements in compared with placebo ADHD symptoms and situational behaviour in adult patients with ADHD, with a prolonged duration of effect and minimal

32 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

First Author, Treatment Objectives and Authors’ Conclusions Publication Year side effects.” (p.268) Beiderman et al. OROS-MPH 36 mg titrated up “To evaluate the safety and efficacy of once-daily OROS MPH 200622 to 1.3 mg/kg/day every day in the treatment of adults with DSM-IV ADHD.” (p.829) compared with placebo “Treatment with OROS MPH in daily doses of up to 1.3 mg/kg/day was effective in the treatment of adults with ADHD.” (p.829) Levin et al. SR-MPH, 10 mg up to “To compare the efficacy of sustained-release MPH or 200623 80 mg/day twice a day sustained-release bupropion to placebo in treating adult ADHD compared with SR-bupropion- symptoms in methadone-maintained patients.” (p.137) ER, 100 mg up to 400 mg/day twice a day compared with “The results of this study do not support an advantage of placebo sustained-release MPH or sustained-release bupropion over placebo for the treatment of adult ADHD in methadone- maintained patients.” (p.145) ADHD = attention-deficit/hyperactivity disorder; ADHD-RS-IV = ADHD Rating Scale, Version IV; ATX = atomoxetine; AWE = adult workplace environment ; CBT = cognitive behavioural therapy; CGI-I = Clinical Global Impression-Improvement Scale; CT = cognitive therapy; DBT = dialectical behaviour therapy; d-MPH-ER = dexmethylphenidate extended release; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders – 4th edition; ER = extended release; LDX = lisdexamfetamine dimesylate; MAS-ER = mixed amphetamine salts – extended release ; MAS XR = mixed amphetamine salts – extended release; MCT = meta-cognitive therapy; MLR = multi-layer release; MPH = methylphenidate; OROS = osmotic release oral system; PERMP = Permanent Product Measure of Performance; PBO = placebo; PR = prolonged release ; SR = sustained release; vs. = versus; WRAADS = Wender- Reimherr Adult Attention Deficit Disorder Scale.

6 DISCUSSION CAARS-O, CGI-I, CGI-S, and WRAADDS).9-23 The study findings showed that MPH was associated with greater improvement in ADHD 6.1 Summary of Evidence symptoms compared with placebo when measured using ADHD-RS-IV, AISRS, CGI-S, This systematic review on the efficacy of and WRAADDS. Ten trials used the CGI-I therapies for ADHD in adults summarizes measure,9,13,15,18-23,37 two of which 15,23 showed clinical data from 33 clinical trials. Five trials greater improvement associated with placebo; evaluated the efficacy of amphetamine-based one trial provided similar association with 4-8 medications, 15 trials assessed the efficacy of symptoms measured using CAARS-O.11 9-23 MPH-based drugs, eight trials evaluated the Atomoxetine was associated with a greater 24-31 efficacy of ATX-based medications, and reduction in ADHD symptoms as measured four trials assessed the efficacy of using AISRS, ADHD-RS-IV, CAARS-Inv:SV, 32-35 psychotherapy. One trial evaluated the CGI-I, and WRAADDS.24,26-30,36,38 Six trials efficacy of both amphetamine and ATX used the CGI-S scale,24,26-29,38 two of which 36 medication in two separate cohorts. provided a statistically non-significant improvement in association with the placebo ADHD symptom reduction was associated with group.26,28 Among psychological interventions, all evaluated therapies. The effect of evidence was provided on the efficacy of using amphetamine-based medications on ADHD CBT in the reduction of ADHD symptoms as symptoms was evaluated in six trials using two measured by means of ADHD-RS-IV,34 CGI-I,39 4- outcome measures (ADHD-RS-IV and CGI-I). and CGI-S.34 Meta-cognitive therapy was 8,36 The results from using both measures evaluated in one trial35 and showed a statistically showed greater improvement in ADHD significant reduction of ADHD symptoms as symptoms associated with the use of measured using CAARS-O. Hypnotherapy amphetamine-based medications compared with provided greater reduction of symptoms as placebo. Fifteen trials assessed the effect of measured using CGI-I,39 although this MPH medications on ADHD symptoms using improvement did not reach statistical six outcome measures (ADHD-RS-IV, AISRS, significance. When compared with the control

Pharmacological and Non-pharmacological Therapies for Adults with 33 Attention-Deficit/Hyperactivity Disorder

intervention, cognitive therapy as proposed by The effects of ADHD therapies on the Virta et al.39 provided a lesser degree of depression and anxiety associated with ADHD improvement. were evaluated in one amphetamine trial,8 two MPH trials,11,22 and one psychotherapy trial.35 One previous HTA report62 examined the These studies did not demonstrate statistically efficacy of the medical treatment of ADHD in significant effects of these therapies on adults. The report included nine RCTs, five depression or anxiety. Function and cognitive meta-analyses, and three economic studies. The skills were evaluated in three amphetamine findings from the report indicated that adult trials,4,8,36 two MPH trials,10,19 and one ATX patients who received stimulant medication and trial.28 Methylphenidate was associated with ATX had a greater reduction of ADHD consistent statistically significant improvement symptoms compared with the placebo group. of function as measured using SDS10 and GAF.19 The drug response rate in the treatment group varied from 17% to 59.6% and, in the control In this review, three serious adverse events were group, from 7% to 42%. The authors concluded described, one for each reviewed medication. that medical treatment, including MPH and These included one case of possible transient ATX, had a positive symptom reduction effect. ischemic attack associated with amphetamine,6 The authors also concluded that, to have an one case of cerebrovascular accident associated optimal drug response, dosing is determined on with MPH,17 and one case of atrial fibrillation an individual basis. This review echoes these associated with ATX.24 The most frequently findings in the efficacy of pharmacological reported adverse events included nausea, dry treatment in the reduction of ADHD symptoms mouth, decreased appetite, and headache. Two and in the treatment with fixed doses of systematic reviews61,63 evaluated the safety of amphetamine and MPH, which did not show a ADHD medications. One systematic review61 consistent dose-effect relationship. This supports examined the cardiovascular safety of MPH, the conclusion reached about individualized amphetamine, and ATX. The results indicated dosing in the previous HTA report. This review that MPH, amphetamine, and ATX might cause adds to the previous HTA report because studies minor increases in blood pressure and heart rate on the efficacy of some psychotherapeutic in the long term. Because these findings were interventions, including meta-cognitive training based on research that was not designed to and CBT, were included. investigate the cardiovascular effect of these medications, it is difficult to draw conclusions Changes in quality of life were assessed in five from this review. Another systematic review63 trials;27,28,32,38,39 three trials assessed the effect of evaluated the safety of MPH and found that, in ATX using the AAQoL scale,27,28,38 one trial the short term, MPH was well tolerated with no evaluated the effect of dialectical behavioural serious side effects. The results of long-term therapy using the general well-being studies suggested that the use of MPH was questionnaire,32 and one trial assessed CBT, CT, associated with a modest rise in blood pressure. and hypnotherapy using the Q-LES-Q scale.39 Limitations The studied interventions showed a numerically greater improvement in the quality of life This review examined the clinical efficacy of measures, but the improvement did not reach different therapies for ADHD in adults. Because statistical significance in three trials.27,28,39 A the examined medications were those available previous systematic review40 that evaluated the in Canada, the results from this review may not impact of ADHD medications on the quality of apply in other countries with different life echoed the findings of this review in that availability of medications. This review did not few trials evaluate quality of life as part of their identify the clinical research conducted among protocol. Furthermore, the assessment was done patients with ADHD in prisons, and the in the short period of the clinical trials, which particularities of these patients need to be might not reflect the chronic nature of ADHD. considered in the application of findings to the prison population. Another limitation to this

34 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

review is the duration of the literature search, 7 CONCLUSIONS AND which focused on clinical trial reports published during the last five years before the publication IMPLICATIONS FOR of this report. Therefore, older publications would not have been identified. However, the DECISION- OR selection during the last five years likely reflects POLICY-MAKING current clinical practice, and older publications may be less relevant. Another limitation related The result of the literature search was the to generalizability is that the included population identification of 33 RCTs that addressed in the trials was young, with a maximum therapies for ADHD in adults. However, no average age of 44 years. This could limit the results addressed the adult prison population or extrapolation of findings to geriatric patients. combination therapy of pharmacotherapy and

psychotherapy. The included randomized trials The included trials did not provide the minimal reported that amphetamine, MPH, ATX, CBT, clinically important difference for the numerical meta-cognitive therapy, and hypnotherapy were measures used in the trials, except those using associated with greater ADHD symptom the CGI-I. The results, therefore, need to be reduction compared with placebo or supportive interpreted with caution. On the other hand, therapy. Atomoxetine, CBT, CT, and measures for quality of life including the AIM- hypnotherapy were associated with signs of A64 and the SP3665 health questionnaire were improvement of quality of life, but the evidence rarely used or were not reported in the included is inconclusive. Inconclusive evidence of greater trials. improvement of anxiety and depression is

associated with the use of amphetamine, MPH, Some trials provided an estimate of the between- and meta-cognitive therapy. There is insufficient group difference of means and a corresponding evidence of improvement when the impact of measure of variation or the mean differences using amphetamine and ATX on function and from baseline in each group with the cognitive skills is compared with that of corresponding measures of variation. Other trials placebo. On the other hand, there is evidence of were less ideally reported. Many studies did not greater improvement in function and cognitive provide standard deviations that correspond to skills when MPH is compared with placebo. The the mean changes from baseline in study groups, evaluated pharmacotherapies were associated thereby requiring selection of a correlation value with higher rates of treatment-emergent adverse between baseline and final follow-up measures events compared with placebo. This prevalence to permit imputation of a standard deviation for could affect compliance with treatment. change scores. Without helpful information to However, no formal analyses of compliance inform the selection of correlation, the most among adult patients using ADHD conservative approach is to assume a correlation pharmacotherapy were identified. of 0. However, this approach may unnecessarily inflate the measures of variation for the The available evidence suggests that estimated treatment effect in a given trial. amphetamine, MPH, ATX, CBT, meta-cognitive Conversely, selection of too large a correlation therapy, and hypnotherapy are associated with may artificially improve the precision of greater ADHD symptom reduction compared estimated treatment effects. For this reason, a with placebo or supportive therapy. The value between these extremes was chosen, evidence also suggests that the use of MPH is where necessary. In some of this report‘s meta- associated with better function and cognitive analyses, there was statistical heterogeneity skills. Large, well-designed trials that based on interpretation of chi-square tests. In specifically address the treatment of adults with most cases, study-level estimates favoured the ADHD are needed to accurately assess same therapy and potential causes of functioning, quality of life, and ADHD- heterogeneity were described. associated morbidities.

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30. Barkley RA, Anderson DL, Kruesi M. A pilot 38. Brown TE, Holdnack J, Saylor K, Adler L, study of the effects of atomoxetine on driving Spencer T, Williams DW, et al. Effect of performance in adults with ADHD. Journal of atomoxetine on executive function impairments Attention Disorders. 2007 Feb;10(3):306-16. in adults with ADHD. Journal of Attention Disorders. 2011 Feb;15(2):130-8. 31. Chamberlain SR, del Campo N, Dowson J, Muller U, Clark L, Robbins TW, et al. 39. Virta M, Salakari A, Antila M, Chydenius E, Atomoxetine improved response inhibition in Partinen M, Kaski M, et al. Hypnotherapy for adults with attention deficit/hyperactivity adults with attention deficit hyperactivity disorder. Biol Psychiatry. 2007 Nov disorder: A randomized controlled study. 1;62(9):977-84. Contemporary Hypnosis [Internet]. 2010 [cited 2011 Apr 20];27(1):5-18. Available from: 32. Hirvikoski T, Waaler E, Alfredsson J, Pihlgren http://www.hypnoterapi.com/htdocs/pdf/contem C, Holmstrom A, Johnson A, et al. Reduced porary.pdf ADHD symptoms in adults with ADHD after structured skills training group: Results from a 40. Coghill D. The impact of medications on quality randomized controlled trial. Behaviour Research of life in attention-deficit hyperactivity disorder: & Therapy. 2011 Mar;49(3):175-85. a systematic review. CNS Drugs. 2010 Oct 1;24(10):843-66. 33. Virta M, Salakari A, Antila M, Chydenius E, Partinen M, Kaski M, et al. Short cognitive 41. MedicineNet: health and medical information behavioral therapy and cognitive training for produced by doctors [Internet]. MedicineNet, adults with ADHD - a randomized controlled Inc.; 2011. Attention deficit hyperactivity pilot study. Neuropsychiatric Disease & disorder (ADHD) (ADD); 2010 [cited 2011 Mar Treatment [Internet]. 2010 [cited 2011 Mar 11]. Available from: 29];6:443-53. Available from: http://www.medicinenet.com/attention_deficit_h http://www.ncbi.nlm.nih.gov/pmc/articles/PMC yperactivity_disorder_adhd/page9.htm 2938293/pdf/ndt-6-443.pdf 42. CADDRA [Internet]. Toronto: Canadian ADHD 34. Safren SA, Sprich S, Mimiaga MJ, Surman C, Resource Alliance; 2011. Information for Knouse L, Groves M, et al. Cognitive behavioral educators; 2009 [cited 2011 Mar 11]. Available therapy vs relaxation with educational support from: for medication-treated adults with ADHD and http://www.caddra.ca/cms4/index.php?option=c persistent symptoms: a randomized controlled om_content&view=article&id=21&Itemid=37& trial. JAMA [Internet]. 2010 Aug 25 [cited 2011 lang=en Mar 29];304(8):875-80. Available from: http://jama.ama- 43. National Collaborating Centre for Mental assn.org/content/304/8/875.full.pdf+html Health. Attention deficit hyperactivity disorder: diagnosis and management of ADHD in 35. Solanto MV, Marks DJ, Wasserstein J, Mitchell children, young people and adults [Internet]. K, Abikoff H, Alvir JM, et al. Efficacy of meta- London: National Institute for Clinical cognitive therapy for adult ADHD. Am J Evidence; 2008 Sep. 59 p. [cited 2011 Jun 1]. Psychiatry. 2010 Aug;167(8):958-68. (NICE clinical guideline 72). Available from: http://www.nice.org.uk/nicemedia/live/12061/42 36. Kay GG, Michaels MA, Pakull B. Simulated 059/42059.pdf driving changes in young adults with ADHD receiving mixed amphetamine salts extended 44. Polanczyk G, de Lima MS, Horta BL, release and atomoxetine. Journal of Attention Biederman J, Rohde LA. The worldwide Disorders. 2009 Jan;12(4):316-29. prevalence of ADHD: a systematic review and

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metaregression analysis. Am J Psychiatry. 2007 53. Spencer TJ, Landgraf JM, Adler LA, Weisler Jun;164(6):942-8. RH, Anderson CS, Youcha SH. Attention- deficit/hyperactivity disorder-specific quality of 45. PRISMA [Internet]. York (UK): PROSPERO. life with triple-bead mixed amphetamine salts The PRISMA statement; 2011 [cited 2011 Jun (SPD465) in adults: results of a randomized, 1]. Available from: http://www.prisma- double-blind, placebo-controlled study. J Clin statement.org/statement.htm Psychiatry. 2008 Nov;69(11):1766-75.

46. Health concerns: straight facts about drugs & 54. Brown TE, Landgraf JM. Improvements in drug abuse. Ottawa: Health Canada; 2009 Sep executive function correlate with enhanced 11. performance and functioning and health-related quality of life: evidence from 2 large, double- 47. Methodology checklist 2: randomized controlled blind, randomized, placebo-controlled trials in trials [Internet]. In: SIGN 50: a guideline ADHD. Postgrad Med. 2010 Sep;122(5):42-51. developer's handbook. Edinburgh: Scottish Intercollegiate Guidelines Network; 2008 [cited 55. Verster JC, Bekker EM, de RM, Minova A, 2011 Jul 12]. Available from: Eijken EJ, Kooij JJ, et al. Methylphenidate http://www.sign.ac.uk/guidelines/fulltext/50/che significantly improves driving performance of cklist2.html. adults with attention-deficit hyperactivity disorder: a randomized crossover trial. J 48. Abrams KR, Gillies CL, Lambert PC. Meta- Psychopharmacol. 2008 May;22(3):230-7. analysis of heterogeneously reported trials assessing change from baseline. Stat Med. 2005 56. Biederman J, Mick E, Fried R, Wilner N, Dec 30;24(24):3823-44. Spencer TJ, Faraone SV. Are stimulants effective in the treatment of executive function 49. Follmann D, Elliott P, Suh I, Cutler J. Variance deficits? Results from a randomized double imputation for overviews of clinical trials with blind study of OROS-methylphenidate in adults continuous response. J Clin Epidemiol. 1992 with ADHD. Eur Neuropsychopharmacol. 2011 Jul;45(7):769-73. Mar 8;21(7):508-15.

50. Egger M, Davey Smith G, Schneider M, Minder 57. Buitelaar JK, Kooij JJ, Ramos-Quiroga JA, C. Bias in meta-analysis detected by a simple, Dejonckheere J, Casas M, van Oene JC, et al. graphical test. BMJ [Internet]. 1997 Sep 13 Predictors of treatment outcome in adults with [cited 2011 Apr 4];315(7109):629-34. Available ADHD treated with OROS® methylphenidate. from: Prog Neuropsychopharmacol Biol Psychiatry. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC 2011 Mar 30;35(2):554-60. 2127453/pdf/9310563.pdf 58. Rösler M, Ginsberg Y, Arngrim T, Adamou M, 51. Adler LA, Goodman D, Weisler R, Hamdani M, Niemela A, Dejonkheere J, et al. Correlation of Roth T. Effect of lisdexamfetamine dimesylate symptomatic improvements with functional on sleep in adults with attention- improvements and patient-reported outcomes in deficit/hyperactivity disorder. Behavioral and adults with attention-deficit/hyperactivity Brain Functions [Internet]. 2009 Aug [cited disorder treated with OROS methylphenidate. 2011 Mar 29];5(34). Available from: World J Biol Psychiatry. 2011 Apr 26. http://www.behavioralandbrainfunctions.com/co ntent/pdf/1744-9081-5-34.pdf 59. Robison RJ, Reimherr FW, Gale PD, Marchant BK, Williams ED, Soni P, et al. Personality 52. Adler LA, Weisler RH, Goodman DW, disorders in ADHD Part 2: The effect of Hamdani M, Niebler GE. Short-term effects of symptoms of personality disorder on response to lisdexamfetamine dimesylate on cardiovascular treatment with OROS methylphenidate in adults parameters in a 4-week clinical trial in adults with ADHD. Ann Clin Psychiatry. 2010 with attention-deficit/hyperactivity disorder. J May;22(2):94-102. Clin Psychiatry. 2009 Dec;70(12):1652-61. 60. Biederman J, Mick EO, Surman C, Doyle R, Hammerness P, Michel E, et al. Comparative acute efficacy and tolerability of OROS and

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immediate release formulations of 69. Guy W. EDUCU assessment manual for methylphenidate in the treatment of adults with psychopharmacology. Rockville (MD): National attention-deficit/hyperactivity disorder. BMC Institute of Mental Health; 1976. 218 p. (DHEW Psychiatry [Internet]. 2007 [cited 2011 Mar Publication no. 76-338). 29];7 Sep 2007, ArtID 49. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC 70. Wender PH. Attention-deficit hyperactivity 2075491/pdf/1471-244X-7-49.pdf disorder in adults. New York: Oxford University Press; 1995. [cited 2011 Jun 10]. 61. Stiefel G, Besag FMC. Cardiovascular effects of methylphenidate, amphetamines and 71. Brod M, Perwien A, Adler L, Spencer T, atomoxetine in the treatment of attention-deficit Johnston J. Conceptualization and assessment of hyperactivity disorder. Drug Saf. quality of life for adults with attention- 2010;33(10):821-42. deficit/hyperactivity disorder. Prim Psychiatry [Internet]. 2005 [cited 2011 Jun 10];12(6):58-64. 62. Benkert D, Krause KH, Wasem J, Aidelsburger Available from: P. Effectiveness of pharmaceutical therapy of http://www.primarypsychiatry.com/aspx/articled ADHD (Attention-Deficit/Hyperactivity etail.aspx?articleid=96 Disorder) in adults - health technology assessment. GMS Health Technology 72. Brod M, Johnston J, Able S, Swindle R. Assessment [Internet]. 2010 [cited 2011 Mar Validation of the adult attention- 29];6: Doc 13. Available from: deficit/hyperactivity disorder quality-of-life http://www.ncbi.nlm.nih.gov/pmc/articles/PMC Scale (AAQoL): a disease-specific quality-of- 3010888/pdf/HTA-06-13.pdf life measure. Qual Life Res. 2006 Feb;15(1):117-29. 63. Godfrey J. Safety of therapeutic methylphenidate in adults: a systematic review 73. Beck AT, Steer RA. Manual for the Beck of the evidence. J Psychopharmacol. 2009 anxiety inventory. San Antonio, TX: Mar;23(2):194-205. Psychological Association; 1990.

64. Landgraf JM. Monitoring quality of life in adults 74. Beck AT, Steer RA, Brown GK. Manual for the with ADHD: reliability and validity of a new Beck depression inventory-II. San Antonio, TX: measure. J Atten Disord. 2007 Nov;11(3):351- Psychological Association; 1996. 62. 75. Hamilton, M. The assessment of anxiety states 65. Weiss MD, Gibbins C, Goodman DW, by rating. Br J Med Psychol. 1959;32(1):50-5. Hodgkins PS, Landgraf JM, Faraone SV. Moderators and mediators of symptoms and 76. Hamilton, M. A rating scale for depression. J quality of life outcomes in an open-label study Neurol Neurosurg Psychiatry [Internet]. 1960 of adults treated for attention- Feb [cited 2011 Jun 10];23:56-62. Available deficit/hyperactivity disorder. J Clin Psychiatry. from: 2010 Apr;71(4):381-90. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC 495331 66. Du Paul GJ, Power TL. ADHD rating scale. New York: The Guilford Press; 1988. 77. Liebowitz MR. Social phobia. Mod Probl Pharmacopsychiatry. 1987;22:141-73. 67. Spencer T, Adler L. Diagnostic approaches to adult attention-deficit/hyperactivity disorder. 78. Buysse DJ, Reynolds CF, III, Monk TH, Prim Psychiatry. 2004;11(7):49-53. Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric 68. Conners CK, Erhardt D, Sparrow E. Connors' practice and research. Psychiatry Res. 1989 adult ADHD rating scales - self-report: short May;28(2):193-213. version (CAARS-S:S) [Internet]. North Tonawanda (NY): Multi-Health Systems; 1999. 79. Endicott J, Nee J, Harrison W, Blumenthal R. [cited 2011 Jun 10]. Quality of Life Enjoyment and Satisfaction

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Questionnaire: a new measure. 85. Cambridge Cognition [Internet]. Cambridge, Psychopharmacol Bull. 1993;29(2):321-6. UK: Cambridge Cognition. CANTAB tests: rapid visual information processing (RVP); 2011 80. Rosenberg M. Society and the adolescent self- [cited 2011 Jun 10]. Available from: image. Princeton, NJ: Princeton University http://www.camcog.com/en/science/tests/rvp Press; 1965. 86. Sheehan DV. Anxiety disease. New York: 81 .van Loon-Vervoorn WA. de 15-woorden teset Scibner's; 1983. A en B (Een vorlopige handleiding). Groningen, Netherlands: Universiteit Groningen; 1986. 87 .Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin 82. Endicott J, Nee J. Endicott Work Productivity Psychopharmacol. 1996 Jun;11 Suppl 3:89-95. Scale (EWPS): a new measure to assess treatment effects. Psychopharmacol Bull. 88. Owen AM, Downes JJ, Sahakian BJ, Polkey CE, 1997;33(1):13-6. Robbins TW. Planning and spatial working memory following frontal lobe lesions in man. 83. Diagnostic and statistical manual of mental Neuropsychologia. 1990;28(10):1021-34. disorders. 4th ed. text rev. Washington: American Psychiatric Association; 2000. 89. Robinson ESJ, Eagle DM, Bannerjee G, Robbins TW. Effects of atomoxetine on 84. Wigal SB, Wigal TL. The laboratory school inhibitory control in the rat stop-signal task. J protocol: its origin, use, and new applications. J Psychopharmacol. 2006;20:A67. Atten Disord. 2006 Aug;10(1):92-111.

Pharmacological and Non-pharmacological Therapies for Adults with 41 Attention-Deficit/Hyperactivity Disorder

9 APPENDICES: APPENDIX 1: Literature Search Strategy OVERVIEW Interface: Ovid Databases: MEDLINE (1946-) with in-process records and daily updates EMBASE (1996 to 2001 Week 9) PsychINFO via Ovid (2002 to March Week 2 2011) Note: Subject headings have been customized for each database. Duplicates between databases were removed in Ovid. Date of Search: March 10, 2011 Alerts: Monthly search updates began March 11, 2011 and ran until July 27, 2011. Study Types: Systematic reviews; meta-analyses; technology assessments; randomized controlled trials; controlled clinical trials; multicenter studies; cohort studies; cross-over studies; case control studies; comparative studies; epidemiologic studies; clinical practice guidelines; also costs and cost analysis studies, quality of life studies, and economic literature. Pharmacological interventions: Systematic reviews; meta-analyses; technology assessments; randomized controlled trials. Non-pharmacological interventions: Systematic reviews; meta-analyses; technology assessments; randomized controlled trials; controlled clinical trials; multicenter studies; cohort studies; cross-over studies; case control studies; comparative studies; epidemiologic studies. Prison population: all study types (listed above) Limits: Publication dates 2006 to March 10, 2011 Humans

SYNTAX GUIDE / At the end of a phrase, searches the phrase as a subject heading MeSH Medical Subject Heading exp Explode a subject heading * Before a word, indicates that the marked subject heading is a primary topic; or, after a word, a truncation symbol (wildcard) to retrieve plurals or varying endings ADJ Requires words are adjacent to each other (in any order) ADJ# Adjacency within # number of words (in any order) .ti Title .ab Abstract .pt Publication type

Multi-database Strategy EMBASE, Ovid MEDLINE(R), PsycINFO # Searches Results (Pharmacotherapy* or ((pharmacologic* or pharamaceutic* or drug or drugs or medicat*) 1 adj4 (intervene* or therapy or therapies or therapeutic* or treat or treated or treatment* or 402489 management or control*))).ti,ab. 2 (Stimulant* or non stimulant* or nonstimulant* or psychostimulant* or Amphetamine).ti,ab. 59477 (Focalin or focalinXR or Methylin or Daytrana or Centedrin or Tsentedrin or Ritalin or 3 9057 ritalinSR or ritaline or Phenidylate or Equasym or Metadate or concerta or lorentin Rubifen or

42 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

biphentin or methylphenidate or Dexmethylphenidate).ti,ab. (Dexedrine or procentra or Dexamphetamine or Dextroamphetamine or Adderall or 4 1620 adderallXR or obetrol or dextrostat or desoxyn).ti,ab. 5 (Lisdexamfetamine or vyvanse or lisdexamfetaminedimesylate).ti,ab. 197 6 (Modafinil or alertec or modavigil or modiodal or Provigil).ti,ab. 2299 7 (Atomoxetine or Strattera).ti,ab. 1796 (Bupropion or aplezin or budeprion or buproban or wellbutrin or wellbutrinSR or wellbutrinXR 8 5889 or Zyban or prexaton or quomen).ti,ab. 9 (Antidepress* adj3 tricyclic).ti,ab. 13779 (TCA or despiramine or norpramin or pertofane or imipramine or antideprin or deprimin or deprinol or depsonil or dynaprin or rupramin or imipramil or irmin or janimine or melipramin or surplix or tofranil or impril or tofranil or amitriptyline or elavil or tryptizol or triavil or laroxyl or sarotex or lentizol or etrafon or levate or Amoxapine or Clomipramine or anafranil or Doxepin or doxipine or aponal or adapine or deptran or sinquan or sinequan or Maprotiline or 10 35718 Nortriptyline or sensavol or aventyl or pamelor or norpress or allegron or noritren or nortrilen or Protriptyline or vivactil or triptil or Trimipramine or rhotrimine or surmontil or butriptyline or evadene or evadyne or evasidol or centrolese or dosulepin or dothiepin or prothiaden or dothep or thaden or dopress or inprindole or prondol or galatur or tertran or lofepramine or gamanil or tymelyt or lomont).ti,ab. (Antihypertensive or anti-hypertensive or antihypertension or anti-hypertension or clonidine 11 or Catapres or guanfacine or Tenex or Duraclon or Kapvay or Nexiclon or Dixarit or 75249 Intuniv).ti,ab. (Chlorpromazine or Thioridazine or Mellaril or Melleril or Mesoridazine or Perphenazine or Trifluoperazine or stelazine or Fluphenazine or Thiothixene or Molindone or Methotrimeprazine or Loxapine or Clozapine or Haloperidol or Haldol or Serenace or Risperidone or Olanzapine or Seroquel or Geodon or Zeldox or Abilify or Abilitat or Aripiprazole or Droperidol or Droleptan or Thorazine or Largactil or Prolixin or Trilafon or Butyrophenone* or Phenothiazine* or Thioxanthenes or Prochlorperazine or Compazine or Periciazine or promazine or triflupromazine or vesprinp or levomepromazine or nozinan or promethazine or Phenergan or pimozide or orap or chlorprothixine or cloxan or tractan or truxal or clopenthixol or sordinol or flupenthixol or depixol or fluanxol or thiothixene or navane or zuclopenthixol or cisordinol or clopixol or acuphase or Clozaril or Zyprexa or Risperdal or Quetiapine or Ziprasidone or Amisulpride or Solian or Asenapine or Saphris or Paliperidone or invega sustenna or Invega or Iloperidone or Fanapt or Zotepine or Nipolept or Losizopilon or Lodopin or Setous or Sertindole or Serdolect or Serlect or Dozic or Einalon S or Eukystol or Fortunan or Galoperidol or Halopal or Keselan or Mixidol or Peluces or Pernox or Sernel 12 or Ulcolind or Lyogen or Prolixin or Elinol or Fluorophenazine or Pacinol or Sevinol or 110156 Siqualine or Siqualon or Vespazine or Flupentixol or Emergil or Fluanxol or Fluanxol or Fluxanxol or Siplaril or Siplarol or Cisordinol or Clopixol or Sordinol or Pipothiazine or pipotiazin or Apexidone or Psychodal or Consta or Risperin or Rispolept or Sequinan or Spiron or Acepromazine or Acetopromazine or Acetylpromazine or Acetazine or Calmivet or Vetranquil or Plegicil or amperozide or Aminazine or Chlordelazine or Contomin or Fenactil or Propaphenin or Chlorazine or Chlorprotixen or taractan or Benperidol or Glianimon or Frenactil or Anquil or Spirodiflamine or Fluspi or Fluspirilen or Fluspirilene or Imap or Redeptin or kivat or Cloxazepine or Oxilapine or Metitepine or Methiothepine or Levopromazine or Levomeprazin or Levomepromazine or Tisercin or Tizercine or Tizertsin or Molindone or Moban or Penfluridol or Semap or Pernazine or Taxilan or Antalon or Sparine or Sinophenin or Protactyl or Reserpine or Sulperide or Sulpiride or Aiglonyl or Tepavil or Sulp or Sulpor or Sulpivert or Sulpitil or Trifluperazine or Trifluoroperazine or Eskazine or Flupazine or Stelazine or Trifluperidol or Trisedil or Siquil or Fluopromazine or Trifluopromazine or Remoxipride or perazine).ti,ab. 13 (agent* or drug* or pharmacotherap*).ti,ab. 2437678 14 (Antipsychotic* or Neuroleptic*).ti,ab. 75715 15 ((agent* or drug* or pharmacotherap*) adj3 (Antipsychotic* or Neuroleptic*)).ti,ab. 24296 16 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 15 664979

Pharmacological and Non-pharmacological Therapies for Adults with 43 Attention-Deficit/Hyperactivity Disorder

exp Amphetamine/ or Methylphenidate/ or Dextroamphetamine/ or Bupropion/ or 17 modafinil.nm. or atomoxetine.nm. or lisdexamfetamine dimesylate.nm. or exp Antidepressive 697136 Agents, Tricyclic/ or exp Antihypertensive Agents/ or exp Antipsychotic Agents/ 18 17 use pmez 341359 exp Amphetamine/ or Methylphenidate/ or Dextroamphetamine/ or Bupropion/ or 19 Atomoxetine/ or exp Tricyclic Antidepressant Drugs/ or exp Antihypertensive Drugs/ or exp 385912 neuroleptic drugs/ 20 19 use psya 16577 exp *amphetamine/ or *psychostimulant agent/ or *amphetamine/ or *dexamphetamine/ or 21 *dexmethylphenidate/ or *methylphenidate/ or *amfebutamone/ or exp *TRICYCLIC 299188 ANTIDEPRESSANT AGENT/ or exp *antihypertensive agent/ or exp *neuroleptic agent/ 22 21 use emef 114636 23 exp Attention Deficit Disorder with Hyperactivity/dt 10634 24 23 use pmez 4192 25 exp *attention deficit disorder/dt 7234 26 25 use emef 4409 27 exp *Attention Deficit Disorder with Hyperactivity/ 32517 28 27 use pmez 12122 29 exp *attention deficit disorder with hyperactivity/ 32517 30 29 use psya 7519 31 exp *attention deficit disorder/ 32760 32 31 use emef 12876 33 (Attention deficit* or Attentiondeficit* or ADHD* or AD HD).ti. 25635 (Adolescent/ or exp Child/ or exp Infant/ or exp Pediatrics/ or (child or children or childhood or infant or infants or baby or babies or newborn or newborns or neonate or neonatal or neonates or preemie or preemies or infancy or paediatric or pediatric or girl or girls or boy or boys or kid or kids or teen or teens or teenage or teenager or teenagers or youngster or 34 2342843 youngsters or youth or youths or adolescent or adolescents or adolescence or preadolescent or preadolescence or pre adolescent or pre adolescence or preschooler or school age or school aged).ti,ab.) not (exp Adult/ or (adult or adults or adulthood or middle age or middle aged or elderly or senior or seniors or man or men or woman or women).ti,ab.) 35 34 use pmez 1466132 (exp Pediatrics/ or childhood birth 12 yrs.ag. or adolescence 13 17 yrs.ag. or (child or children or childhood or infant or infants or baby or babies or newborn or newborns or neonate or neonatal or neonates or preemie or preemies or infancy or paediatric or pediatric or girl or girls or boy or boys or kid or kids or teen or teens or teenage or teenager or 36 teenagers or youngster or youngsters or youth or youths or adolescent or adolescents or 1924425 adolescence or preadolescent or preadolescence or pre adolescent or pre adolescence or preschooler or school age or school aged).ti,ab.) not (adulthood 18 yrs older.ag. or (adult or adults or adulthood or middle age or middle aged or elderly or senior or seniors or man or men or woman or women).ti,ab.) 37 36 use psya 135759 (exp adolescent/ or exp child/ or exp infant/ or exp PEDIATRICS/ or (child or children or childhood or infant or infants or baby or babies or newborn or newborns or neonate or neonatal or neonates or preemie or preemies or infancy or paediatric or pediatric or girl or girls or boy or boys or kid or kids or teen or teens or teenage or teenager or teenagers or 38 youngster or youngsters or youth or youths or adolescent or adolescents or adolescence or 2345446 preadolescent or preadolescence or pre adolescent or pre adolescence or preschooler or school age or school aged).ti,ab.) not (adult/ or exp aged/ or middle aged/ or (adult or adults or adulthood or middle age or middle aged or elderly or senior or seniors or man or men or woman or women).ti,ab.) 39 38 use emef 706406

44 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

40 exp Prisoners/ or exp Prisons/ 29831 41 40 use pmez 15311 42 exp Correctional Institutions/ or exp Prisoners/ or exp Criminals/ or Incarceration/ 31011 43 42 use psya 10619 44 exp *prison/ or prisoner/ 21135 45 44 use emef 7395 (prison* or imprison* or jail* or incarcerat* or inmate or in mate or inmates or in mates or 46 offender* or ((Penitentiar* or correctional) and (system or systems or institution* or 55427 facilit*))).ti,ab. exp Behavior Therapy/ or exp Bibliotherapy/ or exp Gestalt Therapy/ or exp Hypnosis/ or exp "Imagery (Psychotherapy)"/ or exp Nondirective Therapy/ or exp Psychoanalytic Therapy/ or 47 exp Psychotherapeutic Processes/ or exp Psychotherapy, Brief/ or exp Psychotherapy, 399391 Multiple/ or exp Psychotherapy, Rational-Emotive/ or exp Feedback, Psychological/ or exp Socioenvironmental Therapy/ or exp Reality Therapy/ 48 47 use pmez 94004 Psychotherapy/ or exp behavior therapy/ or cognitive therapy/ or exp cognitive behavior therapy/ or dialectical behavior therapy/ or Bibliotherapy/ or Gestalt Therapy/ or exp 49 Hypnosis/ or exp Imagery/ or exp psychotherapeutic processes/ or exp Brief Psychotherapy/ 288332 or exp Analytical Psychotherapy/ or exp Group Psychotherapy/ or Rational Emotive Behavior Therapy/ or exp biofeedback/ or Reality Therapy/ 50 49 use psya 45272 *psychotherapy/ or *behavior modification/ or exp *behavior therapy/ or exp *cognitive behavioral stress management/ or exp *cognitive therapy/ or exp *gestalt therapy/ or exp 51 148528 *group therapy/ or exp *guided imagery/ or exp *milieu therapy/ or exp *relaxation training/ or exp *hypnosis/ or exp *psychoanalysis/ or exp *feedback system/ 52 51 use emef 38740 53 (non pharmacologic* or non pharamaceutic* or drug free or medication free).ti,ab. 19500 ((cognitive or cognition or cognitively or (behaviour or behavior or behaviours or behaviors or behavioural or behavioral or behaviourally or behaviorally)) adj4 (therap* or modification or 54 98777 management or treatment or treatments or treated or treating or treats or counsel* or rehab*)).ti,ab. (psychoeducation or psychotherapy or psychotherapies or psychotherapeutic* or psychodynamic* or Psychosocial or psychoanalytic or nondirective or gestalt or hypnosis or 55 248616 conditioning therapy or conditioning therapies or CCBT or CBT or MBCT or MCT or group therap* or BMT).ti,ab. (DBT or linehan or dialectic* or mindful* or talking therapy or talking therapies or narrative 56 psychology* or emotion regulat* or distress toleran* or interpersonal effective* or reality 17370 test*).ti,ab. 57 (biofeedback or neurofeedback or NF or NFB or nuerobiofeedback or neurotherap*).ti,ab. 105469 (acceptance therap* or commitment therap* or ACT or comprehensive distanc* or functional 58 282844 contextualism or self as context or cognitive diffusion or cognitive shift*).ti,ab. 59 (FAP or CRB or REBT or rational emotive or rational therap* or emotive therap*).ti,ab. 9891 (Interpersonal skill* or skill base* or skill therap* or skill counsel* or skills base* or social skill* or skill train* or skills train* or operant condition* or cognitive technique* or coach or coaching 60 34216 or modelling community reinforcement or respondent condition* or operant condition* or job train* or job skill* or goal setting*).ti,ab. (problem focused therap* or problem focused counsel* or problem management or computer assist* or technology assist* or anger management or stress management or (relax* adj2 61 therap*) or impulse control* or impulse manag* or coping or cognitive remediation or 1419048 organise or organize or organisation* or organization* or diary or journal* or log book or logging or bibliotherap*).ti,ab. 62 (environmental or socioenvironment* or EBM).ti,ab. 396443

Pharmacological and Non-pharmacological Therapies for Adults with 45 Attention-Deficit/Hyperactivity Disorder

63 reality therap*.ti,ab. 273 64 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 or 61 or 62 or 63 2435628 65 ((18 or 16) and (28 or 33)) or 24 10080 66 65 not 35 6683 67 (20 or 16) and (30 or 33) 7937 68 67 not 37 6805 69 ((22 or 16) and (32 or 33)) or 26 9887 70 69 not 39 7023 71 70 not conference abstract.pt. 6972 72 66 or 68 or 71 9655 73 (28 or 33) and (41 or 46) 173 74 73 not 35 160 75 (30 or 33) and (43 or 46) 162 76 75 not 37 154 77 (32 or 33) and (45 or 46) 166 78 77 not 39 159 79 78 not conference abstract.pt. 157 80 ((48 or 64) and (28 or 33)) not 35 7439 81 ((50 or 64) and (30 or 33)) not 37 5869 82 ((52 or 64) and (32 or 33)) not 39 7364 83 82 not conference abstract.pt. 7348 84 80 or 81 or 83 8861 85 74 or 76 or 79 201 86 72 or 85 or 84 15556 87 limit 86 to english language 13989 88 limit 87 to yr="2006 -Current" 8015 89 85 201 90 limit 89 to english language 179 91 limit 90 to yr="2006 -Current" 104 92 remove duplicates from 91 58 93 meta-analysis.pt. 27255 meta-analysis/ or systematic review/ or meta-analysis as topic/ or exp technology 94 123739 assessment, biomedical/ ((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or 95 74627 overview*))).ti,ab. ((quantitative adj3 (review* or overview* or synthes*)) or (research adj3 (integrati* or 96 10044 overview*))).ti,ab. ((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or 97 14629 (pool* adj3 analy*)).ti,ab. 98 (data synthes* or data extraction* or data abstraction*).ti,ab. 20405 99 (handsearch* or hand search*).ti,ab. 8299 (mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin 100 18783 square*).ti,ab. 101 (met analy* or metanaly* or health technology assessment* or HTA or HTAs).ti,ab. 4195 102 (meta regression* or metaregression* or mega regression*).ti,ab. 2785

46 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

(meta-analy* or metaanaly* or systematic review* or biomedical technology assessment* or 103 182636 bio-medical technology assessment*).mp,hw. 104 (medline or Cochrane or pubmed or medlars).ti,ab,hw. 124648 105 (cochrane or health technology assessment or evidence report).jw. 19498 106 (meta-analysis or systematic review).md. 8149 107 or/93-106 310890 108 Randomized Controlled Trial.pt. 301697 109 Randomized Controlled Trials as Topic/ 313570 110 Randomized Controlled Trial/ 544068 111 Randomization/ 114346 112 Random Allocation/ 114346 113 Double-Blind Method/ 183895 114 Double Blind Procedure/ 75291 115 Double-Blind Studies/ 167216 116 Single-Blind Method/ 27210 117 Single Blind Procedure/ 12549 118 Single-Blind Studies/ 27210 119 Placebos/ 157919 120 Placebo/ 130287 121 (random* or sham or placebo*).ti,ab,hw. 1519114 122 ((singl* or doubl*) adj (blind* or dumm* or mask*)).ti,ab,hw. 268473 123 ((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti,ab,hw. 499 124 or/108-123 1547614 125 (Randomized Controlled Trial or Controlled Clinical Trial).pt. 378907 (Clinical Trial or Clinical Trial, Phase II or Clinical Trial, Phase III or Clinical Trial, Phase 126 470283 IV).pt. 127 Multicenter Study.pt. 127033 128 Randomized Controlled Trial/ 544068 129 Randomized Controlled Trials as Topic/ 313570 130 Controlled Clinical Trial/ 245057 131 Controlled Clinical Trials as Topic/ 167494 132 Clinical Trial/ or Phase 2 Clinical Trial/ or Phase 3 Clinical Trial/ or Phase 4 Clinical Trial/ 1140848 Clinical Trials as Topic/ or Clinical Trials, Phase II as Topic/ or Clinical Trials, Phase III as 133 835677 Topic/ or Clinical Trials, Phase IV as Topic/ 134 Multicenter Study/ or Multicenter Study as Topic/ 201799 135 Randomization/ 114346 136 Random Allocation/ 114346 137 Double-Blind Method/ 183895 138 Double Blind Procedure/ 75291 139 Double-Blind Studies/ 167216 140 Single-Blind Method/ 27210 141 Single Blind Procedure/ 12549 142 Single-Blind Studies/ 27210 143 Placebos/ 157919

Pharmacological and Non-pharmacological Therapies for Adults with 47 Attention-Deficit/Hyperactivity Disorder

144 Placebo/ 130287 145 Control Groups/ 21172 146 Control Group/ 21172 147 Cross-Over Studies/ or Crossover Procedure/ 53077 148 (random* or sham or placebo*).ti,ab,hw. 1519114 149 ((singl* or doubl*) adj (blind* or dumm* or mask*)).ti,ab,hw. 268473 150 ((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti,ab,hw. 499 151 (control* adj3 (study or studies or trial*)).ti,ab,hw. 3688253 152 (clinical adj3 (study or studies or trial*)).ti,ab,hw. 2457106 153 (Nonrandom* or non random* or non-random* or quasi-random* or quasirandom*).ti,ab,hw. 42206 154 (phase adj3 (study or studies or trial*)).ti,ab,hw. 146170 155 ((crossover or cross-over) adj3 (study or studies or trial*)).ti,ab,hw. 61107 156 ((multicent* or multi-cent*) adj3 (study or studies or trial*)).ti,ab,hw. 255531 157 allocated.ti,ab,hw. 57490 158 ((open label or open-label) adj5 (study or studies or trial*)).ti,ab,hw. 32543 159 trial.ti. 175526 160 or/125-159 5579206 161 exp animals/ 15749907 162 exp animal experimentation/ 704362 163 exp models animal/ 791677 164 exp animal experiment/ 704362 165 nonhuman/ 2212411 166 exp vertebrate/ 22923752 167 animal.po. 94211 168 or/161-167 24106624 169 exp humans/ 18353350 170 exp human experiment/ 156273 171 human.po. 995387 172 or/169-171 19348982 173 168 not 172 5739990 174 160 not 173 4304832 175 epidemiologic methods.sh. 26267 176 epidemiologic studies.sh. 4914 177 cohort studies/ 206092 178 cohort analysis/ 206430 179 longitudinal studies/ 99686 180 longitudinal study/ 98994 181 prospective studies/ 430728 182 prospective study/ 430605 183 follow-up studies/ 827698 184 follow up/ 411597 185 followup studies/ 416205 186 retrospective studies/ 562062

48 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

187 retrospective study/ 561987 188 case-control studies/ 164085 189 exp case control study/ 543329 190 cross-sectional study/ 162754 191 observational study/ 18595 192 quasi experimental methods/ 40 193 quasi experimental study/ 743 194 (observational adj3 (study or studies or design or analysis or analyses)).ti,ab. 83911 195 (cohort adj7 (study or studies or design or analysis or analyses)).ti,ab. 167324 196 (prospective adj7 (study or studies or design or analysis or analyses or cohort)).ti,ab. 404063 197 ((follow up or followup) adj7 (study or studies or design or analysis or analyses)).ti,ab. 132954 ((longitudinal or longterm or (long adj term)) adj7 (study or studies or design or analysis or 198 247905 analyses or data or cohort)).ti,ab. (retrospective adj7 (study or studies or design or analysis or analyses or cohort or data or 199 357223 review)).ti,ab. 200 ((case adj control) or (case adj comparison) or (case adj controlled)).ti,ab. 114032 201 (case-referent adj3 (study or studies or design or analysis or analyses)).ti,ab. 820 202 (population adj3 (study or studies or analysis or analyses)).ti,ab. 155274 203 (descriptive adj3 (study or studies or design or analysis or analyses)).ti,ab. 59192 ((multidimensional or (multi adj dimensional)) adj3 (study or studies or design or analysis or 204 3681 analyses)).ti,ab. (cross adj sectional adj7 (study or studies or design or research or analysis or analyses or 205 182187 survey or findings)).ti,ab. 206 ((natural adj experiment) or (natural adj experiments)).ti,ab. 1535 207 (quasi adj (experiment or experiments or experimental)).ti,ab. 10093 ((non experiment or nonexperiment or non experimental or nonexperimental) adj3 (study or 208 1563 studies or design or analysis or analyses)).ti,ab. 209 (prevalence adj3 (study or studies or analysis or analyses)).ti,ab. 34179 210 case series.ti,ab. 47926 211 case reports.pt. 1506344 212 case report/ 2356879 213 case study/ 1514981 214 (case adj3 (report or reports or study or studies or histories)).ti,ab. 747447 215 organizational case studies.sh. 7545 216 or/175-215 5214547 217 72 and (107 or 124) 3148 218 84 and (107 or 174 or 216) 3611 219 217 or 218 5750 220 219 or 92 5805 221 220 5805 222 limit 221 to english language 5379 223 limit 222 to yr="2006 -Current" 3186 224 remove duplicates from 223 1963 225 (comment or newspaper article or editorial or letter or note).pt. 2146314 226 224 not 225 1923

Pharmacological and Non-pharmacological Therapies for Adults with 49 Attention-Deficit/Hyperactivity Disorder

227 limit 226 to english language 1923 228 limit 227 to yr="2006 -Current" 1923 229 remove duplicates from 228 1923 230 exp Attention Deficit Disorder with Hyperactivity/ 46309 231 230 use pmez 15497 232 exp attention deficit disorder with hyperactivity/ 46309 233 232 use psya 8255 234 exp *attention deficit disorder/ 32760 235 234 use emef 12876 236 (Attention deficit* or Attentiondeficit* or ADHD* or AD HD).ti,ab. 42315 237 ((231 or 236) and (41 or 46)) not 35 353 238 ((233 or 236) and (43 or 46)) not 37 326 239 ((235 or 236) and (45 or 46)) not 39 344 240 239 not conference abstract.pt. 341 241 237 or 238 or 240 396 242 limit 241 to english language 364 243 limit 242 to yr="2006 -Current" 204 244 remove duplicates from 243 115 245 229 or 244 1984 246 remove duplicates from 245 1982

OTHER DATABASES PubMed Same MeSH, keywords, limits, and study types used as per Medline search, with appropriate syntax used. Cochrane Library Same MeSH, keywords, and date limits used as per Medline search, Issue 2, 2011 excluding study types and Human restrictions. Syntax adjusted for Cochrane Library databases.

50 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

GREY LITERATURE Dates for March 11-15 2011 Search: Keywords: attention deficit, ADD, ADHD, hyperactivity, stimulant, stimulants, amphetamine, Focalin , Methylin , Daytrana , Centedrin , Tsentedrin Ritalin, Phenidylate, Metadate, Concerta, Dexmethylphenidate, Dexedrine, Procentra, Adderall, Dextrostat, Desoxyn, Lisdexamfetamine, Vyvanse, Lisdexamfetaminedimesylate, Modafinil, Alertec, Modavigil, Modiodal, Provigil, Atomoxetine, Strattera, Bupropion, Aplezin, Budeprion, Buproban, Wellbutrin, Zyban, Prexaton, Quomen, non-stimulant, CBT, cognitive behaviour therapy, psychotherapy, behaviour modification therapy, BMT, group therapy, biofeedback, neurofeedback, adult, adults, prison, incarcerated, jail, in mate, convict, prisoner. Limits: Publication dates 2006 to March 15, 2011 Humans

The following sections of the CADTH grey literature checklist, “Grey matters: a practical tool for evidence- based searching” (http://www.cadth.ca/resources/grey-matters) were searched:

Health Technology Assessment Agencies Clinical Practice Guidelines Databases (free) Internet Search Open Access Journals

Pharmacological and Non-pharmacological Therapies for Adults with 51 Attention-Deficit/Hyperactivity Disorder

APPENDIX 2: Selection of Included Trials

1,957 citations identified from the electronic literature search, and screened

1,804 citations excluded

153 potentially relevant articles retrieved for scrutiny (full text)

3 potentially relevant reports retrieved from other sources (grey literature, hand search)

156 potentially relevant reports

110 reports excluded: -inappropriate study design (37) -inappropriate intervention (14) -inappropriate population (10) -inappropriate comparator (8) -inappropriate outcomes (1) -other (e.g., duplicate, letter, protocol, review) (40)

46 reports describing 33 studies included in the review

52 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

APPENDIX 3: Included Trials Amphetamine-based medication Adler LA, Goodman DW, Kollins SH, Weisler RH, Krishnan S, Zhang Y, et al. Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2008 Sep;69(9):1364-73. Adler LA, Goodman D, Weisler R, Hamdani M, Roth T. Effect of lisdexamfetamine dimesylate on sleep in adults with attention-deficit/hyperactivity disorder. Behavioral and Brain Functions. 2009; 5:34.

Adler LA, Weisler RH, Goodman DW, Hamdani M, Niebler GE. Short-term effects of lisdexamfetamine dimesylate on cardiovascular parameters in a 4-week clinical trial in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2009 Dec;70(12):1652-61.

Brown TE, Landgraf JM. Improvements in executive function correlate with enhanced performance and functioning and health-related quality of life: evidence from 2 large, double- blind, randomized, placebo-controlled trials in ADHD. Postgrad Med. 2010 Sep;122(5):42-51.

Kay GG, Michaels MA, Pakull B. Simulated driving changes in young adults with ADHD receiving mixed amphetamine salts extended release and atomoxetine. Journal of Attention Disorders. 2009 Jan;12(4):316-29.

Spencer TJ, Adler LA, Weisler RH, Youcha SH. Triple-bead mixed amphetamine salts (SPD465), a novel, enhanced extended-release amphetamine formulation for the treatment of adults with ADHD: a randomized, double-blind, multicenter, placebo-controlled study. J Clin Psychiatry. 2008 Sep;69(9):1437-48.

Spencer TJ, Landgraf JM, Adler LA, Weisler RH, Anderson CS, Youcha SH. Attention- deficit/hyperactivity disorder-specific quality of life with triple-bead mixed amphetamine salts (SPD465) in adults: results of a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2008 Nov;69(11):1766-75.

Weisler RH, Biederman J, Spencer TJ, Wilens TE, Faraone SV, Chrisman AK, et al. Mixed amphetamine salts extended-release in the treatment of adult ADHD: a randomized, controlled trial. CNS Spectr. 2006 Aug;11(8):625-39. Weiss M, Hechtman L, Adult ADHD Research Group. A randomized double-blind trial of paroxetine and/or dextroamphetamine and problem-focused therapy for attention- deficit/hyperactivity disorder in adults. J Clin Psychiatry. 2006 Apr;67(4):611-9.

Wigal T, Brams M, Gasior M, Gao J, Squires L, Giblin J. Randomized, double-blind, placebo- controlled crossover study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder: Novel findings using a simulated adult workplace environment design. Behavioral and Brain Functions. 2010;6:34.

Pharmacological and Non-pharmacological Therapies for Adults with 53 Attention-Deficit/Hyperactivity Disorder

Methylphenidate-based medication Adler LA, Zimmerman B, Starr HL, Silber S, Palumbo J, Orman C, et al. Efficacy and safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, double-blind, parallel group, dose-escalation study. J Clin Psychopharmacol. 2009 Jun;29(3):239-47.

Biederman J, Mick E, Surman C, Doyle R, Hammerness P, Harpold T, et al. A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2006 May 1;59(9):829-35.

Biederman J, Mick EO, Surman C, Doyle R, Hammerness P, Michel E, et al. Comparative acute efficacy and tolerability of OROS and immediate release formulations of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder. BMC Psychiatry [Internet]. 2007 [cited 2011 Mar 29];7:49. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2075491/pdf/1471-244X-7-49.pdf

Biederman J, Mick E, Surman C, Doyle R, Hammerness P, Kotarski M, et al. A randomized, 3- phase, 34-week, double-blind, long-term efficacy study of osmotic-release oral system- methylphenidate in adults with attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2010 Oct;30(5):549-53.

Biederman J, Mick E, Fried R, Wilner N, Spencer TJ, Faraone SV. Are stimulants effective in the treatment of executive function deficits? Results from a randomized double blind study of OROS-methylphenidate in adults with ADHD. Eur Neuropsychopharmacol. 2011 Mar 8.

Buitelaar JK, Kooij JJ, Ramos-Quiroga JA, Dejonckheere J, Casas M, van Oene JC, et al. Predictors of treatment outcome in adults with ADHD treated with OROS® methylphenidate. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Mar 30;35(2):554-60.

Chronis-Tuscano A, Seymour KE, Stein MA, Jones HA, Jiles CD, Rooney ME, et al. Efficacy of osmotic-release oral system (OROS) methylphenidate for mothers with attention- deficit/hyperactivity disorder (ADHD): preliminary report of effects on ADHD symptoms and parenting. J Clin Psychiatry. 2008 Dec;69(12):1938-47.

Jain U, Hechtman L, Weiss M, Ahmed TS, Reiz JL, Donnelly GA, et al. Efficacy of a novel biphasic controlled-release methylphenidate formula in adults with attention-deficit/hyperactivity disorder: results of a double-blind, placebo-controlled crossover study. J Clin Psychiatry. 2007 Feb;68(2):268-77.

Konstenius M, Jayaram-Lindstrom N, Beck O, Franck J. Sustained release methylphenidate for the treatment of ADHD in amphetamine abusers: a pilot study. Drug & Alcohol Dependence. 2010 Apr 1;108(1-2):130-3.

Levin FR, Evans SM, Brooks DJ, Kalbag AS, Garawi F, Nunes EV. Treatment of methadone- maintained patients with adult ADHD: double-blind comparison of methylphenidate, bupropion and placebo. Drug Alcohol Depend. 2006 Feb 1;81(2):137-48.

54 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Levin FR, Evans SM, Brooks DJ, Garawi F. Treatment of cocaine dependent treatment seekers with adult ADHD: double-blind comparison of methylphenidate and placebo. Drug & Alcohol Dependence. 2007 Feb 23;87(1):20-9.

Medori R, Ramos-Quiroga JA, Casas M, Kooij JJ, Niemela A, Trott GE, et al. A randomized, placebo-controlled trial of three fixed dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2008 May 15;63(10):981-9.

Retz W, Rosler M, Ose C, Scherag A, Alm B, Philipsen A, et al. Multiscale assessment of treatment effi cacy in adults with ADHD: a randomized placebo-controlled, multi-centre study with extended-release methylphenidate. World J Biol Psychiatry. 2010 Dec:1-12.

Reimherr FW, Williams ED, Strong RE, Mestas R, Soni P, Marchant BK. A double-blind, placebo-controlled, crossover study of osmotic release oral system methylphenidate in adults with ADHD with assessment of oppositional and emotional dimensions of the disorder. J Clin Psychiatry. 2007 Jan;68(1):93-101.

Robison RJ, Reimherr FW, Gale PD, Marchant BK, Williams ED, Soni P, et al. Personality disorders in ADHD Part 2: The effect of symptoms of personality disorder on response to treatment with OROS methylphenidate in adults with ADHD. Ann Clin Psychiatry. 2010 May;22(2):94-102.

Rösler M, Ginsberg Y, Arngrim T, Adamou M, Niemela A, Dejonkheere J, et al. Correlation of symptomatic improvements with functional improvements and patient-reported outcomes in adults with attention-deficit/hyperactivity disorder treated with OROS methylphenidate. World J Biol Psychiatry. 2011 Apr 26.

Rosler M, Fischer R, Ammer R, Ose C, Retz W. A randomised, placebo-controlled, 24-week, study of low-dose extended-release methylphenidate in adults with attention-deficit/hyperactivity disorder. European Archives of Psychiatry & Clinical Neuroscience. 2009 Mar;259(2):120-9.

Rosler M, Retz W, Fischer R, Ose C, Alm B, Deckert J, et al. Twenty-four-week treatment with extended release methylphenidate improves emotional symptoms in adult ADHD. World J Biol Psychiatry. 2010 Aug;11(5):709-18.

Spencer TJ, Adler LA, McGough JJ, Muniz R, Jiang H, Pestreich L, et al. Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007 Jun 15;61(12):1380-7.

Verster JC, Bekker EM, Kooij JJ, Buitelaar JK, Verbaten MN, Volkerts ER, et al. Methylphenidate significantly improves declarative memory functioning of adults with ADHD. Psychopharmacology (Berl ) [Internet]. 2010 Oct [cited 2011 Mar 29];212(2):277-81. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937141/pdf/213_2010_Article_1952.pdf

Verster JC, Bekker EM, de RM, Minova A, Eijken EJ, Kooij JJ, et al. Methylphenidate significantly improves driving performance of adults with attention-deficit hyperactivity disorder: a randomized crossover trial. J Psychopharmacol. 2008 May;22(3):230-7.

Pharmacological and Non-pharmacological Therapies for Adults with 55 Attention-Deficit/Hyperactivity Disorder

Wender PH, Reimherr FW, Marchant BK, Sanford ME, Czajkowski LA, Tomb DA. A one year trial of methylphenidate in the treatment of ADHD. Journal of Attention Disorders. 2011 Jan;15(1):36-45

Atomoxetine-based medication Adler LA, Spencer TJ, Levine LR, Ramsey JL, Tamura R, Kelsey D, et al. Functional outcomes in the treatment of adults with ADHD. Journal of Attention Disorders. 2008 May;11(6):720-7.

Adler LA, Liebowitz M, Kronenberger W, Qiao M, Rubin R, Hollandbeck M, et al. Atomoxetine treatment in adults with attention-deficit/hyperactivity disorder and comorbid social anxiety disorder. Depression & Anxiety. 2009;26(3):212-21.

Adler LA, Spencer T, Brown TE, Holdnack J, Saylor K, Schuh K, et al. Once-daily atomoxetine for adult attention-deficit/hyperactivity disorder: a 6-month, double-blind trial. J Clin Psychopharmacol. 2009 Feb;29(1):44-50.

Barkley RA, Anderson DL, Kruesi M. A pilot study of the effects of atomoxetine on driving performance in adults with ADHD. Journal of Attention Disorders. 2007 Feb;10(3):306-16.

Brown TE, Holdnack J, Saylor K, Adler L, Spencer T, Williams DW, et al. Effect of atomoxetine on executive function impairments in adults with ADHD. Journal of Attention Disorders. 2011 Feb;15(2):130-8.

Chamberlain SR, del Campo N, Dowson J, Muller U, Clark L, Robbins TW, et al. Atomoxetine improved response inhibition in adults with attention deficit/hyperactivity disorder. Biol Psychiatry. 2007 Nov 1;62(9):977-84.

Kay GG, Michaels MA, Pakull B. Simulated driving changes in young adults with ADHD receiving mixed amphetamine salts extended release and atomoxetine. Journal of Attention Disorders. 2009 Jan;12(4):316-29.

Rae-Clark AL, Carter RE, Killeen TK, Carpenter MJ, White KG, Brady KT. A placebo-controlled trial of atomoxetine in marijuana-dependent individuals with attention deficit hyperactivity disorder. American Journal on Addictions. 2010 Nov;19(6):481-9.

Wilens TE, Adler LA, Weiss MD, Michelson D, Ramsey JL, Moore RJ, et al. Atomoxetine treatment of adults with ADHD and comorbid alcohol use disorders. Drug & Alcohol Dependence. 2008 Jul 1;96(1-2):145-54.

Young JL, Sarkis E, Qiao M, Wietecha L. Once-daily treatment with atomoxetine in adults with attention-deficit/hyperactivity disorder: a 24-week, randomized, double-blind, placebo-controlled trial. Clin Neuropharmacol. 2011 Mar;34(2):51-60.

56 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Psychotherapy Hirvikoski T, Waaler E, Alfredsson J, Pihlgren C, Holmstrom A, Johnson A, et al. Reduced ADHD symptoms in adults with ADHD after structured skills training group: Results from a randomized controlled trial. Behaviour Research & Therapy. 2011 Mar;49(3):175-85.

Safren SA, Sprich S, Mimiaga MJ, Surman C, Knouse L, Groves M, et al. Cognitive behavioral therapy vs relaxation with educational support for medication-treated adults with ADHD and persistent symptoms: a randomized controlled trial. JAMA. 2010 Aug 25;304(8):875-80.

Solanto MV, Marks DJ, Wasserstein J, Mitchell K, Abikoff H, Alvir JM, et al. Efficacy of meta- cognitive therapy for adult ADHD. Am J Psychiatry. 2010 Aug;167(8):958-68.

Virta M, Salakari A, Antila M, Chydenius E, Partinen M, Kaski M, et al. Short cognitive behavioral therapy and cognitive training for adults with ADHD - a randomized controlled pilot study. Neuropsychiatric Disease & Treatment [Internet]. 2010 [cited 2011 Mar 29];6:443-53. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938293/pdf/ndt-6-443.pdf

Virta M, Salakari A, Antila M, Chydenius E, Partinen M, Kaski M, et al. Hypnotherapy for adults with attention deficit hyperactivity disorder: A randomized controlled study. Contemporary Hypnosis. 2010;27(1):5-18.

Pharmacological and Non-pharmacological Therapies for Adults with 57 Attention-Deficit/Hyperactivity Disorder

APPENDIX 4: Excluded Studies

Inappropriate study design

Kooij SJJ, Bejerot S, Blackwell A, Caci H, Casas-Brugué M, Carpentier PJ, et al. European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD. BMC Psychiatry. 2010 [cited 2011 Mar 29];10: Art. No.: 67.

Lasser R, Dirks B, Adeyi B, Babcock T. Comparative efficacy and safety of lisdexamfetamine dimesylate and mixed amphetamine salts extended release in adults with attention- deficit/hyperactivity disorder. Prim Psychiatry. 2010;17(9):44-54.

Adler LA, Orman C, Starr HL, Silber S, Palumbo J, Cooper K, et al. Long-term safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: An open-label, dose- titration, 1-year study. J Clin Psychopharmacol. 2011;31(1):108-14.

Castells X, Ramos-Quiroga JA, Rigau D, Bosch R, Nogueira M, Vidal X, et al. Efficacy of methylphenidate for adults with attention-deficit hyperactivity disorder: a meta-regression analysis. CNS Drugs. 2011 Feb 1;25(2):157-69.

Bejerot S, Ryden EM, Arlinde CM. Two-year outcome of treatment with central stimulant medication in adult attention-deficit/hyperactivity disorder: a prospective study. J Clin Psychiatry. 2010 Dec;71(12):1590-7.

Coghill D. The impact of medications on quality of life in attention-deficit hyperactivity disorder: a systematic review. CNS Drugs. 2010 Oct 1;24(10):843-66.

Faraone SV, Glatt SJ. A comparison of the efficacy of medications for adult attention- deficit/hyperactivity disorder using meta-analysis of effect sizes. J Clin Psychiatry. 2010 Jun;71(6):754-63.

Krisanaprakornkit T, Ngamjarus C, Witoonchart C, Piyavhatkul N. Meditation therapies for attention-deficit/hyperactivity disorder (ADHD). Cochrane Database Syst Rev. 2010; 2010 Jun 16;(6):CD006507.

Takahashi M, Takita Y, Goto T, Ichikawa H, Saito K, Matsumoto H, et al. An open-label, dose- titration tolerability study of atomoxetine hydrochloride in Japanese adults with attention- deficit/hyperactivity disorder. Psychiatry Clin Neurosci. 2011;65(1):55-63.

Thomson A, Maltezos S, Paliokosta E, Xenitidis K. Amfetamine for attention deficit hyperactivity disorder in people with intellectual disabilities. Cochrane Database Syst Rev. 2009;(1).

Thomson A, Maltezos S, Paliokosta E, Xenitidis K. Risperidone for attention-deficit hyperactivity disorder in people with intellectual disabilities. Cochrane Database Syst Rev [Internet]. 2009;(2).

Mitchell JT, Nelson-Gray RO, Anastopoulos AD. Adapting an emerging empirically supported cognitive-behavioral therapy for adults with AD/HD and comorbid complications: An example of

58 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

two case studies (Clinical Case Studies (2008) 7, 5, (423-448) DOI: 10.1177/1534650108316934). Clinical Case Studies. 2009;8(1):95.

Buitelaar JK, Ramos-Quiroga JA, Casas M, Kooij JJ, Niemelä A, Konofal E, et al. Safety and tolerability of flexible dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Neuropsychiatric Disease & Treatment [Internet]. 2009 [cited 2011 Mar 30];5:457-66. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747385

Weisler R, Young J, Mattingly G, Gao J, Squires L, Adler L, et al. Long-term safety and efficacy of lisdexamfetamine dimesylate in adults with attention-deficit/ hyperactivity disorder. CNS Spectr. 2009 Oct;14(10):573-85.

Adler L, Wilens T, Zhang S, Durell T, Walker D, Schuh L, et al. Retrospective safety analysis of atomoxetine in adult ADHD patients with or without comorbid alcohol abuse and dependence. American Journal on Addictions. 2009 Sep;18(5):393-401.

Arns M, de Ridder S, Strehl U, Breteler M, Coenen A. Efficacy of neurofeedback treatment in ADHD: the effects on inattention, impulsivity and hyperactivity: a meta-analysis. Clinical EEG & Neuroscience: Official Journal of the EEG & Clinical Neuroscience Society (ENCS). 2009 Jul;40(3):180-9.

Koesters M, Becker T, Kilian R, Fegert JM, Weinmann S. Limits of meta-analysis: methylphenidate in the treatment of adult attention-deficit hyperactivity disorder. J Psychopharmacol. 2009 Sep;23(7):733-44.

Meszaros A, Czobor P, Balint S, Komlosi S, Simon V, Bitter I. Pharmacotherapy of adult attention deficit hyperactivity disorder (ADHD): a meta-analysis. Int J Neuropsychopharmacol. 2009 Sep;12(8):1137-47.

Potter AS, Ryan KK, Newhouse PA. Effects of acute ultra-low dose mecamylamine on cognition in adult attention-deficit/hyperactivity disorder (ADHD). Hum Psychopharmacol [Internet]. 2009 Jun [cited 2011 Mar 30];24(4):309-17. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776071/

Kollins SH, English J, Robinson R, Hallyburton M, Chrisman AK. Reinforcing and subjective effects of methylphenidate in adults with and without attention deficit hyperactivity disorder (ADHD). Psychopharmacology (Berl ) [Internet]. 2009 May [cited 2011 Mar 29];204(1):73-83. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688681

Verbeeck W, Tuinier S, Bekkering GE. Antidepressants in the treatment of adult attention-deficit hyperactivity disorder: a systematic review. Adv Ther. 2009 Feb;26(2):170-84.

Adler LA, Spencer T, McGough JJ, Jiang H, Muniz R. Long-term efficacy and safety of dexmethylphenidate extended-release capsules in adult ADHD. Journal of Attention Disorders. 2009 Mar;12(5):449-59.

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Godfrey J. Safety of therapeutic methylphenidate in adults: a systematic review of the evidence. J Psychopharmacol. 2009 Mar;23(2):194-205.

Adler LA, Spencer TJ, Williams DW, Moore RJ, Michelson D. Long-term, open-label safety and efficacy of atomoxetine in adults with ADHD: final report of a 4-year study. Journal of Attention Disorders. 2008 Nov;12(3):248-53.

Cortese S, Angriman M, Maffeis C, Isnard P, Konofal E, Lecendreux M, et al. Attention- deficit/hyperactivity disorder (ADHD) and obesity: a systematic review of the literature. Critical Reviews in Food Science & Nutrition. 2008 Jun;48(6):524-37.

Peterson K, McDonagh MS, Fu R. Comparative benefits and harms of competing medications for adults with attention-deficit hyperactivity disorder: a systematic review and indirect comparison meta-analysis. Psychopharmacology (Berl ). 2008 Mar;197(1):1-11.

Sobanski E, Sabljic D, Alm B, Skopp G, Kettler N, Mattern R, et al. Driving-related risks and impact of methylphenidate treatment on driving in adults with attention-deficit/hyperactivity disorder (ADHD). J Neural Transm. 2008;115(2):347-56.

Wilens TE, Adler LA, Adams J, Sgambati S, Rotrosen J, Sawtelle R, et al. Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature. Journal of the American Academy of Child & Adolescent Psychiatry. 2008 Jan;47(1):21-31.

Sobanski E, Schredl M, Kettler N, Alm B. Sleep in adults with attention deficit hyperactivity disorder (ADHD) before and during treatment with methylphenidate: A controlled polysomnographic study. Sleep: Journal of Sleep and Sleep Disorders Research. 2008;31(3):375-81.

Yovel I, Safren SA. Measuring homework utility in psychotherapy: Cognitive-behavioral therapy for adult attention-deficit hyperactivity disorder as an example. Cognitive Therapy and Research. 2007;31(3):385-99.

Philipsen A, Richter H, Peters J, Alm B, Sobanski E, Colla M, et al. Structured group psychotherapy in adults with attention deficit hyperactivity disorder: results of an open multicentre study. Journal of Nervous & Mental Disease. 2007 Dec;195(12):1013-9.

Boonstra AM, Kooij JJ, Oosterlaan J, Sergeant JA, Buitelaar JK, Van Someren EJ. Hyperactive night and day? Actigraphy studies in adult ADHD: a baseline comparison and the effect of methylphenidate. Sleep. 2007 Apr 1;30(4):433-42.

Polzer J, Bangs ME, Zhang S, Dellva MA, Tauscher-Wisniewski S, Acharya N, et al. Meta- analysis of aggression or hostility events in randomized, controlled clinical trials of atomoxetine for ADHD. Biol Psychiatry. 2007 Mar 1;61(5):713-9.

Mick E, Biederman J, Spencer T, Faraone SV, Sklar P. Absence of association with DAT1 polymorphism and response to methylphenidate in a sample of adults with ADHD. Am J Med Genet [Internet]. 2006 Dec 5 [cited 2011 Mar 29];Part B, Neuropsychiatric Genetics: the Official

60 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Publication of the International Society of Psychiatric Genetics. 141B(8):890-4. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715939

Biederman J, Mick EO, Surman C, Doyle R, Hammerness P, Michel E, et al. Comparative acute efficacy and tolerability of OROS and immediate release formulations of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder. BMC Psychiatry [Internet]. 2007 [cited 2011 Mar 29];7:49. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2075491/pdf/1471-244X-7-49.pdf

Thrash LA. A meta-analysis of psychologically-based treatments of adult attention-deficit hyperactivity disorder. Edmond (OK): Oklahoma State University; 2007.

Schubiner H, Hassunizadeh B, Kaczynski R. A Controlled Study of Autonomic Nervous System Function in Adults With Attention-Deficit/Hyperactivity Disorder Treated With Stimulant Medications: Results of a Pilot Study. Journal of Attention Disorders. 2006;10(2):205-11.

Inappropriate intervention

Sanz-Garcia O, Dueas RM, Burges V, Muro A, Perez F. Comorbidity in patients with attention deficit hyperactivity disorder in psychiatric population in prison [abstract]. Eur Neuropsychopharmacol. 2010;20:S616. (Presented at 23rd European College of Neuropsychopharmacology, ECNP Congress Amsterdam Netherlands;20100828;- 20100901).

Ginsberg Y, Hirvikoski T, Lindefors N. Attention Deficit Hyperactivity Disorder (ADHD) among longer-term prison inmates is a prevalent, persistent and disabling disorder. BMC Psychiatry [Internet]. 2010 Dec [cited 2011 Mar 29];10:112. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3016316/pdf/1471-244X-10-112.pdf

Asbjornsen AE, Jones LO, Munkvold LH, Obrzut JE, Manger T. An examination of shared variance in self-report and objective measures of attention in the incarcerated adult population. Journal of Attention Disorders. 2010 Sep;14(2):182-93.

Gudjonsson GH, Wells J, Young S. Motivation for offending among prisoners and the relationship with Axis I and Axis II disorders and ADHD symptoms. Personality and Individual Differences. 2011;50(1):64-8.

Coolidge FL, Segal DL, Klebe KJ, Cahill BS, Whitcomb JM. Psychometric properties of the Coolidge Correctional Inventory in a sample of 3,962 prison inmates. Behavioral Sciences & the Law. 2009 Sep;27(5):713-26.

Gehricke JG, Hong N, Whalen CK, Steinhoff K, Wigal TL. Effects of transdermal nicotine on symptoms, moods, and cardiovascular activity in the everyday lives of smokers and nonsmokers with attention-deficit/hyperactivity disorder. Psychology of Addictive Behaviors. 2009 Dec;23(4):644-55.

Rösler M, Retz W, Yaqoobi K, Burg E, Retz-Junginger P. Attention deficit/hyperactivity disorder in female offenders: prevalence, psychiatric comorbidity and psychosocial implications. European Archives of Psychiatry & Clinical Neuroscience. 2009 Mar;259(2):98-105.

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Mick E, Faraone SV, Spencer T, Zhang HF, Biederman J. Assessing the validity of the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form in adults with ADHD. Journal of Attention Disorders. 2008 Jan;11(4):504-9.

Pelsser LMJ, Frankena K, Toorman J, Savelkoul HFJ, Pereira RR, Buitelaar JK. A randomised controlled trial into the effects of food on ADHD. Eur Child Adolesc Psychiatry. 2009;18(1):12-9.

McCarthy S, Asherson P, Coghill D, Hollis C, Murray M, Potts L, et al. Attention-deficit hyperactivity disorder: Treatment discontinuation in adolescents and young adults. Br J Psychiatry. 2009 [cited 2011 Mar 29];194(3):273-7.

Rostain AL, Ramsay JR. A combined treatment approach for adults with ADHD--results of an open study of 43 patients. Journal of Attention Disorders. 2006 Nov;10(2):150-9.

Wilens TE, Verlinden MH, Adler LA, Wozniak PJ, West SA. ABT-089, a neuronal nicotinic receptor partial agonist, for the treatment of attention-deficit/hyperactivity disorder in adults: results of a pilot study. Biol Psychiatry. 2006 Jun 1;59(11):1065-70.

Biederman J, Mick E, Faraone S, Hammerness P, Surman C, Harpold T, et al. A double-blind comparison of galantamine hydrogen bromide and placebo in adults with attention- deficit/hyperactivity disorder: a pilot study. J Clin Psychopharmacol. 2006 Apr;26(2):163-6.

Riahi F, Tehrani-Doost M, Shahrivar Z, Alaghband-Rad J. Efficacy of reboxetine in adults with attention-deficit/hyperactivity disorder: A randomized, placebo-controlled clinical trial. Human Psychopharmacology. Hum Psychopharmacol. 2010;25(7):570-7.

Inappropriate population

Pelsser LM, Frankena K, Buitelaar JK, Rommelse NN. Effects of food on physical and sleep complaints in children with ADHD: a randomised controlled pilot study. Eur J Pediatr [Internet]. 2010 Sep [cited 2011 Mar 29];169(9):1129-38. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908441/pdf/431_2010_Article_1196.pdf

Lutz A, Slagter HA, Rawlings NB, Francis AD, Greischar LL, Davidson RJ. Mental training enhances attentional stability: neural and behavioral evidence. Journal of Neuroscience [Internet]. 2009 Oct 21 [cited 2011 Mar 29];29(42):13418-27. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789281

Harel Y, Appleboim N, Lavie M, Achiron A. Single dose of methylphenidate improves cognitive performance in multiple sclerosis patients with impaired attention process. J Neurol Sci. 2009 Jan 15;276(1-2):38-40.

Szobot CM, Rohde LA, Katz B, Ruaro P, Schaefer T, Walcher M, et al. A randomized crossover clinical study showing that methylphenidate-SODAS improves attention-deficit/hyperactivity disorder symptoms in adolescents with substance use disorder. Brazilian Journal of Medical & Biological Research. 2008 Mar;41(3):250-7.

62 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Newcorn JH, Kratochvil CJ, Allen AJ, Casat CD, Ruff DD, Moore RJ, et al. Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response. Am J Psychiatry. 2008 Jun;165(6):721-30.

Tamayo JM, Pumariega A, Rothe EM, Kelsey D, Allen AJ, Velez-Borras J, et al. Latino versus Caucasian response to atomoxetine in attention-deficit/hyperactivity disorder. Journal of Child & Adolescent Psychopharmacology. 2008 Feb;18(1):44-53.

Torres-Reveron A, Gray JD, Melton JT, Punsoni M, Tabori NE, Ward MJ, et al. Early postnatal exposure to methylphenidate alters stress reactivity and increases hippocampal ectopic granule cells in adult rats. Brain Research Bulletin. 2009;78(4-5):175-81.

Jasinski DR, Faries DE, Moore RJ, Schuh LM, Allen AJ. Abuse liability assessment of atomoxetine in a drug-abusing population. Drug Alcohol Depend. 2008;95(1-2):140-6.

Gustafsson P, Svedin CG, Ericsson I, Linden C, Karlsson MK, Thernlund G. Reliability and validity of the assessment of neurological soft-signs in children with and without attention-deficit- hyperactivity disorder. Dev Med Child Neurol. 2010;52(4):364-70.

Faber A, Kalverdijk LJ, De Jong-Van Den Berg, Hugtenburg JG, Minderaa RB, Tobi H. Co- morbidity and patterns of care in stimulant-treated children with ADHD in the Netherlands. Eur Child Adolesc Psychiatry [Internet]. 2010 [cited 2011 May 19];19(2):159-66. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2809312/pdf/787_2009_Article_75.pdf

Inappropriate comparator

Prevatt F, Lampropoulos GK, Bowles V, Garrett L. The use of between session assignments in ADHD coaching with college students. Journal of Attention Disorders. 2011 Jan;15(1):18-27.

Salakari A, Virta M, Gronroos N, Chydenius E, Partinen M, Vataja R, et al. Cognitive- behaviorally-oriented group rehabilitation of adults with ADHD: results of a 6-month follow-up. Journal of Attention Disorders. 2010 Mar;13(5):516-23.

Edel MA, Pfutze EM, Lieder A, Assion HJ, Ribbert H, Juckel G, et al. Self Concept, action control and ADHD symptoms under methylphenidate treatment in adults with ADHD. Pharmacopsychiatry. 2009;42(3):109-13.

Zylowska L, Ackerman DL, Yang MH, Futrell JL, Horton NL, Hale TS, et al. Mindfulness meditation training in adults and adolescents with ADHD: a feasibility study. Journal of Attention Disorders. 2008 May;11(6):737-46.

Adler L, Dietrich A, Reimherr FW, Taylor LV, Sutton VK, Bakken R, et al. Safety and tolerability of once versus twice daily atomoxetine in adults with ADHD. Ann Clin Psychiatry. 2006 Apr;18(2):107-13.

Adler LA, Sutton VK, Moore RJ, Dietrich AP, Reimherr FW, Sangal RB, et al. Quality of life assessment in adult patients with attention-deficit/hyperactivity disorder treated with atomoxetine. J Clin Psychopharmacol. 2006 Dec;26(6):648-52.

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Spencer TJ, Faraone SV, Michelson D, Adler LA, Reimherr FW, Glatt SJ, et al. Atomoxetine and adult attention-deficit/hyperactivity disorder: the effects of comorbidity. J Clin Psychiatry. 2006 Mar;67(3):415-20.

Spencer TJ, Mick E, Surman CB, Hammerness P, Doyle R, Aleardi M, et al. A Randomized, Single-Blind, Substitution Study of OROS Methylphenidate (Concerta) in ADHD Adults Receiving Immediate Release Methylphenidate. J Atten Disord. 2011 May;15(4):286-94.

Inappropriate outcomes

Bush G, Spencer TJ, Holmes J, Shin LM, Valera EM, Seidman LJ, et al. Functional magnetic resonance imaging of methylphenidate and placebo in attention-deficit/hyperactivity disorder during the multi-source interference task. Arch Gen Psychiatry. 2008 Jan;65(1):102-14.

Other (e.g., duplicate, letter, protocol, review)

Neurofeedback for attention deficit hyperactivity disorder. The evidence base for this therapy is weak, although a new, well-designed study addresses some concerns. The Harvard mental health letter / from Harvard Medical School. 2010;26(9):4-5.

Ramsay JR. CBT for adult ADHD: Adaptations and hypothesized mechanisms of change. Journal of Cognitive Psychotherapy. 2010;24(1):37-45.

Sprich SE, Knouse LE, Cooper-Vince C, Burbridge J, Safren SA. Description and demonstration of CBT for ADHD in adults. Cognitive and Behavioral Practice. 2010;17(1):9-15.

Stiefel G, Besag FMC. Cardiovascular effects of methylphenidate, amphetamines and atomoxetine in the treatment of attention-deficit hyperactivity disorder. Drug Saf. 2010;33(10):821-42.

Williams JM. Does neurofeedback help reduce Attention-Deficit hyperactivity disorder? Journal of Neurotherapy. 2010;14(4):261-79.

Cornforth C, Sonuga-Barke E, Coghill D. Stimulant drug effects on attention deficit/hyperactivity disorder: a review of the effects of age and sex of patients. Curr Pharm Des. 2010;16(22):2424- 33.

Brams M, Moon E, Pucci M, Lopez FA. Duration of effect of oral long-acting stimulant medications for ADHD throughout the day. Current Medical Research & Opinion. 2010 Aug;26(8):1809-25.

Young S, Amarasinghe JM. Practitioner review: Non-pharmacological treatments for ADHD: a lifespan approach. Journal of Child Psychology & Psychiatry & Allied Disciplines. 2010 Feb;51(2):116-33.

Young S, Goodwin E. Attention-deficit/hyperactivity disorder in persistent criminal offenders: The need for specialist treatment programs. Expert Rev Neurother. 2010;10(10):1497-500.

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Ramsay JR. Career counseling and workplace support. In: Ramsay JR, editor. Nonmedication treatments for adult ADHD: Evaluating impact on daily functioning and well-being. Washington: American Psychological Association; US; 2010. p. 77-90.

Castells X, Ramos-Quiroga JA, Bosch R, Nogueira M, Casas M. Amfetamines for Attention Deficit Hyperactivity Disorder(ADHD) in adults. Cochrane Database of Systematic Reviews 2009, Issue 2. Art.No.:CD007813

Mitchell JT, Nelson-Gray RO, Anastopoulos AD. "Adapting an emerging empirically supported cognitive-behavioral therapy for adults with AD/HD and comorbid complications: An example of two case studies": Erratum. Clinical Case Studies. 2009;8(1):95.

Knight LA, Rooney M, Chronis-Tuscano A. Psychosocial treatments for attention- deficit/hyperactivity disorder. Current Psychiatry Reports. 2008;10(5):412-8.

Hosenbocus S, Chahal R. A review of long-acting medications for ADHD in Canada. Journal of the Canadian Academy of Child & Adolescent Psychiatry = Journal de l Acade mie canadienne de psychiatrie de l enfant et de l adolescent [Internet]. 2009 Nov [cited 2011 Mar 30];18(4):331- 9. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765387

Moen MD, Keam SJ. Dexmethylphenidate extended release: a review of its use in the treatment of attention-deficit hyperactivity disorder. CNS Drugs. 2009 Dec 1;23(12):1057-83.

Rostain AL. Lisdexamfetamine in the treatment of attention-deficit/hyperactivity disorder in adults. Current Psychiatry Reports. 2009 Oct;11(5):341-2.

Ghanizadeh A, Akhondzadeh S. Attention deficit hyperactivity disorder in prison [letter]. Journal of the American Academy of Psychiatry & the Law [Internet]. 2009 [cited 2011 Mar 29];37(2):278.

Eme RF. Attention-deficit/hyperactivity disorder and correctional health care. Journal of Correctional Health Care. 2009 Jan;15(1):5-18.

Weber J, Siddiqui MA. Lisdexamfetamine dimesylate: in attention-deficit hyperactivity disorder in adults. CNS Drugs. 2009;23(5):419-25.

Cowles BJ. Lisdexamfetamine for treatment of attention-deficit/hyperactivity disorder. Ann Pharmacother. 2009 Apr;43(4):669-76.

Burns KA. The top ten reasons to limit prescription of controlled substances in prisons. Journal of the American Academy of Psychiatry & the Law. 2009;37(1):50-2.

Appelbaum KL. Attention deficit hyperactivity disorder in prison: a treatment protocol. Journal of the American Academy of Psychiatry & the Law. 2009;37(1):45-9.

Najib J. The efficacy and safety profile of lisdexamfetamine dimesylate, a prodrug of d- amphetamine, for the treatment of attention-deficit/hyperactivity disorder in children and adults. Clin Ther. 2009 Jan;31(1):142-76.

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Knouse LE, Cooper-Vince C, Sprich S, Safren SA. Recent developments in the psychosocial treatment of adult ADHD. Expert Rev Neurother [Internet]. 2008 Oct [cited 2011 Mar 29];8(10):1537-48. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628311

Rostain AL. Attention-deficit/hyperactivity disorder in adults: evidence-based recommendations for management. Postgrad Med. 2008 Sep;120(3):27-38.

Toplak ME, Connors L, Shuster J, Knezevic B, Parks S. Review of cognitive, cognitive- behavioral, and neural-based interventions for Attention-Deficit/Hyperactivity Disorder (ADHD). Clin Psychol Rev. 2008 Jun;28(5):801-23.

Weiss M, Safren SA, Solanto MV, Hechtman L, Rostain AL, Ramsay JR, et al. Research forum on psychological treatment of adults with ADHD. Journal of Attention Disorders. 2008 May;11(6):642-51.

Reaser AL. ADHD coaching and college students. Tallahassee: The Florida State University; 2008.

Rossler M, Fischer R, Ammer R, Ose C, Retz W. A randomised, placebo-controlled, 24-week, study of low-dose extended-release methylphenidate in adults with attention-deficit/hyperactivity disorder. Eur Arch Psychiatry Clin Neurosci. 2009;259(6):368.

Gibbins C, Weiss M. Clinical recommendations in current practice guidelines for diagnosis and treatment of ADHD in adults. Current Psychiatry Reports. 2007;9(5):420-6.

Safren SA. Cognitive-behavioral approaches to ADHD treatment in adulthood. Prim Care Companion J Clin Psychiatry. 2006;8(4):230-1.

Monastra VJ, Lynn S, Linden M, Lubar JF, Gruzelier J, La Vaque TJ. Electroencephalographic biofeedback in the treatment of attention-deficit/hyperactivity disorder. Journal of Neurotherapy. 2006;9(4):5-34.

Thapar A, Langley K, Owen MJ, O'Donovan MC. Advances in genetic findings on attention deficit hyperactivity disorder. Psychol Med. 2007 Dec;37(12):1681-92.

Ramsay JR. Current status of cognitive-behavioral therapy as a psychosocial treatment for adult attention-deficit/hyperactivity disorder. Current Psychiatry Reports. 2007 Oct;9(5):427-33.

Biederman J, Mick E, Surman C, Doyle R, Hammerness P, Harpold T, et al. A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry 2006; 59: 829-835. Biol Psychiatry. 2007;61(12):1402. Erratum.

Adams JS. An examination of the effects of stimulant medication on the IQ test performance of children with AD/HD. Greensboro (NC): The University North Carolina at Greensboro (UNCG); 2009.

66 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Martsenkovsky I, Melakh I, Bikshaeva Y. Milnacipran and atomoxetine efficacy over time in adolescents and adults with depression who have comorbid attention-deficit/hyperactivity disorder. Int J Neuropsychopharmacol. 2008;11(Suppl 1):199.

Brady KT, Wilens TE, Adler LA, Weiss MD, Ramsey JL, Michelson D. Atomoxetine treatment of adults with ADHD and comorbid alcohol abuse disorder. Neuropsychopharmacology. 2006;31(Suppl 1):S141.

Marchant BK, Reimherr FW, Robison RJ, Olsen JL, Kondo DG. Methylphenidate transdermal system in adult ADHD and impact on emotional and oppositional symptoms. J Atten Disord. 2011 May;15(4):295-304.

Benkert D, Krause KH, Wasem J, Aidelsburger P. Efficacy of pharmaceutical therapy of ADHD (Attention-Deficit/Hyperactivity Disorder) in adults - health technology assessment. GMS Health Technology Assessment [Internet]. 2010 [cited 2011 Mar 29];6: Doc 13. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010888/pdf/HTA-06-13.pdf

Pharmacological and Non-pharmacological Therapies for Adults with 67 Attention-Deficit/Hyperactivity Disorder

APPENDIX 5: Description of Outcome Measures

1) ADHD symptoms measures: ADHD-RS-IV: o 18-item scale designed to reflect current ADHD symptomology.66 Completed by the investigator, and each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms). o Higher total score indicates more severe ADHD symptoms. AISRS – Adult investigator System Report Scale: o Used to evaluate each of the 18 individual criteria symptoms of ADHD in DSM-IV on a severity grid (0= not present; 3= severe; overall minimum score = 0; maximum score = 54).67 CAARS-Inv/O:SV o A 30-item scale containing 3 subscales (inattention, hyperactivity-impulsivity, and the ADHD index). o The 18-item CAARS-Inv/O:SV total ADHD symptom score is the sum of the inattention and hyperactivity-impulsivity subscales. o Each item is scored, by the investigator (Inv) or an observer (O), on a 4-point scale( 0= not at all or never; 1=just a little or once in a while; 2= pretty much or often; and 3= very much or very frequently).68 CGI-I: o Provides a global evaluation of improvement from baseline in ADHD symptoms over time.69 o A 7-point scale that assesses patients‟ improvement, ranging from 1 (very much improved) to 7 (very much worse). CGI-S: o Evaluates baseline severity on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill).69 WRAADDS: o A clinician-administered structured interview which evaluates the even symptoms of the Utah Criteria. o The symptoms are rated from 0= not present, 1= slight, 2=moderate, 3=quite a bit, to 4=very much.70

2) Quality of life and associated morbidity: AAQoL – Adult ADHD Quality of Life Measure : o Examines the disease specific functional impairments and quality of life for adults with ADHD. It produces an overall score and four subscale scores.71,72 o It is a 29-item measure with response options using a five-point Likert-type scale. The measure contains four key quality of life domains; Life Productivity, Psychological Health, Relationships, and Life outlook. o Higher scores on the AAQoL indicate better functioning. BAI – Beck Anxiety Inventory73 o A self-report inventory containing 21-multiple choice questions; it is used to measure the severity of an individual's anxiety. o Patients have 4 answering choices; 0= not at all, 1=mildly (It did not bother me much), 2= moderately (It was very unpleasant, but I could stand it), and 3= severely (I could barely stand it). o The maximum score is 63, and patients can be classified according to their score in four classes:

68 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

. 0-7: minimal level of anxiety . 8-15: mild anxiety . 16-25: moderate anxiety . 26-63: severe anxiety BDI-II – Beck Depression Inventory74 o A self-report inventory containing 21-multiple choice questions; it is used to measure the severity of an individual's depression. o The maximum score is 63, and patients can be classified according to their score in four classes: . 0-13: minimal level of anxiety . 14-19: mild anxiety . 20-28: moderate anxiety . 29-63: severe anxiety ELS – Emotional Liability Scale:68 o A self-report scale containing six items (taken from the long version of Conners Symptom Scale). o Patients respond on a four-point Likert scale (0-3); the maximum score is 18. Ham-A – Hamilton Anxiety Scale:75 o A 14-symptom anxiety scale. o Each symptom is rated 0=not present, 4=very severe symptom o Classification criteria: . mild anxiety (minimum for anxiolytic): 18 . moderate anxiety: 25 . severe anxiety: 30 Ham-D – Hamilton Depression Scale:76 o A 17-item scale used to evaluate depression symptoms. o Each item has three to five possible answers. o Higher score indicates greater depression. LSAS – Liebowitz Social Anxiety Scale:77 o A 24-item scale that evaluates the range of social interaction and performance. It is intended to be completed by the investigator. Higher scores indicate greater anxiety and handicap. PSQI – Pittsburgh Sleep Quality Index:78 o Consists of 19 self-rated questions and five questions intended to be completed by the patient‟s roommate or bed partner. o The 19 questions generate seven "component" scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. o Each component score ranges from 0 (no difficulty) to 3 (severe difficulty) and contributes equally to a PSQI global score that ranges from 0 to 21. Q-LES-Q – Quality of Life Enjoyment and Satisfaction Questionnaire:79 o Consists of 93 self-report items; 91 items can be grouped in eight subscales that indicate satisfaction with physical health, subjective feelings, work, household duties, school, leisure activities, social relationships, and general activities. o Higher scores indicate greater enjoyment or satisfaction. RSEI – Rosenberg self-esteem inventory:80 o Contains 10 items that can be answered on a four-point Likert-type scale ranging from strongly agree to strongly disagree. o Higher score indicates better self-esteem.

Pharmacological and Non-pharmacological Therapies for Adults with 69 Attention-Deficit/Hyperactivity Disorder

3) Function and cognitive skills: DSS – Driving safety score:36 o Includes eight variables derived from seven simulators. The variables include total citations (e.g., traffic tickets), total collisions, time to collision, driving out-of-lane incidents, percentage of time above excessive speed threshold, number of times over-cornering, number of times tailgating, and the rating of the driver‟s response to crash-likely events. o Lower numerical DSS scores indicate better driving performance. IWR and DWR – Word recall test:81 o Computerized and standardized test for immediate and delayed word recall (IWR/ DWR). o Consists of 12 parallel lists of 15 monosyllabic meaningful nouns (immediate and delayed recall), complemented with 15 distracter words in the recognition test. o The delayed recall test is conducted two hours after the immediate recall test. o Recognition is expressed in recognition time (ms) and recognition score (number of correctly recognized words); lower recognition time and higher recognition score indicate better performance. EWPS – Endicott Work Productivity Scale:82 o A self-report questionnaire consisting of 25 items that evaluate work attendance, lost hours of work, and presenteeism (feelings and behaviours at work that lower production and efficiency). o Each question is rated according to the frequency of occurrence (0=never, 4=almost always). o A higher score indicates greater impairment. GAF – Global Assessment of Functioning Scale83 o A single-item instrument that is used to evaluate psychosocial, social, and occupational functioning. o The instrument is rated on a 100-point scale; 0= most impaired and 100= healthiest. PERMP – Permanent Product Measure of Performance:84 o A skill-matched test consisting of simple math problems to be attempted and completed at multiple time points. It is used to measure the ability to stay on task and attend to work. o The total PERMP score is the sum of the number of math problems attempted (PERMP-A) and the number of math problems answered correctly (PERMP-C) in a 10-minute session. RVIP – Rapid Visual Information Processing Test:85 o A test of sustained attention (similar to the Continuous Performance Task). o It covers latency, probabilities and sensitivity (calculated using Signal Detection Theory), and hits, misses, false alarms and rejections. SDS - Sheehan Disability Scale:86,87 o A composite of three self-rated items designed to measure the extent to which three major sectors in the patient‟s life are impaired by panic, anxiety, phobic, or depressive symptoms. o The three items are measured on a scale of 10; 0= item is not at all affected by the symptoms, 10= symptoms extremely affects the item in question. o Higher score indicates greater disability. SWM - Spatial Working Memory:85,88 o A test consisting of self-ordered task that measures the patient‟s ability to retain spatial information and to manipulate remembered items in working memory.

70 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

o The 24 outcome measures for SWM include errors, a measure of strategy, and latency measures. SSRT – Stop-Signal Reaction Time:85,89 o One of five measures used in the stop-signal task (SST). o Gives a measure of an individual‟s ability to inhibit a prepotent response, and it consists of five outcome measures, each of which can have various options applied to it; direction errors, proportion of successful stops, reaction time on GO trials, SSD (50%), and SSRT.

Pharmacological and Non-pharmacological Therapies for Adults with 71 Attention-Deficit/Hyperactivity Disorder

APPENDIX 6: Trial Characteristics

Table A1: Study Characteristics of Trials Evaluating Amphetamine-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) 4 Wigal 2011; 142/ 127/ RCT, double- LDX - Vyvanse® age 18-55 yrs. comorbid psychiatric Symptoms US; 105 blind, crossover; - 30 mg/day assessment using diagnosis with significant - ADHD-RS-IV Industry 4-week open- titrated to ADHD-RS-IV symptoms; low intelligence; Function & Cognitive Skills funding label dose maximum of 70 perceived risk for suicide - PERMP** optimization mg/day, QD attempt; history of seizures; Quality of Life 2-weeks Placebo hypertension; None randomized cardiovascular disease; ADHD- Associated Morbidity treatment pregnant or lactating None women recent history of substance abuse 36 Kay 2009; Cohort I: RCT, double- Cohort I: age 19-25 yrs. recent drug dependence or Symptoms US; NR/ 35/ 35 blind, crossover; MAS XR – valid driver‟s substance abuse (past 6 - ADHD-RS-IV** ® Industry 6 weeks Adderall XR - license; ≥ 3 yrs. months) - CGI-I funding Cohort II: titrated to driving certain cardiac conditions; - CGI-S NR/35/31 50mg/day, QD experience; current comorbid Function & Cognitive Skills Placebo abstinence from psychiatric diagnosis; - DSS illegal drug use history of at least one Quality of Life Cohort II: during trial seizure within past 2 yrs; None Atomoxetine – assessment using family history of Tourette‟s ADHD- Associated Morbidity ® Stratera - ADHD-RS-IV syndrome; pregnant or None titrated to 80 lactating women mg/day, QD Placebo Adler NR/420/414 RCT, parallel, LDX - Vyvanse® age 18-55 yrs. comorbid psychiatric Symptoms 5,51,52 2008; double-blind, -30g/d, QD assessment using diagnosis with significant - ADHD-RS-IV US; multicentre; LDX - Vyvanse® ADHD-RS-IV (≥ symptoms; history of Function & Cognitive Skills Industry 1-4 weeks - 50mg/d, forced 28) seizures; known cardiac None funding washout period; dose, QD structural abnormality; Quality of Life LDX - Vyvanse® hypertension; pregnant or None 4 weeks - 70mg/d, forced lactating women ADHD- Associated Morbidity randomization dose, QD recent history of substance - PSQI period; Placebo abuse

72 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A1: Study Characteristics of Trials Evaluating Amphetamine-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) Spencer 280/ 274/ RCT, double- TB MAS-ER – ages 18-55 yrs. morbid obesity; certain Symptoms 6,53 2008, 268 blind, extended assessment using cardiac conditions; current - ADHD-RS-IV 54 Brown; multicentre, release ADHD RS-INV comorbid psychiatric - CGI-I ® US; parallel-group; Adderall XR - diagnosis; family history of - CGI-S Industry 7 weeks titrated to Tourette‟s syndrome; low Function & Cognitive Skills funding optimal dose intelligence; using None 12.5 to 75 mg/ psychotropic medications Quality of Life day, QD requiring 28-day washout None Placebo period; hypertension; ADHD- Associated Morbidity pregnant or lactating - PSQI women recent drug dependence or substance abuse 7 Weisler 2006, 339/ 255/ RCT, double- MAS XR - age ≥ 18 yrs. recent drug dependence or Symptoms US; 248 blind, Escalating dose assessment using substance abuse - ADHD-RS-IV Industry multicentre, 20, 40, or 60 ADHD-RS-IV current comorbid - CGI-I funding parallel-group; mg/ day, QD psychiatric diagnosis (i.e., - CGI-S 4 weeks Placebo psychosis, bipolar illness, Function & Cognitive Skills pervasive developmental None disorder, severe OCD, Quality of Life severe depressive and None anxiety disorder); mental ADHD- Associated Morbidity retardation; Tourette‟s None syndrome; pregnant or lactating women

Pharmacological and Non-pharmacological Therapies for Adults with 73 Attention-Deficit/Hyperactivity Disorder

Table A1: Study Characteristics of Trials Evaluating Amphetamine-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) 8 Weiss 2006; 140/ 98/ 98 RCT, Dextroampheta age 18-66 yrs. eating disorders; organic Symptoms Canada and 2 x 2 factorial mine (10mg to assessment using brain syndrome; neurologic - ADHD-RS-IV US; design, at 2 40mg/day) CAARS and disease; psychosis; active - CGI-I Industry sites; and/or SCID-I suicide risk - GAF funding 20 weeks Paroxetine substance abuse disorders - HAM-D** (20mg to - HAM-A** 40md/day) Function & Cognitive Skills (both titrated to None optimal dose over Quality of Life 4 weeks) None Placebo ADHD- Associated Morbidity All groups had None problem-focused therapy ADHD-RS-IV=ADHD Rating Scale; ADHD-RS-IV:Inv= ADHD Rating Scale-Investigator; CAARS-S=Conners Adult ADHD Rating Scale-Self-report; CGI-I= Clinical Global Impression- Improvement Scale; CGI-S= Clinical Global Impression-Severity Scale; DSS=Driving Safety Score; GAF=Global Assessment of Functioning Scale; HAM-A=Hamilton Anxiety Rating Scale; HAM-D=Hamilton Depression Rating Scale; LDX=lisdexamfetamine dimesylate ; NR=not reported; OCD=obsessive compulsive disorder; PERMp=Permanent Product Measure of Performance; RCT=randomized controlled trial; SCID-I=Structured Clinical Interview for Axis I DSM-IV Disorders ; vs=versus; yrs=years

Table A2: Study Characteristics of Trials Evaluating Methylphenidate-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) 9 Wender 2011; 210/ 116/ RCT, crossover, MPH 10mg age 21-55 yrs. other Axis I and Axis II Symptoms US; 105 double-blind; titrated up up to assessment using diagnoses - CGI-I No industry 1 week run-in 60mg/day TID Utah Criteria, - WRAADDS** funding period; Placebo WRAADDS Function & Cognitive Skills 4 weeks None

crossover; Quality of Life 12 months None open-label ADHD- Associated Morbidity follow-up None

74 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A2: Study Characteristics of Trials Evaluating Methylphenidate-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) 10 Retz 2010; NR/162/ 155 RCT, parallel, MPH-ER 40, age ≥ 18 yrs. low intelligence; dementia; Symptoms Germany; double-blind, 60, 80, assessment using schizophrenia; bipolar - WRAADDS** Industry multicentre; 120mg/day BID; ADHD-DC, disorder; current major Function & Cognitive Skills funding 2-week titration; None maximum 1 WURS (≥30) depression; acute anxiety 6-week Quality of Life mg/kg/day disorders and other maintenance None unstable psychiatric Placebo ADHD- Associated Morbidity conditions; serious None medical illness; pregnant or lactating women drug or alcohol dependence during preceding 6 months Konstenius 34/ 24/ NR RCT, parallel, OROS-MPH age 18-64 yrs. major psychiatric disorder Symptoms 11 2010; double-blind; 18mg titrated up amphetamine (e.g., schizophrenia or - CAARS-O** Sweden; 1-week baseline to 72mg/day dependence major depression); use of Function & Cognitive Skills Industry measurement; None BID during last 12 opioid medication or illicit funding 12 weeks Quality of Life Placebo months opiates in last month; treatment None current use of assessment using ADHD- Associated Morbidity DSM-IV benzodiazepines; serious - BDI-II somatic disease (e.g., - BAI hypertension); pregnant or lactating women Verster NR/ 18/ 18 RCT, crossover, MPH - 10- age 21-55 yrs. comorbid anxiety or Symptoms 12,55 2010; double-blind; 30mg/day QD assessment using depression; use of None Netherlands; 3 sessions in a Placebo ADHD-RS-IV, psychoactive medication Function & Cognitive Skills No industry week; - Word learning test CAARS, STAI, history or presence of funding Evaluation done - Memory functioning 1-3 hours after CES-D alcohol or drug abuse Quality of Life administration None ADHD- Associated Morbidity None

Pharmacological and Non-pharmacological Therapies for Adults with 75 Attention-Deficit/Hyperactivity Disorder

Table A2: Study Characteristics of Trials Evaluating Methylphenidate-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) Biederman 296/ 227/ RCT, parallel, OROS-MP age 19-60 yrs. significant chronic medical Symptoms 13 56 2010; , 223 double-blind; 36mg titrated up patients with conditions; low - CGI-I US; 6 weeks acute to 1.3mg/kg, anxiety disorders intelligence; delirium, - AISRS Industry efficacy trial; daily schedule and depression dementia, or amnestic Function & Cognitive Skills funding 24 week None maintenance was not who were stable disorders; bipolar disorder; Quality of Life phase; reported on medication for psychosis; suicidality; None 4 week Placebo ≥ 3 months pregnant or lactating ADHD- Associated Morbidity discontinuation assessment using women - Ham-A phase AISRS ( ≥ 24), drug or alcohol abuse or - Ham-D CGI-S (≤ 3) dependence within 6 months preceding trial 37 Rosler 2010 363/ 359/ RCT, parallel, MPH-ER 10mg age > 18 yrs. low intelligence, Symptoms 14 Rosler 2009; 249 double-blind, titrated up to assessment using schizophrenia, bipolar - CGI-I Germany; multicentre; 60mg/day BID ADHD-DC-Inv, disorder, acute depressive - WRAADDS** Industry 24 weeks Placebo WURS episode, acute anxiety Function & Cognitive Skills funding disorders, other unstable None psychiatric conditions, Quality of Life None serious medical illness, ADHD- Associated Morbidity pregnant or lactating - ELS women, treatment with other psychopharmacological drugs evidence of drug or alcohol dependence in preceding 6 months

76 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A2: Study Characteristics of Trials Evaluating Methylphenidate-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) 15 Adler 2009; 348/ 229/149 RCT, parallel, OROS- MPH, age 18-65 yrs. depressive or anxiety Symptoms ® US; double-blind, Concerta , weight ≥ 100 lb. disorder; cardiac - AISRS** Industry multicentre; dose-escalation assessment using abnormality; diagnosis or - CGI-I funding enrichment 36, 54, 72, 90, AISRS (≥ 24) family history of Tourette‟s Function & Cognitive Skills design None (excluded MPH or 108 mg/day, syndrome or tics; history of Quality of Life non- daily schedule seizure disorder; None responders); was not uncontrolled ADHD- Associated Morbidity 7 weeks reported hyperthyroidism or None Placebo hypothyroidism; bipolar disorder; cyclothymic disorder; obsessive- compulsive disorder; schizophrenia; pervasive developmental disorder; taking antipsychotic medication; suicidal ideation or behaviour during past year history of drug or alcohol abuse within past 6 months Chronis- 71/ 23/20 RCT, parallel, OROS-MPH mothers and any other Axis I disorder; Symptoms Tuscano double-blind; - CGI-S 16 maximal children (age 6-12 depression, severe tics or 2008 5 weeks titration effective dose yrs.), both Tourette‟s syndrome; Function & Cognitive Skills ADHD; phase; obtained in the assessed with history of seizures; high None US; 2 weeks Quality of Life Industry randomization titration phase, ADHD blood pressure; None funding period daily schedule assessment using narrowing/blockage of ADHD- Associated Morbidity was not CAARS-S:SV gastrointestinal tract; None reported pregnant or lactating Placebo women; concomitant psychotropic medication use

Pharmacological and Non-pharmacological Therapies for Adults with 77 Attention-Deficit/Hyperactivity Disorder

Table A2: Study Characteristics of Trials Evaluating Methylphenidate-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) 17 Medori 2008; 448/401/365 RCT, parallel, OROS-MPH, age 18-65 yrs. clinically unstable Symptoms 57 Buitelaar; double-blind, ® - CAARS-O** 58 Concerta , 18, assessment using psychiatric condition (e.g., Rosler; multicentre; 36, or 72mg/day CAADID, CAARS acute mood disorder, - CGI-S Europe; 4 weeks QD (≥24) bipolar disorder, acute Function & Cognitive Skills Industry washout period; None funding 5 weeks Placebo obsessive-compulsive randomization disorder); family history of Quality of Life schizophrenia or affective None

psychosis; serious medical ADHD- Associated Morbidity None illness; hyperthyroidism,

myocardial infarction, or stroke within 6 months of screening; seizures, glaucoma, uncontrolled hypertension diagnosed with substance abuse disorder within last 6 months 18 Levin 2007; 1125/ 106/ RCT, parallel, SR-MPH age 18-60 yrs. other current psychiatric Symptoms US; 47 double-blind, 10mg/day up to cocaine disorders; suicidal or - CGI-I No industry multicentre; 60mg/day BID dependence homicidal behaviour within Function & Cognitive Skills funding 1-week placebo Placebo past 2 yrs; prescribed None lead; assessment using Quality of Life 2-week dose DSM-IV- SCID, psychotropic medication; None titration; WURS, AARS unstable medical ADHD- Associated Morbidity 11 weeks at condition; pregnant or None stable dose lactating women

physiologically dependent on opioids, sedatives or alcohol, requiring medical attention during periods of abstinence

78 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A2: Study Characteristics of Trials Evaluating Methylphenidate-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) Spencer 295/ 221/ RCT, parallel, D-MPH-ER 20, age 18-60 yrs. any psychiatric or medical Symptoms 19 2007; * 184 double-blind, 30, or 40mg QD assessment using comorbidity that may - ADHD-RS-IV** US; multicentre; Placebo ADHD-RS-IV interfere with trial - CGI-I Industry 5 weeks participation; pregnant or - CGI-S funding (≥24), GAF (≤ 60) lactating women Function & Cognitive Skills history of alcohol or - GAF substance abuse within Quality of Life past 6 months None ADHD- Associated Morbidity None

Reimherr 47/43/ 41 RCT, crossover, OROS-MPH age 18-65 yrs. major depressive disorder; Symptoms 20 2007; double-blind; 18mg titrated up oppositional generalized anxiety - ADHD-RS-IV Robison 8 week to 90mg/day defiant disorder; disorder; panic disorder; - CGI-I 2010;59 crossover QD obsessive-compulsive - WRAADDS** US; emotional

Industry Placebo dysregulation disorder; posttraumatic Function & Cognitive Skills None funding assessed using stress disorder; bipolar CAADID, Utah disorder; schizophrenia; Quality of Life None Criteria, PRS, other psychotic disorder; ADHD- Associated Morbidity WRAADDS seizures; hyperthyroidism None or hypothyroidism;

significant medical condition (e.g., cardiovascular disease)

21 Jain 2007; 54/ 50/ 44 RCT, crossover, MLR-MPH 10, age 18-60 yrs. low intelligence; serious or Symptoms Canada; double-blind, 15, 20, 30, 40, weight 50-90 kg unstable medical illness; - CGI-I** Industry multicentre; 50, 60, or assessment using serious hypertension; - CAARS-O funding 1 week washout; 80mg/day QD DSM-IV, Utah severe anxiety or Function & Cognitive Skills 3 weeks of None Only PP titration; Placebo Criteria, CAARS- depression; disorders of analysis 2 weeks S (≥65), CAARS- the sensory organs; Quality of Life None given treatment on a O, WAIS-III autism; psychosis or other stable dose ADHD- Associated Morbidity

Pharmacological and Non-pharmacological Therapies for Adults with 79 Attention-Deficit/Hyperactivity Disorder

Table A2: Study Characteristics of Trials Evaluating Methylphenidate-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) unstable psychiatric None conditions requiring treatment history of drug or alcohol abuse

Biederman 204/ 149/ RCT, parallel, OROS-MPH age 19-60 yrs. clinically significant chronic Symptoms 22,60 2006; 120 double-blind ; 36mg titrated up assessment using medical conditions; - AISRS** US; 6 weeks to 1.3mg/kg/day SCID- DSM-IV, delirium; dementia; - CGI Industry QD amnestic disorders; bipolar Function & Cognitive Skills funding CGI-I Placebo disorder; psychosis; None suicidality; low intelligence; Quality of Life pregnant or lactating None

women ADHD- Associated Morbidity - Ham-A drug or alcohol abuse or - Ham-D dependence within

preceding 6 months

23 Levin 2006; 2715/ 98/69 RCT, parallel, SR-MPH, 10mg age 18-60 yrs. other psychiatric disorders Symptoms US; double-blind ; up to 80mg/day opiate which required psychiatric - CGI Industry 2-week placebo BID dependency and intervention; history of Function & Cognitive Skills funding lead-in-phase; eating disorder; suicidal or None unclear 2-week dose SR-Bupropion- on same dose of Quality of Life titration; ER, 100mg up methadone for ≥ homicidal behaviour within None 8 weeks at to 400mg/day 3 weeks past 2 yrs; taking ADHD- Associated Morbidity stable dose BID assessment using prescription psychotropic None Placebo WURS, DSM-IV- medications except SCID, AARS methadone; unstable (≥23) medical condition; nursing or lactating women physiologically dependent

80 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A2: Study Characteristics of Trials Evaluating Methylphenidate-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) on sedatives or alcohol requiring medical attention during periods of abstinence

ADHD-DC=ADHD Diagnostic Checklist ; ADHD-RS-IV= ADHD Rating Scale; AISRS=Adult ADHD Investigator Symptom Rating Scale ; BAI=Beck Anxiety Inventory ; BDI-II=Beck Depression Inventory ; BID=twice daily; CAADID=Conners Adult ADHD Diagnostic Interview; CAARS-O= Conners Adult ADHD Rating Scale-Observer; CAARS-S=Conners Adult ADHD Rating Scale-Self-report; CAARS-S:SV=Conners Adult ADHD Rating Scale-Self report:screening version; CES-D=Center for Epidemiologic Trials Depression Scale; CGI-I= Clinical Global Impression-Improvement Scale; CGI-S= Clinical Global Impression-Severity Scale; DSS=Driving Safety Score; GAF=Global Assessment of Functioning Scale; HAM- A=Hamilton Anxiety Rating Scale; HAM-D=Hamilton Depression Rating Scale; MPH=methylphenidate; NR=not reported; OCD=obsessive compulsive disorder; PRS=Psychiatrists Rating Scale; RCT=randomized controlled trial; SCID-I=Structured Clinical Interview for Axis I DSM-IV Disorders ; STAI=State-Trait Anxiety Inventory vs=versus; TAADDS=Targeted Adult Attention Deficit Disorder Scale; WAIS-III=Wechlser Adult Intelligence Scale; WRAADDS= Wender-Reimherr Adult Attention Deficit Disorder Scale; WURS=Wender Utah Rating Scale; yrs=years

Table A3: Study Characteristics of Trials Evaluating Atomoxetine-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) 24 Young 2011; 728/ 502 / RCT, parallel, Atomoxetine age ≥ 18 yrs. history of bipolar or Symptoms USA; 261 double-blind, 60-100mg QD assessment using psychotic disorder; current - AISRS Industry multicentre; Placebo CAADID; CGI- major depression; anxiety - CAARS-Inv:SV** funding 2 weeks open ADHD-S (≥ 4) disorder; current use of any - CGI-S label titration psychotropic medication Function & Cognitive Skills 24 weeks substance abuse None randomization Quality of Life period None ADHD- Associated Morbidity None

Pharmacological and Non-pharmacological Therapies for Adults with 81 Attention-Deficit/Hyperactivity Disorder

Table A3: Study Characteristics of Trials Evaluating Atomoxetine-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) 38 Brown 2011, 749 / 501/ RCT, parallel, Atomoxetine up age 18-54 yrs. current major depression, Symptoms 25 Adler 2009; 216 double-blind, to 100 mg QD assessment using anxiety disorder, history of - AISRS** US; multicentre; Placebo AACDS; CGI- bipolar disorder or - CAARS-Inv:SV Industry 26 weeks ADHD-S ( ≥ 4); psychotic disorder - CGI-S funding randomization AISRS Function & Cognitive Skills period None Quality of Life - AAQoL ADHD- Associated Morbidity - BADDS McRae-Clark 126/ 78/ 38 RCT, parallel, Atomoxetine up age 18-68 yrs. psychotic disorder; current Symptoms 26 2010; double-blind ; to 100mg/d marijuana major depression or eating - CGI-S US; 12 weeks Placebo dependency disorder; current treatment - WRAADDS Industry assessment using with psychoactive Function & Cognitive Skills funding CAADID medication; cognitive None impairment; pregnant or Quality of Life lactating women None dependence on any ADHD- Associated Morbidity substance except None marijuana 36 Kay 2009; Cohort I: RCT, double- Cohort I: age 19-25 yrs. recent drug dependence or Symptoms US; NR/ 35/ 35 blind, crossover; MAS XR – valid driver‟s substance abuse (past 6 - ADHD-RS-IV** ® Industry 6 weeks Adderall XR - license; ≥ 3 yrs. months) - CGI-I funding Cohort II: titrated to driving certain cardiac conditions; - CGI-S NR/35/31 50mg/day, QD experience; current comorbid Function & Cognitive Skills Placebo abstinence from psychiatric diagnosis; DSS illegal drug use history of at least one Quality of Life Cohort II: during trial seizure within past 2 yrs; None Atomoxetine – assessment using family history of Tourette‟s ® ADHD- Associated Morbidity Stratera - ADHD-RS-IV syndrome; pregnant or None titrated to 80 lactating women mg/day, QD Placebo

82 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A3: Study Characteristics of Trials Evaluating Atomoxetine-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) 27 Adler 2009; 590/ 442/ RCT, parallel, Atomoxetine up age 18-65 yrs. diagnosis of obsessive- Symptoms US; 264 double-blind, to 100 mg/day concomitant Axis I compulsive disorder; - CAARS-Inv:SV** Industry multicentre; BID diagnoses, bipolar affective disorder; - CGI-S funding 14 weeks Placebo specific phobias, psychosis; factitious Function & Cognitive Skills generalized disorder; somatoform None anxiety disorder, disorders; panic disorder; Quality of Life and dysthymia posttraumatic stress - AAQoL were allowed disorder; eating disorder ADHD- Associated Morbidity assessment using alcohol, drug or - LSAS CAADID, CGI-S (≥ prescription medication 4) abuse 28 Adler 2008; NR/ 410/ RCT, parallel, Atomoxetine up age 18-50 yrs. generalized anxiety Symptoms US; 410 double-blind, to 100 mg/ day; employed for ≥ 20 disorder; current major - CAARS-Inv:SV Industry multicentre; single dose or hrs/week for 6 depression; illness or - CGI-S funding 4 week divided if not months prior to psychotic disorder; Function & Cognitive Skills screening and tolerated trial hypertension; bipolar - EWPS washout; Placebo assessment using illness; history of organic Quality of Life 26 week CAADID, CGI-S (≥ brain disease or seizures - AAQoL randomization 4) alcohol or substance abuse ADHD- Associated Morbidity period; None 16 week open- label follow-up 29 Wilens 2008; 215/ 147/ 80 RCT, parallel, Atomoxetine age ≥ 18 yrs major depressive disorder; Symptoms Canada and double-blind, 25- 100mg/day; alcohol abuse or bipolar disorder; psychosis; - AISRS** US; multicentre; single dose or dependence; use of other - CGI- S Industry 12 weeks divided if not abstinent for 4-30 psychopharmacological Function & Cognitive Skills funding tolerated days prior to trial treatments during trial None Placebo assessment using Quality of Life AISRS (≥ 20) None ADHD- Associated Morbidity None

Pharmacological and Non-pharmacological Therapies for Adults with 83 Attention-Deficit/Hyperactivity Disorder

Table A3: Study Characteristics of Trials Evaluating Atomoxetine-based Medications in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) Barkley 32/ 20/ 18 RCT, crossover, Atomoxetine age 21-65 yrs. evidence of deafness, Symptoms 30 ® 2007; double-blind; Stratera , 0.6- valid driver‟s blindness, severe language - ADHD-RS-IV US; 4 weeks 1.2mg/kg, daily license delay, cerebral palsy, Function & Cognitive Skills Industry schedule was assessment using epilepsy, or autism; history None funding not reported DSM-IV of bipolar or psychotic Quality of Life placebo disorder; organic brain None disease; seizure disorder; ADHD- Associated Morbidity use of antipsychotic None medication with 8 wks of trial current use of alcohol or drugs of abuse Chamberlain NR/22/20 RCT, crossover, Atomoxetine 60 adults, including low intelligence; history of Symptoms 31 2007 double-blind; mg single dose those with Axis 2 renal or liver disease; None single day Cluster B significant motor or visual Function & Cognitive Skills personality traits impairment; neurologic - RVIP assessment using disorder (e.g., tic spectrum, - SSRT DSM-IV epilepsy); history of - SWM schizophrenia, psychotic Quality of Life disorders, or bipolar None disorder; current major ADHD- Associated Morbidity depressive disorder; None substance abuse in last 2 months AAQoL=adult ADHD quality of life measure; ADHD-RS-IV=ADHD Rating Scale; ADHD-RS-IV:Inv= ADHD Rating Scale-Investigator; CAADID=Conners Adult ADHD Diagnostic Interview ; CAARS-Inv= Conners Adult ADHD Rating Scale-Investigator; CAARS-S=Conners Adult ADHD Rating Scale-Self-report; CGI-I= Clinical Global Impression-Improvement Scale; CGI-S= Clinical Global Impression-Severity Scale; DBS=Disruptive Behaviour Scale; DSS=Driving Safety Score; GAF=Global Assessment of Functioning Scale; HAM- A=Hamilton Anxiety Rating Scale; HAM-D=Hamilton Depression Rating Scale; LDX=lisdexamfetamine dimesylate; NR=not reported; OCD=obsessive compulsive disorder; PERMp=Permanent Product Measure of Performance; RCT=randomized controlled trial; RVIP = Rapid Visual Information Processing; SCID-I=Structured Clinical Interview for Axis I DSM-IV Disorders ; vs=versus; SSRT = Stop-Signal Reaction Time; SWM = Spatial Working Memory; WRAADDS=Wender-Reimherr Adult Attention Deficit Disorder Scale; yrs=years

84 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A4: Study Characteristics of Trials Evaluating the Psychotherapeutic Interventions in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) Hirvikoski NR/144/ 46 RCT - parallel dialectical age ≥ 18 yrs. ongoing substance abuse Symptoms 32 2011; groups behavioural documented (during last 3 months); low None Sweden; 14 sessions, therapy lifetime substance intelligence; suicidality; Function & Cognitive Skills No industry assessment vs. abuse were clinically unstable None funding done 0, 3, 12 loosely allowed to psychosocial Quality of Life months after structured participate (45%) circumstances General well being treatment discussion assessment using severe depression, ADHD- Associated Morbidity group DSM-IV; WURS; psychosis, or bipolar - BDI-II (results reported in WAIS-R syndrome not under stable graphic presentation and could comorbidity (73%) pharmacological treatment not be reported in this review) 33 39 Virta 2010; , NR/54/ 26 RCT - parallel CBT* age 18-49 yrs. psychosis; severe Symptoms Finland; groups vs. depression (34%); depression; paranoia - CGI-I No industry 11-13 weeks CT* anxiety (10%); current alcohol Function & Cognitive Skills funding vs. personality dependency or drug use None Hypnotherapy disorder (14%) Quality of Life vs. assessment using - Q-LES-Q Control* WURS, DSM-IV ADHD- Associated Morbidity - BDI-II

34 Safren 2010; NR/136/ 86 RCT - parallel CBT age 18-65 yrs. moderate to severe major Symptoms US; groups vs. stabilized on depression; clinically - ADHD-RS-IV No industry 12 sessions relaxation with psychotropic significant panic disorder; - CGI-S funding with 12-month educational medications organic mental disorders; Function & Cognitive Skills follow-up support assessment using psychotic spectrum None CGI, DSM-IV disorders; bipolar Quality of Life disorders; low intelligence None or pervasive developmental ADHD- Associated Morbidity disorders; active suicidality; None history of cognitive behavioural therapy; antisocial personality disorder active substance abuse or dependence

Pharmacological and Non-pharmacological Therapies for Adults with 85 Attention-Deficit/Hyperactivity Disorder

Table A4: Study Characteristics of Trials Evaluating the Psychotherapeutic Interventions in the Treatment of ADHD in Adults First Author; No. of pts. Trial Design; Therapy Inclusion Criteria Exclusion Criteria Outcomes Measured Publication (screened/ Duration Year; randomized Country; /completed Funding trial) Solanto NR/355/ 88 RCT - parallel meta-cognitive age 18-65 yrs. suicidality; overtly hostile Symptoms 35 2010; groups therapy* assessment using or aggressive behaviour; - CAARS-O USA; 12 weeks vs. CAADID (21), cognitive disability; Function & Cognitive Skills No industry supportive CAARS-S (22, 23) psychosis; borderline None funding psychotherapy* stabilized on personality disorder; Quality of Life psychotropic Alzheimer‟s disease or None medication other dementia; overt ADHD- Associated Morbidity patients with Axis I neurological disorder; - BDI-II psychiatric childhood history of abuse - Ham-A disorders were or trauma - RSEI eligible active substance abuse or dependence ADHD-RS-IV=ADHD Rating Scale; ADHD-RS-IV:Inv= ADHD Rating Scale-Investigator; BDI-II=Beck Depression Inventory; CAADID=Conners Adult ADHD Diagnostic Interview; CAARS-O= Conners Adult ADHD Rating Scale-Observer; CAARS-S=Conners Adult ADHD Rating Scale-Self-report; CBT=cognitive behavioural therapy; CGI-I= Clinical Global Impression-Improvement Scale; CGI-S=Clinical Global Impression-Severity Scale; CT=cognitive therapy; PSS= Perceived Stress Scale; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire; RCT=randomized controlled trial; vs=versus; WAIS=Wechlser Adult Intelligence Scale; WURS=Wender Utah Rating Scale; yrs=years

86 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

APPENDIX 7: Patient Characteristics Table A5: Patient Characteristics of Trials Included for Amphetamine-based Treatment of ADHD in Adults ADHD No. of Previous Comorbidities First Author, Age of Employed subtype Patients; ADHD Publication Trial Arms Patients or studying, (Combined/ Personality Men/ Mean (SD); Medication Year n (%) Inattentive/ Depression Anxiety /Mood Women, Range n (%) Hyperactive) Disorder 4 Wigal 2011 * LDX / Placebo 142; 30.5 (10.7); NR NR NR NR NR 98/ 39/ 5 Placebo / LDX 88/54 18-55 years NR NR NR NR NR 36 Kay 2009, * MAS XR 50 mg/ day 19; NR NR NR Cohort 22.3 (2.1) NR NR NR Placebo 17/2 NR NR NR 1 and 2 Atomoxetine 80 mg/ day 16; NR NR NR 22.4 (1.8) NR NR NR Placebo 14/2 NR NR NR Alder 119; 35.3 (10.1) LDX 30mg/day NR NR NR NR NR NR 20085,51,52 67/52 117; 34.2 (10.0) LDX 50mg/day NR NR NR NR NR NR 66/51 122; 35.8 (10.5) LDX 70mg/day NR NR NR NR NR NR 63/59 62; 35.2 (10.9) Placebo NR NR NR NR NR NR 32/30 Spencer TB MAS 12.5 to 75 mg/ 137; 36.1 6,53,54 NR 95/ 38/ 4 33 (24.1) NR NR NR 2008 day 69/68 (10.1);18-55

135; 37.0 (10.3); Placebo NR 97/ 34/ 4 33 (24.4) NR NR NR 67/68 18-55 Weisler 64; MAS XR 20 mg/ day 38.8; 19-65 NR 64/ 0/ 0 15 (23.4) NR NR NR 20067 41/23 64; MAS XR 40 mg/ day 38.9; 20-68 NR 64/ 0/ 0 17 (26.6) NR NR NR 38/26 60; Mas XR 60 mg/ day 39.9; 18-76 NR 60/ 0/ 0 15 (25.0) NR NR NR 29/31 60; Placebo 39.3; 18-59 NR 60/ 0/ 0 8 (13.3) NR NR NR 41/19 Weiss Dextroamphetamine NR NR NR NR NR 8 (10mg to 40mg/day) 98; 2006 37.5 (10.8)** 59/ 35/ 4** 63/35** Placebo NR NR NR NR NR LSD=lisdexamfetamine dimesylate; MAS XR=mixed amphetamine salts-extended release; NR=not reported; TB MAS=triple-bead mixed amphetamine salt * crossover trial design ** pooled data for the trial arms, no significant difference between treatment arms on these variables with the exception of there being less women in the placebo group.

Pharmacological and Non-pharmacological Therapies for Adults with 87 Attention-Deficit/Hyperactivity Disorder

Table A6: Patient Characteristics of Trials Included for Methylphenidate-based Treatment of ADHD in Adults ADHD First No. of Previous Comorbidities Age of Employed subtype Author, Patients; ADHD Trial Arms Patients or studying, (Combined/ Personality Publication Men/ Mean (SD); Medication n (%) Inattentive/ Depression Anxiety /Mood Year Women, Range n (%) Hyperactive) Disorder Wender MPH 10 TID up to 9 NR NR NR 2011 60mg/day 116; 36.9 (8.5) † 82(75) NR NR 84/ 32 Placebo NR NR NR Retz 201010 MPH ER up to 84; 36.6 (10.4) NR NR NR NR NR NR 1mg/kg/day 32/ 52 78; 38.2 (9.9) Placebo NR NR NR NR NR NR 44/ 34 Konstenius OROS-MPH 12; 34.6 (10.1) 3 (25) NR NR NR NR NR 201011 up to 72mg/day BID 9/ 3 12; 39.7 (9.8) Placebo 2 (16.7) NR NR NR NR NR 10/ 2 Verster MPH (10-30mg) 18; NR NR NR 201012,12,55 38.3 (7.7) NR 18/0/0 18 (100) † Placebo 11/ 7 NR NR NR Biederman OROS-MP up to 109; 34.7 (9.2) NR NR NR 13,56 1.3mg/kg 43/ 66 2010; NR NR NR 114; 36.4 (8.6) Placebo NR NR NR 59/ 55 Rosler MPH-ER up-to 60mg/day 239; 35.2 (10.1) 37/ 31/ 171 92 (38.2) NR NR NR 2010,37 BID 120/ 119 NR Rosler 118; 33.8 (10.6) Placebo 17/ 15/ 86 45 (38.3) NR NR NR 200914 58/ 60 Adler 200915 OROS-MPH up to 110; 39.9 (12.3) 93% didn‟t 87/ 22/ 1 NR NR NR 108mg/day 63/ 47 have ADHD NR 116; 38.2 (11.4) medication Placebo 94/ 21/ 1 NR NR NR 64/ 52 at baseline Chronis- OROS-MPH maximal 9; 39.8 (5.5) NR NR NR effective dose 0/9 (n=23) 13/8/2 Tuscano NR NR 16 11; (n=23) 2008 Placebo NR NR NR 0/11 Medori 64/ 32/ 4/ NR NR PR-OROS-MPH 101; 34.2 (95%CI: 17 1(not 10 (9.9%) 2008; 18mg/day 58/ 43 32.1, 36.3) Buitelaar;57 specified) 58 PR-OROS-MPH 102; 33.8 (95%CI: NR NR NR NR Rosler 76/ 19/ 7 11 (10.8%) 36mg/day 46/ 56 31.7, 35.8) PR-OROS-MPH 102; 33.6 (95%CI: 77/ 22/ 3 NR 17 (16.7%) NR

88 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A6: Patient Characteristics of Trials Included for Methylphenidate-based Treatment of ADHD in Adults ADHD First No. of Previous Comorbidities Age of Employed subtype Author, Patients; ADHD Trial Arms Patients or studying, (Combined/ Personality Publication Men/ Mean (SD); Medication n (%) Inattentive/ Depression Anxiety /Mood Year Women, Range n (%) Hyperactive) Disorder 72mg/day 55/ 47 31.5, 35.6) 67/ 24/ 2/ NR NR 96; 34.5 (95%CI: Placebo 3(not 10 (10.4%) 59/ 37 32.5, 36.4) specified) Levin 200718 SR-MPH up to 60mg/day 53; 37 (7) NR NR 35 (66) 22 (42%) BID 44/ 9 NR NR 53; 37 (6) NR NR Placebo 45 (85) 26 (49%) 44/ 9 Spencer D-MPH-ER 20mg QD 39/ 17/ 2 20 (34.5) NR NR NR 200719 168; 38.8 (NR) D-MPH-ER 30mg QD 38/ 14/ 3 12 (21.8) NR NR NR 100/ 68 (n=168) D-MPH-ER 40mg QD NR 38/ 16/ 1 22 (40.0) NR NR NR 53; 38.1 (NR) Placebo 40/ 12/ 1 26 (49.1) NR NR NR 27/ 26 (n=53) Reimherr OROS-MPH up to 20 NR NR NR 2007; † 90mg/day 47; 30.6 (10.8) NR NR NR Robison 31/16 (n=47) Placebo NR NR NR 201059 Jain 200721† MLR-MPH up to 48; NR NR NR 80mg/day QD 37.2 (11.2) NR NR NR 30/18 Placebo NR NR NR Biederman OROS-MPH up to 67; 32.7 (18.5) NR NR NR 200622,60 1.3mg/kg/day QD 38/ 29 74; 37.6 (8.4) NR NR NR Placebo 35/ 39 NR NR NR

Levin 200623 SR-MPH, 10mg up to 32; 40 (6) 18 (58) NR NR NR 80mg/day BID 19/13 SR-Bupropion-ER,100mg 33; 38 (8) 25 (89) NR NR NR NR NR up to 400mg/day BID 19/14 33; 39 (8) Placebo 13 (43) NR NR NR 18/15 BID=twice daily; MPH=methylphenidate; NR=not reported; QD=daily † Crossover trial design

Pharmacological and Non-pharmacological Therapies for Adults with 89 Attention-Deficit/Hyperactivity Disorder

Table A7: Patient Characteristics of Trials Included for Atomoxetine-based Treatment of ADHD in Adults ADHD Comorbidities No. of subtype First Age of Employed Previous Patients; Patients (Combined/ Author, or studying, ADHD Personality Trial Arms Men/ Mean (SD); Inattentive/ Publication n (%) Medication Women, Range Hyperactive) Depression Anxiety /Mood Year n (%) Disorder

Young 268; 201124 ATX 60-100 mg/day 137/ 131 41.2 (6.9) NR 179/ 89/ 0 NR NR NR NR

234; Placebo 102/ 132 41.4 (7.5) NR 166/ 67/ 1 NR NR NR NR

Brown 150; 38 37.7 (10.4); 2011, ATX up to 100 mg/day 124/ 126 NR 181/ 66/ 3 56 (22.6) NR NR NR 25 18.2-54.9 Adler 2009 251; 37.4 (9.9); Placebo 130/ 121 NR 180/ 67/ 4 70 (27.9) NR NR NR 18.7-54.6

McRae- 19; HAM-D: 5.4 HAM-A: 7.4 26 ATX up to 100 mg/day 16/ 3 29.4 (10.0) NR NR NR NR Clark 2010 (3.1) (4.5)

19; HAM-D: 6.6 HAM-A: 9.1 Placebo 13/ 6 30.4 (13.0) NR NR NR NR (3.7) (5.9)

27 Adler 2009 ATX up to 100 mg/day NR NR 23.3% 86.9% NR 442; 38 253/NR/NR Placebo 237/205 NR NR 23.3% 86.9% NR

Adler 200828 271; 37.1 (8.3) ATX up to 100 mg/day 152/ 119 271 (100) 185/ 84/ 2 71 (26.2) NR NR NR

139; 36.0 (8.4) Placebo 88/ 51 139 (100) 95/ 43/ 0 28 (20.4) NR NR NR

Wilens 72; 34.3 (10.2) 200829 ATX 25mg to 100 mg/day 61/ 11 61 (84.7) 60/ 11/ 1 NR NR NR NR

75; 34.8 (9.9) Placebo 64/ 11 64 (86.5) 63/ 10/ 1 NR NR NR NR

Barkley ATX 0.6mg to 1.2mg/kg 36.1 (12.2); NR NR NR NR NR NR

90 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A7: Patient Characteristics of Trials Included for Atomoxetine-based Treatment of ADHD in Adults ADHD Comorbidities No. of subtype First Age of Employed Previous Patients; Patients (Combined/ Author, or studying, ADHD Personality Trial Arms Men/ Mean (SD); Inattentive/ Publication n (%) Medication Women, Range Hyperactive) Depression Anxiety /Mood Year n (%) Disorder

200730† 18; 22-60 Placebo NR/NR NR NR NR

Chamberlain ATX 60 mg single dose 20; 31.6 (8.3) NR NR NR 31 NR 13/6/1 11 (55) 2007 Placebo 14/6 NR NR NR ATX=atomoxetine; NR=not reported † Crossover trial design

Pharmacological and Non-pharmacological Therapies for Adults with 91 Attention-Deficit/Hyperactivity Disorder

Table A8: Patient Characteristics of Trials Included for Psychotherapy Treatment of ADHD in Adults ADHD First No. of Age of Previous Comorbidities Employed or subtype Author, Patients; Patients ADHD Trial Arms Mean studying, n (Combined/ Personality Publication Men/ Medication (SD); (%) Inattentive/ Depression Anxiety /Mood Year Women, n (%) Range Hyperactive) Disorder Hirvikoski, Dialectical behavioural 26; 40.6 (9.4); 32 14 (53.8) 18/ 6/ 1 15 NR 7 (27%) 13 (50%) 2011 therapy 7/19 21-58

25; 37.2 (9.3); Control 13 (52%) 20/ 6/ 0 14 NR 7 (28%) 16 (62%) 12/13 23-66 Virta, Cognitive behavioural 10; 38.2; 4 (40) NR 5 6 (60%) 0 1 (10%) 201033,39 therapy 3/7 25-49 9; 32.0; Cognitive training 7 (77.8) NR 5 1 (11%) 1 (11%) 3 (33%) 7/2 21-44 9; 33.9; Hypnotherapy NR NR 7 2 (22%) 2 (22%) 1 (11%) 3/6 21-48 10; 34.0; Control 7 (70) NR 7 3 (30%) 2 (20%) 0 4/6 22-49 Safren, Cognitive behavioural 43; 34 42.3 (10.3) NR NR 43 NR NR NR 2010 therapy 24/19 43; Control 44 (12.2) NR NR 43 NR NR NR 24/19 Solanto, 45; 35 Meta-cognitive therapy 41.0 (11.6) 33 (73.3) 14/31/0 19 NR 25 (56%) 13 (28%) 2010 13/32 43; Control 42.4 (12.1) 31 (72.1) 15/28/0 20 NR 23 (53%) 15 (35%) 17/26 NR=not reported; SD=standard deviation

92 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

APPENDIX 8: Summary of Trial Results Table A9: Outcome Results of Trials Evaluating Amphetamine-based Medication for ADHD in Adults Outcomes Trial/ Drug Amphetamine Group Placebo Group Inter-group Difference Formulation Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Final - Baseline Final - Baseline (95% CI)‡ Mean(SD) Mean(SD) ADHD symptoms and general level of impairment ADHD-RS- Wigal LDX Mean(SD) percent Mean(SD) percent LSMC: NR; P<0.0001 IV 20104† optimal change change MD of percent change: dose -51.5% (24.2) -21.3% (24.4) -30.2 (SE= 3.7; -37.5, - (n=104) (n=104) 23.0)*

Kay MAS XR NR NR 13.3% (p=0.0004) more 200936 50mg/ patients with significant day score improvement (≥30 decrease from baseline) in MAX XR group compared with placebo

Alder LDX Mean Change (SD) Mean Change (SD) Placebo-adjusted LSMC 20085,51,5 30mg/ (95%CI): 2 day -16.2 (1.06) -8.2 (1.43) -8.0 (SE=0.2*; -12.1, - (n=115) (n=62) 3.9), , p<0.0001 LDX Mean Change (SD) Placebo-adjusted LSMC 50mg/ (95%CI): day -17.4 (1.05) -9.2 (SE=0.2*; -13.2,- 5.1), p<0.0001 (n=117) LDX Mean Change (SD) Placebo-adjusted LSMC 70mg/ -18.6 (1.03) (95%CI): day (n=120) -10.4 (SE=0.2*; -14.5, - 6.3), p<0.0001 Spencer TB MAS LSMC: LSMC: LSMC: 20086,53,5 ER 12.5 -14.3 (12.1) -6.3 (11.2) -8.1 (SE= 1.4*; 95% CI: - 4 – 75 (n=136) (n=132) 10.8, 5.4), p<0.0001, mg/day Weisler MAS XR -12.6 (13.7)* (n=60) Placebo-adjusted 20067 20mg (n=64) difference (95% CI) /day -6.6 (SE=2.2*; -11.0, - 2.3)

Weisler MAS XR -12.9 (12.3)* Placebo-adjusted 20067 40mg (n=64) difference (95% CI) /day -7.2 (SE=2.2*; -11.5, - 2.8)

Weisler MAS XR -14.4 (13.3)* Placebo-adjusted 20067 60mg (n=60) difference (95% CI) /day -7.8 (SE=2.2*; -12.2, - 3.4)

Weiss DEX -11.4 (10.7)* -8.7 (12.8)* MD: 20068 10 – 40 (n=23) (n=26) -2.7 (SE=3.3; -9.17, mg/day 3.77)* CGI–I; Wigal LDX 89 (76.5) patients were 27 (23.1) patients were p <0.0001 n(%) 20104 optimal rated as “very much rated as “very much dose improved” and “much improved” and “much OR: improved” (score ≤2) improved” (score ≤2) 10.9 (5.9, 20.0)*

Pharmacological and Non-pharmacological Therapies for Adults with 93 Attention-Deficit/Hyperactivity Disorder

Table A9: Outcome Results of Trials Evaluating Amphetamine-based Medication for ADHD in Adults Outcomes Trial/ Drug Amphetamine Group Placebo Group Inter-group Difference Formulation Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Final - Baseline Final - Baseline (95% CI)‡ Mean(SD) Mean(SD) (N=115) (N=117) Kay MAS XR 66.7% patients were 0.0% patients were rated NR 200936 50mg/ rated as “very much as “very much improved” day improved” and “much and “much improved” improved” (score ≤2) (score ≤2) (n NR) (n NR) Alder LDX 68 (57) patients were 29% patients were rated p<0.01 20085,51,5 30mg/ rated as “very much as “very much improved” 2 day improved” and “much and “much improved” OR: improved” (score ≤2) (score ≤2) (N=119) 3.3 (1.7,6.4)* LDX 73 (62) patients were (N=62, ITT) p<0.01 50mg/ rated as “very much day improved” and “much OR: improved” (score ≤2) (N=117) 4.1 (2.1, 7.9)* LDX 74 (61) patients were p<0.01 70mg/ rated as “very much day improved” and “much OR: improved” (score ≤2) (N=122) 3.8 (2.0, 7.3)* Spencer TB MAS 70 (51) patients were 29 (21.2) patients were OR: 20086,53,5 ER 12.5 rated as “very much rated as “very much 3.9 (2.3, 6.6)* 4 – 75 improved” and “much improved” and “much mg/day improved” (score ≤2) improved” (score ≤2) (N=137) (N=137) Weisler MAS XR 32 (50) patients were 16 (27) patients were OR: 20067 20mg/ rated as “very much rated as “very much 2.8 (1.3, 5.8)* day improved” and “much improved” and “much improved” (score ≤2) improved” (score ≤2) (N=64) (N=60) MAS XR 36 (56) patients were OR: 40mg/ rated as “very much 3.5 (1.7, 7.5)* day improved” and “much improved” (score ≤2) (N=64) MAS XR 35 (58) patients were OR: 60mg/ rated as “very much 3.9 (1.8, 8.3)* day improved” and “much improved” (score ≤2) (n=60) Weiss DEX 15 (63.6) patients were 6 (28) patients were rated OR: 20068 10 – 40 rated as “very much as “very much improved” 5.1 (1.5, 18.8) mg/day improved” and “much and “much improved” improved” (score ≤2) (score ≤2) (N=23) (N=23) Quality of lifeADHD-associated morbidities PSQI – Alder LDX - 0.8 (SE= 0.11, -0.5 (SE= 0.26, SD= 2.0) p=0.33 51 Self Rated 2008 30mg SD=2.0*) (Global /day (n=61) MD= -0.3 (0.3; -0.9, 0.3)* Score) LDX (n=341) 50mg /day LDX

94 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A9: Outcome Results of Trials Evaluating Amphetamine-based Medication for ADHD in Adults Outcomes Trial/ Drug Amphetamine Group Placebo Group Inter-group Difference Formulation Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Final - Baseline Final - Baseline (95% CI)‡ Mean(SD) Mean(SD) 70mg /day AIM-A: Q1 Spencer TB MAS 1.0(2.5)* 0.4(2.6)* MD= 0.6 (0.3; 0.01, 1.2)* 20086,53,5 ER 12.5 (n=136) (n=132) 4 – 75 mg/day AIM-A: Q4 Spencer TB MAS -0.5(1.3)* -0.1(1.4)* MD= -0.4 (0.2; -0.8, - 20086,53,5 ER 12.5 (n=136) (n=132) 0.01) 4 – 75 mg/day ADHD-associated morbidities PSQI – Alder LDX - 0.8 (SE= 0.11, -0.5 (SE= 0.26, SD= 2.0) p=0.33 51 Self Rated 2008 30mg SD=2.0*) (Global /day (n=61) MD= -0.3 (0.3; -0.9, 0.3)* Score) LDX (n=341) 50mg /day LDX 70mg /day HAM-A Weiss DEX -3.5(8.8)* -5.0(7.0) MD= 1.5 (2.3; -3.0, 6.0)* 20068 10 – 40 (n=23) (n=26) mg/day HAM-D Weiss DEX -1.6 (8.1) -3.2(5.8) MD= 1.6 (2.0; -2.3, 5.5)* 20068 10 – 40 (n=23) (n=26) mg/day Function and cognitive skills PERMP-A Wigal LDX 26.2 (55.7)* 13.1 (48.3)* LSMC : 20104 optimal (n=115) (n=117) 12.0 ( 8.1, dose SE=6.8*; 15.8), p<0.0001 PERMP-B Wigal LDX 26.4 (55.2)* 13.1(47.7)* LSMC : 20104 optimal (n=115) (n=117) 11.5 ( 7.6, dose SE=6.8*; 15.4), p<0.0001 PERMP Wigal LDX 52 (110.8)* 26.2 (96.0)* LSMC : total 20104 optimal (n=115) (n=117) 23.4 ( 15.6, dose SE=13.6*; 31.2), p<0.0001 DP – DSS Kay MAS XR Cohort I: Cohort I: Cohort I: 200936 50mg/ -0.29 (NR) 0.3 (NR) -0.59 day (n=15) (n=14) (p=0.014) GAF Weiss DEX 6.9(15.9)* 5.8(11.0) MD= 1.1 (4.0; -6.7, 8.9)* 20068 10 – 40 (n=23) (n=23) mg/day Adverse events Spencer TB MAS 1 possible transient 0 not estimable 6,53,5 2008 ER 12.5 ischemic attack 4 – 75 Number of (required mg/day Serious hospitalization; patient TEAEs was diagnosed with Tourette‟s syndrome with vocal tic

Pharmacological and Non-pharmacological Therapies for Adults with 95 Attention-Deficit/Hyperactivity Disorder

Table A9: Outcome Results of Trials Evaluating Amphetamine-based Medication for ADHD in Adults Outcomes Trial/ Drug Amphetamine Group Placebo Group Inter-group Difference Formulation Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Final - Baseline Final - Baseline (95% CI)‡ Mean(SD) Mean(SD) Wigal LDX 32 (27.8%) 42 (35.9%) OR= 0.7 (0.4, 1.2)* 4 2010 optimal (n=115) (n=117) dose Kay MAS XR 12 (75.0%) 3 (16.7%) OR= 5.6 (1.4, 22.0)* 200936 50mg/ (n=35) (n=35) day Adler LDX 90 (76%) 36 (58%) OR= 2.2 (1.2, 4.3)* 20085,51,5 30mg/ (n=119) (n=62) 2 day LDX 90 (77%) OR= 2.4(1.2, 4.7)* 50mg/ (n=117) day Total TEAEs, LDX 102 (84%) OR= 3.7 (1.8, 7.4)* no. (%) 70mg/ (n=122) day LDX all 22 severe adverse 3 severe adverse events doses events in 15 patients in 2 patients (n=358) (n=62) Spencer TB MAS 122 (89.1%) 86 (63.7%) OR= 4.66 (2.4, 9.0)* 20086,53,5 ER 12.5 (n=136) (n=132) 4 – 75 mg/day Weisler MAS XR 67 (80.7%) 24 (53.3%) OR= 3.7 (1.6, 8.2) 20067† 60mg (n=83) (n=45) /day Anxiety Wigal LDX 2 (1.7%) 0 OR= 5.1 (0.3, 109.0) 20104 optimal (n=115) (n=117) dose Kay MAS XR Cohort I: Cohort I: Cohort I: 200936 50mg/ 2 (12.5%) 0 OR= 6.4 (0.3, 143.5) day (n=16) (n=18)

Adler LDX 5 (4%) 0 OR= 6.0 (0.3, 110.4) 5,51,5 2008 30mg/ (n=119) (n=62) 2 day LDX 7 (6%) OR= 8.5 (0.5, 151.1) 50mg/ (n=117) day LDX 9 (7%) OR= 10.5 (0.6, 182.8) 70mg/ (n=122) day Spencer TB MAS 9 (6.6%) 4 (3.0%) OR= 2.3 (0.7, 7.7) 20086,53,5 ER 12.5 (n=137) (n=135) 4 – 75 mg/day Weisler MAS XR 4 (6%) 2 (3%) OR= 2 (0.4, 11.3) 20067† 20 mg (n=66) (n=64) /day MAS XR 4 (6%) OR= 2 (0.4, 11.7) 40 mg (n=64) /day MAS XR 6 (10%) OR= 3.4 (0.7, 17.5)

96 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A9: Outcome Results of Trials Evaluating Amphetamine-based Medication for ADHD in Adults Outcomes Trial/ Drug Amphetamine Group Placebo Group Inter-group Difference Formulation Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Final - Baseline Final - Baseline (95% CI)‡ Mean(SD) Mean(SD) 60 mg (n=61) /day Decreased Wigal LDX 4 (3.5%) 2 (1.7%) OR= 2.1 (0.4, 11.5) appetite 20104 optimal (n=115) (n=117) dose Adler LDX 34 (29%) 1 (2%) OR= 24.4 (3.3, 183.1) 5,51,5 2008 30mg/ (n=119) (n=62) 2 day LDX 33 (28%) OR= 24.0 (3.2, 180.0) 50mg/ (n=117) day LDX 28 (23%) OR= 18.2 (2.4, 137.0) 70mg/ (n=122) day Dry mouth Wigal LDXopti 4 (3.5%) 1 (0.9%) OR= 0.4 (0.0, 3.5) 20104 mal dose (n=115) (n=117) Kay MAS XR Cohort I: Cohort I: Cohort I: 200936 50mg/ 3 (18.8%) 0 OR= 9.6 (0.5, 201.6) day (n=16) (n=18)

Adler LDX 25 (21%) 2 (3%) OR= 8.0 (1.8, 35.0) 5,51,5 2008 30mg/ (n=119) (n=62) 2 day LDX 29 (25%) OR= 9.9 (2.3, 43.0) 50mg/ (n=117) day LDX 38 (31%) OR= 13.6 (3.2, 58.4) 70mg/ (n=122) day Spencer TB MAS 31 (22.6%) 7 (5.2%) OR= 5.3 (2.3, 12.6) 20086,53,5 ER 12.5 (n=137) (n=135) 4 – 75 mg/day Weisler MAS XR 16 (24%) 2 (5%) OR= 10.3 (2.3, 47.1) 20067† 20 mg (n=66) (n=64) /day MAS XR 28 (44%) OR= 24.1 (5.4, 107.2) 40 mg (n=64) /day MAS XR 23 (38%) OR= 18.8 (4.1, 84.1) 60 mg (n=61) /day Fatigue Wigal LDX 1 (0.9%) 14 (12.0%) OR= 0.1 (0.0, 0.5) 20104 optimal (n=115) (n=117) dose Adler LDX 9 (7.6%) 3 (4.8%) OR= 1.6 (0.4, 6.2) 5,51,5 2008 30mg/ (n=119) (n=62) 2 day LDX 5 (4.3%) OR= 0.9 (0.2, 3.8) 50mg/ (n=117) day LDX 3 (2.5%) OR= 0.5 (0.1, 2.5) 70mg/ (n=122) day

Pharmacological and Non-pharmacological Therapies for Adults with 97 Attention-Deficit/Hyperactivity Disorder

Table A9: Outcome Results of Trials Evaluating Amphetamine-based Medication for ADHD in Adults Outcomes Trial/ Drug Amphetamine Group Placebo Group Inter-group Difference Formulation Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Final - Baseline Final - Baseline (95% CI)‡ Mean(SD) Mean(SD) Headache Wigal LDX 2 (1.7%) 3 (2.6%) OR= 0.7 (0.1, 4.1) 20104 optimal (n=115) (n=117) dose Kay MAS XR Cohort I: Cohort I: Cohort I: 200936 50mg/ 2 (12.5%) 1 (5.6%) OR= 2.4 (0.2, 29.7) day (n=16) (n=18)

Spencer TB MAS 25 (18.2%) 19 (14.1%) OR= 1.7 (0.7, 2.6) 20086,53,5 ER 12.5 (n=137) (n=135) 4 – 75 mg/day Weisler MAS XR 9(14%) 8(13%) OR= 1.1 (0.4, 3.1) 20067† 20 mg (n=66) (n=64) /day MAS XR 19(30%) OR= 2.9 (1.2, 7.4) 40 mg (n=64) /day MAS XR 16(26%) OR= 2.5 (0.9, 6.3) 60 mg (n=61) /day Insomnia Wigal LDX 3 (2.6%) 2 (1.7%) OR= 1.5 (0.3, 9.4) 20104 optimal (n=115) (n=117) dose Kay MAS XR Cohort I: Cohort I: Cohort I: 200936 50mg/ 3 (18.8%) 0 OR= 9.6 (0.5, 201.6) day (n=16) (n=18) Adler LDX 23 (19%) 3 (5%) OR= 4.7 (1.4, 16.4) 5,51,5 2008 30mg/ (n=119) (n=62) 2 day LDX 20 (17%) OR= 4.0 (1.2, 14.2) 50mg/ (n=117) day LDX 26 (21%) OR= 5.3 (1.5, 18.4) 70mg/ (n=122) day Spencer TB MAS 40 (29.2%) 12 (8.9%) OR= 4.2 (2.1, 8.5) 20086,53,5 ER 12.5 (n=137) (n=135) 4 – 75 mg/day Weisler MAS XR 14(21%) 8(13%) OR= 1.9 (0.7, 4.9) 20067† 20 mg (n=66) (n=64) /day MAS XR 19(30%) OR= 2.9 (1.2, 7.4) 40 mg (n=64) /day MAS XR 16(26%) OR= 2.5 (0.9, 6.3) 60 mg (n=61) /day Nausea Wigal LDX 2 (1.7%) 0 OR= 5.2 (0.3, 109.0) 20104 optimal (n=115) (n=117) dose Kay MAS XR Cohort I: Cohort I: Cohort I: 200936 50mg/ 1 (6.3%) 1 (5.6%) OR= 1.3 (0.1, 19.7) day (n=16) (n=18)

98 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A9: Outcome Results of Trials Evaluating Amphetamine-based Medication for ADHD in Adults Outcomes Trial/ Drug Amphetamine Group Placebo Group Inter-group Difference Formulation Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Final - Baseline Final - Baseline (95% CI)‡ Mean(SD) Mean(SD) Adler LDX 10 (8%) 0 OR= 12.0 (0.7, 208.1) 5,51,5 2008 30mg/ (n=119) (n=62) 2 day LDX 7 (6%) OR= 8.5 (0.5, 151.1) 50mg/ (n=117) day LDX 8 (7%) OR= 9.3 (0.5, 163.5) 70mg/ (n=122) day Spencer TB MAS 10 (7.3%) 6 (4.4%) OR= 1.7 (0.6, 4.8) 20086,53,5 ER 12.5 (n=137) (n=135) 4 – 75 mg/day Weisler MAS XR 5(8%) 1(2%) OR= 5.2 (0.6, 45.5) 20067† 20 mg (n=66) (n=64) /day MAS XR 5(8%) OR= 5.3 (0.6, 47.0) 40 mg (n=64) /day MAS XR 6(10%) OR= 6.9 (0.8, 58.9) 60 mg (n=61) /day Anorexia Kay MAS XR Cohort I: Cohort I: Cohort I: 200936 50mg/ 8 (50.0%) 0 OR= 37 (1.9, 718.0) day (n=16) (n=18) Spencer TB MAS 7 (5.1%) 2 (1.5%) OR= 3.6 (0.7, 17.6) 20086,53,5 ER 12.5 (n=137) (n=135) 4 – 75 mg/day Weisler MAS 13(20%) 2(3%) OR= 7.6 (1.6, 35.2) 20067† XR 20 (n=66) (n=64) mg /day MAS 27(42%) OR= 22.6 (5.1, 100.7) XR 40 (n=64) mg /day MAS 23(38%) OR= 18.8 (4.2, 84.1) XR 60 (n=61) mg /day ADHD-RS-IV= ADHD Rating Scale; AIM-A= ADHD Impact Module for Adults (Q1= How would you rate the overall quality of your life right now? , Q2=How much do you agree with this statement: „Over the past few weeks, I‟ve had more good days than bad days‟? ); CGI-I= Clinical Global Impression-Improvement Scale; DP-DSS=driving performance - Driving Safety Score; GAF=Global Assessment of Functioning Scale; HAM-A= Hamilton Anxiety Rating Scale; HAM-D= Hamilton Depression Rating Scale ; LDX=lisdexamfetamine dimesylate; LSMC= least square mean change ; MAS XR= mixed amphetamine salts extended release; NR= not reported; PERMp= Permanent Product Measure of Performance; PSQI=Pittsburg Sleep Quality Index; TB MAS ER= triple-bead mixed amphetamine salts extended release; TEAE= Treatment emergent adverse event * Results were calculated from data provided in the articles according to the predefined protocol ** Serious adverse events were not specified † Adverse events reported by at least 10% of patients ‡ p-value is reported in the table if it was available in the publication

Pharmacological and Non-pharmacological Therapies for Adults with 99 Attention-Deficit/Hyperactivity Disorder

Table A10: Outcome Results of Trials Evaluating Methylphenidate-based Medication for ADHD in Adults Outcomes Trial/ Drug Methylphenidate Placebo Group Inter-group Difference Formulation Group Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Mean(SD) Mean(SD) (95% CI) ‡ ADHD symptoms and general level of impairment AISRS Biederm OROS- 62% patients had >30% 37% patients had >30% p<0.001 an MP up to improvement (n=109) improvement OR: 201013,56 1.3mg/kg (n=114) 2.84 (1.7, 4.9)*

Adler OROS- -10.6 (SE=1.1, -6.8 (SE, 1.1, SD=11.8*) p=0.012 200915 MPH up SD=11.0*) (n=116) MD= -3.8 (SE= 1.5; -6.7, - to (n=110) 0.9)* 108mg/d ay

Biederm OROS- NR NR Greater proportion of an MPH up OROS MPH patients had 200622,60 to 30% and 50% reductions 1.3mg/kg in AISRS score; /day QD p<0.001

CGI-I Wender MPH 10 78 (74) patients were 23 (22) patients were P<0.001 20119 TID up to rated as “very much rated as “very much OR: 60mg/da improved” and “much improved” and “much 10.30 (5.5, 19.5)* improved” (score ≤2) improved” (score ≤2) y (n=105) (n=105) Biederm OROS- 68 (62) patients had 42 (37) patients had p<0.001 an MP up to >30% improvement >30% improvement OR: 201013,56 1.3mg/kg (n=109) (n=114) 2.8 (1.7, 4.9)* Rosler MPH-ER, 100 (54.6) patients 24 (36.6) patients were p=0.0003 2010,37 up-to were rated as “very rated as “very much OR: Rosler 60mg/da much improved” and improved” and “much 2.1 (1.2, 3.8)* 14 “much improved” (score improved” (score ≤2) 2009 y BID ≤2) (n=66, PP) (n=183, PP) Adler OROS- 3.0 (SE, 0.11, SD=1.1*) 3.43 (SE, 0.11, SD=1.2*) p=0.008 200915 MPH up (n=103, LOCF) (n=115, LOCF) MD= 0.40 (SE=1.2; -2.0, to 2.8)* 108mg/d ay

Levin SR-MPH 18 (34) patients were 16 (30) patients were χ²=0.17, p= 0.68 200718 up to rated as “very much rated as “very much OR: 60mg/da improved” and “much improved” and “much 1.2 (0.5, 2.7)* improved” (score ≤2) improved” (score ≤2) y BID (n=53, ITT) (n=53, ITT) Spencer D-MPH- 27 (47.4) patients were 14 (26.4) patients were χ²=4.9, p= 0.027 2007;19 ER 20mg rated as “very much rated as “very much OR: QD improved” and “much improved” and “much 2.5 (1.1, 5.6)* improved” (score ≤2) improved” (score ≤2) (n=57, ITT) (n=53, ITT) D-MPH- 20 (37.0) patients were χ², p=NS ER 30mg rated as “very much OR: improved” and “much 1.6 (0.7, 3.7)*

100 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A10: Outcome Results of Trials Evaluating Methylphenidate-based Medication for ADHD in Adults Outcomes Trial/ Drug Methylphenidate Placebo Group Inter-group Difference Formulation Group Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Mean(SD) Mean(SD) (95% CI) ‡ QD improved” (score ≤2) (n=54, ITT) D-MPH- 30 (55.6) patients were χ²=9.07, p= 0.003 ER 40mg rated as “very much OR: QD improved” and “much 3.9 (1.5, 7.9)* improved” (score ≤2) (n=54, ITT) Reimher OROS- 22(54%) patients were 9(22%) patients were χ²=5.6, p= 0.018 r MPH up rated as “very much rated as “very much OR: 2007;20† to improved” and “much improved” and “much 4.1 (1.8, 10.8)* 90mg/da improved” (score ≤2) improved” (score ≤2) Robison y (n=41) (n=41) 201059†

Jain MLR- NR NR p<0.005 200721† MPH up to 80mg/da y QD

Biederm OROS- NR NR Greater proportions of an MPH up OROS MPH patients had 200622,60 to CGI-I “very much 1.3mg/kg improved” and “much /day QD improved χ²=12.8, p= 0.01 Levin SR-MPH, 6 (9) patients had score 13 (39) patients had χ²=3.34, p= 0.19 200623 up to <3 score <3 OR: 80mg/da (n=32) (n=33) 0.36 (0.1, 1.1)* y BID CGI-S Medori PR- -0.9 (95%CI: -1.2, -0.7) -0.5 (95%CI: -0.69, -0.32) p=0.003 200817 OROS- (n=97) (n=93) MD= -0.4 (SE= 0.2; -0.8, - MPH 0.0)* 18mg/da y PR- -0.9 (95%CI: -1.1, -0.7) p=0.005 OROS- (n=100) MD= -0.4 (SE= 0.1, -0.6, - MPH 0.2)* 36mg/da y

PR- -1.2 (95%CI: -1.5, -1.0) p<0.001 OROS- (n=98) MD= -0.7 (SE=0.2, -1.1, - MPH 0.3)* 72mg/da y

Spencer D-MPH- 68.4% patients had a 41.5% patients had a χ²=6.75, p= 0.009 ER 20mg decline in CGI-S score decline in CGI-S score at OR: at final visit final visit

Pharmacological and Non-pharmacological Therapies for Adults with 101 Attention-Deficit/Hyperactivity Disorder

Table A10: Outcome Results of Trials Evaluating Methylphenidate-based Medication for ADHD in Adults Outcomes Trial/ Drug Methylphenidate Placebo Group Inter-group Difference Formulation Group Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Mean(SD) Mean(SD) (95% CI) ‡ 200719 QD (n=57, ITT) (n=53, ITT) 3.1 (1.4, 6.7)*

D-MPH- 61.1% patients had a χ², p=NS ER 30mg decline in CGI-S score OR: QD at final visit 2.2 (1.0, 4.8)* (n=54, ITT) D-MPH- 64.8% patients had a χ²=4.63, p= 0.031 ER 40mg decline in CGI-S score OR: QD at final visit 2.6 (1.2, 5.7)* (n=54, ITT) Chronis- OROS- -1.1 (1.1) -0.2(0.8) MD= -0.9 (SE=0.3; -16.4, Tuscano MPH (n=23) (n=23) -3.4)* 200816 maximal effective dose

ADHD-RS- Spencer D-MPH- -13.7 (95%CI: -36.8, - -7.9 (95%CI: -37.5, -29.6) p=0.006 IV 200719 ER 20mg 23.1) (n=53, ITT) MD= -5.8 (SE=4.0; -13.6, QD 2.0)*

D-MPH- -13.4 (95%CI: -36.9, - p=0.012 ER 30mg 23.5) MD= -5.5 (SE=4.0; -13.3, QD 2.3)*

D-MPH- -16.9 (95%CI: -36.9, - p=0.001 ER 40mg 20.0) MD= -9.0 (SE=4.8; -18.4, QD 0.4)*

Reimher OROS- -14.8 (14.6) -4.9 (15.1) p=0.003, Cohen‟s d=0.69 r MPH up (n=41) (n=41) MD= -9.9 (SE=3.3; -16.4, 2007;20† to -3.4)* 90mg/da Robison y 201059†

WRAADD Wender MPH 10 -9.6 (8.3) -1.6 (7.6) p<0.0001, Effect size = S 20119 TID up to (n=105) (n=105) 0.86 60mg/da MD= -8 (SE=1.1; -10.2, - y 5.8)*

Retz MPH ER -13.8 (NR) -6.2 (NR) MD: 201010 up to (n=84, ITT) (n=78, ITT) -6.8 (SE=1.8*; -3.2, -10.4) 1mg/kg/ day

Reimher OROS- -9.5 (8.2) -3 (7.2) p<0.001 r MPH up (n=41) (n=41) MD= -6.5 (SE= 1.7; -9.8, - 2007;20† to 3.2)* 90mg/da Robison y

102 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A10: Outcome Results of Trials Evaluating Methylphenidate-based Medication for ADHD in Adults Outcomes Trial/ Drug Methylphenidate Placebo Group Inter-group Difference Formulation Group Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Mean(SD) Mean(SD) (95% CI) ‡ 201059†

Rosler MPH-ER, NR NR p=0.04, Effect size= 0.39 2010;37 up-to Rosler 60mg/da 200914 y BID

CAARS-O Konsteni OROS- -3.9 (11.9) -4.0 (13.8) p=0.69 us MPH up (n=12, ITT) (n=12, ITT) MD= 0.1 (SE= 5.3; -10.3, 201011 to 72mg 10.5)* BID

Medori PR- -10.6 (95%CI: -12.7, - -7.6 (95%CI: -9.6, -5.6) p=0.015 2008;17 OROS- 8.6) (n=95) MD= -3 (SE= 1.5; -5.9, - MPH (n=99) 0.1)* Rosler 18mg/da 58 2011; y PR- -11.5 (95%CI: -13.4, - p=0.013 Buitelaar OROS- 9.5) MD= -3.9 (SE= 1.4; -6.6, - 57 MPH (n=101) 1.2)* 36mg/da y

PR- -13.7 (95%CI: -15.9, - p<0.001 OROS- 11.5) MD= -6.1 (SE= 1.5; -9.0, - MPH (n=99) 3.2)* 72mg/da y

Jain MLR- -10.9 (13.4)* -6.6 (13.7)* MD= -4.3 (SE=3.1; -10.4, 200721 MPH up (n=38, PP) (n=39, PP) 1.8)* to

ADHD-associated morbidities Konsteni OROS- -6.9 (9.8) -0.4 (6.0) p=0.138 us MPH up (n=12) (n=12) MD= -6.5 (3.3; -13.0, - BDI-II 201011 to 72mg 0.03)* BID

Konsteni OROS- -0.5 (6.4) -3.4 (4.1) p=0.098 us MPH up (n=12) (n=12) MD= 2.9 (2.2; -1.41, 7.2)* BAI 201011 to 72mg BID

Rosler MPH-ER, -3.8 (4.8)* -2.7 (5.3)* p=0.003, Effect size= ELS – 2010;37 up-to (n=241) (n=118) 0.35 from Rosler 60mg/da MD= -1.1 (0.6; -2.3, 0.1)* CAARS- 14 S:L 2009 y BID

Pharmacological and Non-pharmacological Therapies for Adults with 103 Attention-Deficit/Hyperactivity Disorder

Table A10: Outcome Results of Trials Evaluating Methylphenidate-based Medication for ADHD in Adults Outcomes Trial/ Drug Methylphenidate Placebo Group Inter-group Difference Formulation Group Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Mean(SD) Mean(SD) (95% CI) ‡ Biederm OROS- -0.8 (4.9)* -1.1 (3.3)* χ²=0.23, p= 0.6 an MPH up (n=67) (n=74) MD=0.3(0.7; -1.1, 1.7)* 200622 to HAM-A 1.3mg/kg /day QD

Biederm OROS- -1.4 (5.3)* -1.4 (4.2)* χ²=0.03, p= 0.9 an MPH up (n=67) (n=74) MD = 0.0 (0.8; -1.6, 1.6)* HAM-D 200622 to 1.3mg/kg /day QD Function and cognitive skills SDS Retz MPH ER -6.9 (NR) -3.1 (NR) standardized effect size = 201010 up to (n=84) (n=78) 0.40 1mg/kg/ p=0.017 day

Verster MPH (10- NR NR NS IWR 12,55 2010 30mg) Verster MPH (10- NR NR p<0.017; DWR 201012,55 30mg) When adjusted to CES-D score p<0.174 GAF Spencer D-MPH- 11.1 (NR) 5.4 (NR) p<0.001 200719 ER 20mg (n=58) (n=53) QD

D-MPH- 8.7 (NR) p=0.004 ER 30mg (n=55) QD D-MPH- 11.3 (NR) p=0.003 ER 40mg (n=55) QD Adverse events Patients Adler OROS- 93 (84.5) 74 (63.8) OR= 3.1 (1.6, 5.9)* with at 200915 MPH up least one to (n=110) (n=116) adverse 108mg/d event, n(%) ay Medori PR- 237 (77.7) 63 (65.6) OR= 1.8 (1.1, 3.0)* 200817 OROS- MPH 18, (n=305) (n=96) 36, or 72mg/da y Nausea, Wender MPH 10 4 (4) 0 (0) OR= 9.4 (0.5, 176.0)* n(%) 20119 TID up to 60mg/da (n=105) (n=105) y Retz MPH ER 14 (17) 3 (4) OR= 5.0 (1.4, 18.1)* 201010 up to

104 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A10: Outcome Results of Trials Evaluating Methylphenidate-based Medication for ADHD in Adults Outcomes Trial/ Drug Methylphenidate Placebo Group Inter-group Difference Formulation Group Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Mean(SD) Mean(SD) (95% CI) ‡ 1mg/kg/d (n=84) (n=78) ay Adler OROS- 14 (12.7) 3 (2.6) OR= 5.5 (1.5, 19.7)* 200915 MPH up to (n=110) (n=116) 108mg/d ay Medori PR- 39 (12.8) 4 (4.2) OR= 3.4 (1.2, 9.7)* 2008;17 OROS- MPH 18, (n=305) (n=96) Buitelaar 36, or ;57 72mg/da y Rosler58 Reimher OROS- 4 (9.3) 2 (4.6) OR= 2.1 (0.4, 12.1)* r MPH 18- 90 (n=43) (n=43) 2007;20 mg/day

Robison5 9 Jain MLR- 8 (16.0) 4 (8.0) p=0.25 200721† MPH up to (n=50) (n=50) OR= 2.2 (0.6, 7.8)* 80mg/da y QD Rosler MPH-ER, 22 (9) 4 (3) OR= 2.9 (1.0, 8.5)* 2010;37 up-to Rosler 60mg/da (n=241) (n=118) 200914 y BID Dry Wender MPH 10 6 (6) 1 (1) OR= 6.3 (0.8, 53.3)* mouth, 20119 TID up to n(%) 60mg/da (n=105) (n=105) y Retz MPH ER 32 (38) 11 (14) OR= 3.8 (1.7, 8.1)* 201010 up to 1mg/kg/d (n=84) (n=78) ay Rosler MPH-ER, 72 (30) OR= 2.2 (1.3, 3.9)* 2010;37 up-to Rosler 60mg/da (n=241) 19 (16) 200914 y BID (n=118) Adler OROS- 22 (20.0) 6 (5.2) OR= 4.6 [1.8, 11.8)* 2009;15 MPH up to (n=110) (n=116) 108mg/d ay

Pharmacological and Non-pharmacological Therapies for Adults with 105 Attention-Deficit/Hyperactivity Disorder

Table A10: Outcome Results of Trials Evaluating Methylphenidate-based Medication for ADHD in Adults Outcomes Trial/ Drug Methylphenidate Placebo Group Inter-group Difference Formulation Group Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Mean(SD) Mean(SD) (95% CI) ‡ Medori PR- 36 (11.8) 2 (2.1) OR= 6.3 (1.5, 26.6)* 2008;17 OROS- MPH 18, (n=305) (n=96) Buitelaar 36, or ;57 72mg/da y Rosler58 Spencer d-MPH- 26 (15.8) 2 (3.8) OR= 2.8 (0.6, 12.1)* 200719 ER 20-40 mg/day (n=165) (n=53) Jain MLR- 6 (12.0) 1 (2.0) p=0.06 2007;21† MPH up to (n=50) (n=50) OR= 6.7 (0.8, 57.7)* 80mg/da y QD Biederm OROS- 23 (34) 5 (7) χ²=16.8, p<0.001 an MPH up 2006;22 to (n=67) (n=74) OR= 7.2 (2.6, 20.4)* 1.3mg/kg /day QD Decreased Wender MPH 10 8 (8) 1 (1) OR= 8.6 (1.1, 69.9)* appetite, 20119 TID up to n(%) 60mg/da (n=105) (n=105) y Retz MPH ER 40 (48) 8 (10) OR= 8.0 (3.4, 18.6)* 201010 up to 1mg/kg/d (n=84) (n=78) ay Biederm OROS- 26 (24) 6 (5) OR= 5.6 (2.2, 14.3)* an MP up to 13 2010 1.3mg/kg (n=109) (n=114) Adler OROS- 28 (25.5) 7 (6.0) OR= 5.3 (2.2, 12.8)* 200915 MPH up to (n=110) (n=116) 108mg/d ay Medori PR- 77 (25.2) 7 (7.3) OR= 4.3 (1.9, 9.7)* 2008;17 OROS- Buitelaar MPH 18, (n=305) (n=96) ;57 36, or Rosler58 72mg/da y Spencer d-MPH- 30 (18.2) 6 (11.3) OR= 1.7 (0.7, 4.4)* 200719 ER 20-40 mg/day (n=165) (n=53) Biederm OROS- 23 (34) 2 (3) χ²=24.1, p< 0.001 an MPH up 200622 to

106 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A10: Outcome Results of Trials Evaluating Methylphenidate-based Medication for ADHD in Adults Outcomes Trial/ Drug Methylphenidate Placebo Group Inter-group Difference Formulation Group Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Mean(SD) Mean(SD) (95% CI) ‡ 1.3mg/kg (n=67) (n=74) OR= 18.8 (4.2, 83.7)* /day QD Rosler MPH-ER, 92 (38) OR= 4.2 (2.3, 7.7)* 2010;37 up-to Rosler 60mg/da (n=241) 15 (13) 200914 y BID (n=118) Reimher OROS- 5 (12) 0 (0) OR= 63.8 (3.1, r MPH 18- 1277.6)* 90 (n=43) (n=43) 2007;20 mg/day

Robison5 9 Headache, Wender MPH 10 7 (7) 4 (4) OR= 1.8 (0.5, 6.4)* n(%) 20119 TID up to 60mg/da (n=105) (n=105) y Retz MPH ER 25 (30) 13 (17) OR= 2.1 (1.0, 4.5)* 201010 up to 1mg/kg/d (n=84) (n=78) ay Biederm OROS- 29 (27) 23 (20) OR= 1.4 (0.8, 2.7)* an MP up to 13 2010 1.3mg/kg (n=109) (n=114) Adler OROS- 28 (25.5) 16 (13.8) OR= 2.1 (1.1, 4.2)* 200915 MPH up to (n=110) (n=116) 108mg/d ay Medori PR- 64 (21.0) 17 (17.7) OR= 1.2 (0.7, 2.2)* 2008,17 OROS- Buitelaar MPH 18, (n=305) (n=96) ,57 36, or Rosler58 72mg/da y Levin SR-MPH 4 (8) 1 (2) OR= 4.2 (0.5, 39.3)* 200718 up to 60mg/da (n=53) (n=53) y BID Spencer d-MPH- 52 (31.5) 10 (18.9) OR= 2.0 (0.9, 4.2)* 200719 ER 20-40 mg/day (n=165) (n=53) Reimher OROS- 4 (9.3) 6 (14) OR= 0.6 (0.2, 2.4)* r MPH 18- 90 (n=43) (n=43) 2007;20 mg/day

Pharmacological and Non-pharmacological Therapies for Adults with 107 Attention-Deficit/Hyperactivity Disorder

Table A10: Outcome Results of Trials Evaluating Methylphenidate-based Medication for ADHD in Adults Outcomes Trial/ Drug Methylphenidate Placebo Group Inter-group Difference Formulation Group Treatment - Control Intra-group Difference Intra-group Difference MD (SE; 95% CI) / OR Mean(SD) Mean(SD) (95% CI) ‡ Robison5 9 Jain MLR- 13 (26.0) 12 (24.0) p=0.81 200721† MPH up to (n=50) (n=50) OR= 1.1 (0.5, 2.8)* 80mg/da y QD Biederm OROS- 21 (31) 22 (30) χ²=0.04, p=0.8 an MPH up 200622 to (n=67) (n=67) OR= 0.9 (0.5, 1.9)* 1.3mg/kg / day QD ADHD-RS-IV=ADHD Rating Scale; AISRS= Adult ADHD Investigator Symptom Rating Scale; BAI=Beck Anxiety Inventory; BDI-II=Beck Depression Inventory; BID=twice daily; CAARS-O= Conners Adult ADHD Rating Scale-Observer; CGI-I=Clinical Global Impression- Improvement Scale; CGI-S=Clinical Global Impression-Severity Scale; CI=confidence interval; CMH= Cochrane-Mantel Haenszel; DWR= Delayed word recall ; ELS=Emotional Liability Scale; GAF=Global Assessment of Functioning Scale; HAM-A=Hamilton Anxiety Rating Scale; HAM-D=Hamilton Depression Rating Scale; IWR= Immediate word recall; LOCF= last observation carried forward; MD=mean difference; MPH= methylphenidate; NR= not reported; OR=odds ratio; QD=once per day;SD=standard deviation; SDS=Sheehan Disability Scale; WRAADDS=Wender-Reimherr Adult Attention Deficit Disorder Scale * Results were calculated from data provided in the articles according to the predefined protocol † Crossover trial design ‡ p-value is reported in the table if it was available in the publication

Table A11: Outcome Results of Trials Evaluating Atomoxetine-based Medication for ADHD in Adults Outcomes Trial/ Drug Atomoxetine Group Placebo Group Inter-group Difference Formulation Treatment - Control Intra-group Difference Intra-group Difference MD(SE; 95% CI) / OR(95% Mean(SD) Mean(SD) CI) ‡ ADHD symptoms and general level of impairment AISRS Young ATX -13.7 (12.5) -8.0 (11.0) LSMC : p<0.0001 24 2011 ** 60-100 (n=263) (n=232) MD= -5.7 (SE=1.1; -7.9, - mg/day 3.5)* Brown ATX -14.1 (13.3) -10.5 (12.7) p=0.002 38 2011, Up to (n=242) (n=246) MD= -3.6 (SE=1.2; -6.0, - Adler 100 1.3)* 2009a25 mg/day Wilens ATX -13.6 (11.4) -8.3 (11.4) p=0.007 29 2008 Up to (n=72) (n=75) MD=-5.3 (SE= 1.9; -9.0, - 100 1.6)* mg/day ADHD-RS- Kay ATX 40% (n=8) in cohort II 25% (n=8) in cohort II Cohort II: p=0.4 36 IV 2009 80mg/ patients had score patients had score OR: day reduction≥30% reduction≥30% 1.8 (0.2, 15.4)* Barkley ATX <0.041 <0.006 NS 200730† (0.6- MD=-4.7 (SE=4.9; -14.3, 1.2mg/ 4.9)* kg) CAARS- Young ATX -14.3 (11.8) -8.3 (11.0) LSMC : p<0.0001 Inv:SV 201124** 60-100 (n=263)

108 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A11: Outcome Results of Trials Evaluating Atomoxetine-based Medication for ADHD in Adults Outcomes Trial/ Drug Atomoxetine Group Placebo Group Inter-group Difference Formulation Treatment - Control Intra-group Difference Intra-group Difference MD(SE; 95% CI) / OR(95% Mean(SD) Mean(SD) CI) ‡ mg/day (n=232) MD= -6 (SE= 1.0; -8.0, - 4.0)* Brown ATX -7.3 (8.2) -5.0 (7.3) LOCF: p=0.001 38 2011, Up to (n=242) (n=246) MD= -2.2 (SE=0.7; -3.6, - Adler 100 0.8)* 200925 mg/day Adler ATX -8.7 (10.0) -5.6 (10.2) LOCF: p<0.001 27 2009 Up to (n=171) (n=158) MD= -3.1, (SE=1.1; -5.3, - 100 0.9)* mg/day Adler ATX up -11.6 (NR) -11.5 (NR) p=NS 28 2008 to 100 (n=185) (n=109) MD= -0.1* mg/day CGI-I Kay ATX 13.3% (n=8) in cohort II 6.3% (n=8) in cohort II Cohort II: p=0.533 36 2009 † 80mg/ patients were rated as patients were rated as OR: day “very much improved” “very much improved” 1.00 (0.05, 19.36)* and “much improved” and “much improved” (score ≤2) (score ≤2) CGI-S Young ATX -1.2 (1.2) -0.7 (1.0) LSMC : p<0.0001 24 2011 ** 60-100 (n=263) (n=232) MD= -0.5 (SE= 0.1; -0.7, - mg/day 0.3)* Brown ATX -1.2 (1.2) -0.9 (1.2) p=0.010 38 2011, Up to (n=242) (n=246) MD= -0.3 (SE=0.1; -0.5, - Adler 100 0.1)* 200925 mg/day McRae- ATX -1.2 (1.13) -0.89 (1.3) MD=0.337 (SE=0.4; 1.1, Clark Up to (n=19) (n=19) 0.45)* 201026 100 mg/day Wilens ATX -1.0 (1.2) -0.7 (1.1) p=0.048 29 2008 Up to (n=72) (n=75) MD=-0.3 (SE=0.2; -0.7, 100 0.1)* mg/day Adler ATX -0.76 (1.1) -0.6 (1.0) p=0.02 27 2009 Up to (n=171) (n=158) MD= -0.2 (SE=0.1; -0.4, - 100 0.0)* mg/day Adler ATX -2.8 (NR) -2.9 (1.0) p=0.456 28 2008 Up to (n=185) (n=109) MD= 0.1 100 mg/day WRAADD McRae- ATX -15.1 (11.0) -11.1 (7.6) p= 0.23 S Clark Up to (n=19) (n=19) MD= -4.0 (SE=3.1; -10.1, 26 2010 100 2.1)* mg/day Quality of life AAQoL Brown ATX 13.1 (16.1) 8.6 (16.9) p=0.005 2011,38 Up to (n=242) (n=242) MD= 4.5 (1.5; 1.6, 7.4)* Adler 100 200925 mg/day

Pharmacological and Non-pharmacological Therapies for Adults with 109 Attention-Deficit/Hyperactivity Disorder

Table A11: Outcome Results of Trials Evaluating Atomoxetine-based Medication for ADHD in Adults Outcomes Trial/ Drug Atomoxetine Group Placebo Group Inter-group Difference Formulation Treatment - Control Intra-group Difference Intra-group Difference MD(SE; 95% CI) / OR(95% Mean(SD) Mean(SD) CI) ‡ Adler ATX 14.9 (17.1) 11.1 (15.0) p=0.03 27 2009 Up to MD= 3.8 (1.8; 0.3, 7.3)* 100 mg/day Adler ATX 13.9 (NR) 11.2 (NR) p=NS 28 2008 Up to MD= 2.7* 100 mg/day ADHD-associated morbidities LSAS Adler ATX -22.9 (25.3) -14.4 (20.3) p=<0.001 27 2009 Up to MD= -8.5 (2.5; -13.4, -3.6)* 100 mg/day Function and cognitive skills EWPS Adler ATX -16.2 (18.4) -15.6 (16.0) p=0.41 28 2008 Up to (n=271) (n=139) MD= -0.6(1.8; -4.1, 2.9)* 100 mg/day Stop- ATX 60 185.8 (59.6) 235.1 (73.9) p=0.021 Chamber signal: mg (n=20) (n=20) MD= -49.3 (SE=21.2; - lain SSRT single 90.9, -7.8)* 200731† (msec) dose

Rapid 0.6 (0.2) 0.7 (0.3) p=0.4 visual (n=20) (n=20) MD= -0.1 (SE=0.1; -0.3, ATX 60 informatio Chamber 0.1)* mg n lain processin single 200731† g: dose proportion of targets detection Spatial 18.9 (15.2) 22.7 (13.3) p=0.2 ATX 60 working Chamber (n=20) (n=20) MD= -3.8 (SE=4.5; -12.6, mg memory: lain 5.0)* Total single 200731† between- dose search errors Adverse Events Patients Adler ATX 183 (86.3) 167 (79.1) p=0.05 27 with at 2009 Up to (n=212) (n=211) OR= 1.7 (1.0, 2.8)* least one 100 adverse mg/day event, McRae- ATX 19 (100) 16 (84) RR (95% CI): n(%) Clark Up to (n=19) (n=19) 1.19 (0.98, 1.44) 201026 100 mg/day Nausea, Young ATX 91 (34.2) 17 (7.3) Fisher exact test: n(%) 201124 60-100 (n=266) (n=234) p<0.001 mg/day OR= 6.6 (3.8, 11.6)*

110 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A11: Outcome Results of Trials Evaluating Atomoxetine-based Medication for ADHD in Adults Outcomes Trial/ Drug Atomoxetine Group Placebo Group Inter-group Difference Formulation Treatment - Control Intra-group Difference Intra-group Difference MD(SE; 95% CI) / OR(95% Mean(SD) Mean(SD) CI) ‡ Brown ATX 79 (32) 22 (9) Fisher exact test: 2011,38 Up to (n=243) (n=248) p<0.001 Adler 100 OR= 5.0 (3.0, 8.3)* 200925 mg/day Adler ATX 34 (16.0) 16 (7.6) p=0.01 27 2009 Up to (n=212) (n=211) OR= 2.3 (1.2, 4.7)* 100 mg/day Wilens ATX 31 (43.3) 7 (9.6) p=<0.001 29 2008 25-100 (n=72) (n=75) OR= 7.3 (3.0, 18.2)* mg/day Dry Young ATX 69 (25.9) 11 (4.7) Fisher exact test: mouth, 201124 60-100 (n=266) (n=234) p<0.001 n(%) mg/day OR= 7.1 (3.7, 13.8)* Brown ATX 67 (28) 19 (8) Fisher exact test: 2011,38 Up to (n=243) (n=248) p<0.001 Adler 100 OR= 4.6 (2.7, 7.9)* 200925 mg/day McRae- ATX 3 (16) 3 (16) RR (95% CI): Clark Up to (n=19) (n=19) 1.00 (0.23, 4.34) 201026 100 mg/day Adler ATX 33 (15.6) 9 (4.3) p<0.001 27 2009 Up to (n=212) (n=211) OR= 4.1 (1.9, 8.9)* 100 mg/day Wilens ATX 19 (26.9) 8 (11.0) p=0.018 29 2008 25-100 (n=72) (n=75) OR= 3.0 (1.2, 7.4)* mg/day Decreased Young ATX 53 (19.9) 10(4.3) Fisher exact test: appetite, 201124 60-100 (n=266) (n=234) P<0.001 n(%) mg/day OR= 5.6 (2.8, 11.2)* Brown ATX 33 (14) 7 (3) Fisher exact test: 2011,38 Up to (n=243) (n=248) p<0.001 Adler 100 OR= 5.4 (2.3, 12.5)* 200925 mg/day Adler ATX 22 (10.4) 12 (5.7) p=0.11 27 2009 Up to (n=212) (n=211) OR= 1.9 (0.9, 4.0)*] 100 mg/day Wilens ATX 13 (17.9) 2 (2.7) p=0.004 29 2008 25-100 (n=72) N=75 OR= 8.04 (1.8, 37.0)* mg/day Headache, Young ATX 52 (19.5) 57 (24.4) Fisher exact test: n(%) 201124 60-100 (n=266) (n=234) p=0.232 mg/day OR= 0.8 (0.5, 1.2)* Brown ATX 38 (16) 40 (16) Fisher exact test: 2011,38 Up to (n=243) (n=248) p=0.902 Adler 100 OR= 1.0 (0.6, 1.6)* 200925 mg/day McRae- ATX 7 (37) 5 (26) RR (95% CI): Clark Up to (n=19) (n=19) 1.4. (0.54, 3.64) 201026 100

Pharmacological and Non-pharmacological Therapies for Adults with 111 Attention-Deficit/Hyperactivity Disorder

Table A11: Outcome Results of Trials Evaluating Atomoxetine-based Medication for ADHD in Adults Outcomes Trial/ Drug Atomoxetine Group Placebo Group Inter-group Difference Formulation Treatment - Control Intra-group Difference Intra-group Difference MD(SE; 95% CI) / OR(95% Mean(SD) Mean(SD) CI) ‡ mg/day Adler ATX 43 (20.3) 30 (14.2) p=0.12 27 2009 Up to (n=212) (n=211) OR= 1.5 (0.9, 2.6)* 100 mg/day Fatigue, Young ATX 36 (13.5) 20 (8.5) Fisher exact test: n(%) 201124 60-100 (n=266) (n=234) p=0.089 mg/day OR= 1.7 (0.9, 3.0)* Brown ATX 38 (16) 20 (8) Fisher exact test: 2011,38 Up to (n=243) (n=248) p=0.011 Adler 100 OR= 2.1 (1.2, 3.8)* 200925 mg/day Adler ATX 13 (6.1) 12 (5.7) p=1.00 27 2009 Up to (n=212) (n=211) OR= 1.1 (0.5, 2.4)* 100 mg/day Wilens ATX 10 (13.4) 2 (2.7) p=0.026 29 2008 25-100 (n=72) (n=75) OR= 5.9 (1.2, 27.9)* mg/day AAQoL=Adult ADHD Quality of Life Measure; ADHD-RS-IV=ADHD Rating Scale; AISRS=Adult ADHD Investigator Symptom Rating Scale; ATX= atomoxetine; CAARS-S=Conners Adult ADHD Rating Scale-Self report; CGI-I=Clinical Global Impression-Improvement Scale; CGI-S=Clinical Global Impression-Severity Scale; EWPS=Endicott Work Productivity Scale; LOCF= last observation carried forward; LSAS=Liebowitz Social Anxiety Scale; LSMC=least square mean change; NR= not reported; WRAADDS=Wender-Reimherr Adult Attention Deficit Disorder Scale * Results were calculated from data provided in the articles according to the predefined protocol † Crossover trial design ‡ p-value is reported in the table if it was available in the publication

Table A12: Outcome Results of the Psychotherapy Trials for ADHD in Adults Inter-group Difference Trial/ Psychotherapy Control Treatment - Control Outcomes Psychological Intra-group Difference Intra-group Difference MD (SE; 95% CI) / Intervention Mean (SD) Mean (SD) OR(95% CI) Symptoms and general level of impairment ADHD-RS- Safren -11.9 (10.4)* -6.1 (11.0)* 34 CBT MD= -5.8 (2.3; -10.3, -1.3)* IV 2010 (n=43) (n=43) CAARS-O Solanto -5.7 (-3.1,-8.3) -0.9 (-2.0,-3.9) 35 MCT MD= -4.8 (2.0; -8.7, -0.88)* 2010 (n=34) (n=27) CGI-S Safren -1.5 (1.02) -0.9 (1.1) MD= -0.6 (0.2; -0.99, - 34 CBT 2010 (n=43) (n=43) 0.21)* CGI-I Virta 70% patients were rated 201033,39 as “very much improved” CBT and “much improved” OR: 5.4 (0.8, 36.9)* (score ≤2) 30% patients were (n=10) rated as “very much 22% patients were rated improved” and “much as “very much improved” improved” (score ≤2) CT and “much improved” (n=10) OR: 0.7 (0.1, 5.3)* (score ≤2) (n=9) Hypno- 67% patients were rated OR: 4.7 (0.7, 32.7)*

112 Pharmacological and Non-pharmacological Therapies for Adults with Attention-Deficit/Hyperactivity Disorder

Table A12: Outcome Results of the Psychotherapy Trials for ADHD in Adults Inter-group Difference Trial/ Psychotherapy Control Treatment - Control Outcomes Psychological Intra-group Difference Intra-group Difference MD (SE; 95% CI) / Intervention Mean (SD) Mean (SD) OR(95% CI) therapy as “very much improved” and “much improved” (score ≤2) (n=9) Quality of life General Hirvikoski NR NR p< 0.05 32 DBT well being 2011 (n=26) (n=25) Q-LES-Q Virta -5.2 (14.9)* -4.8 (21.3)* MD= -0.4 (SE= 8.2; -16.5, 33,39 CBT 2010 (n=10) (n=10) 15.7)* -4.9 (16.6)* MD= -0.1 (SE= 8.5; -16.8, CT (n=10) 16.6)* -7.2 (17.9)* MD= -2.4 (SE= 9.0; -20.0, HT (n=9) 15.2)* ADHD-associated morbidities BDI-II Solanto Least Squares Mean Least Squares Mean MD= 0.5 (SE= 1.4; -2.2, 201035 Change: Change: 3.2)* MCT -1.8 (-3.7, 0.1) -2.3 (-4.3, -0.3) (n=41) (n=40) HAM-A Solanto Least Squares Mean Least Squares Mean MD= -1.4 (SE= 1.1; -3.7, 201035 Change: Change: 0.8)* MCT -1.2 (-2.7, 0.2) 0.2 (-1.3, 1.7) (n=41) (n=40) RSEI Solanto Least Squares Mean Least Squares Mean MD= 0.0 (SE= 0.9; -1.8, 201035 Change: Change: 1.8)* MCT 1.3 (-0.0, 2.6) 1.3 (-0.1, 2.7) (n=41) (n=40) ADHD-RS-IV=ADHD Rating Scale; BDI-II=Beck Depression Inventory; CAARS-O=Conners Adult ADHD Rating Scale-Observer; CBT=cognitive behavioural therapy; CGI-I=Clinical Global Impression-Improvement Scale; CGI-S=Clinical Global Impression-Severity Scale; CT=cognitive therapy; DBT= Dialectical behavioural therapy; HAM-A=Hamilton Anxiety Rating Scale; HT= Hypnotherapy; MCT=meta-cognitive therapy; OR=odds ratio; RSEI=Rosenberg Self Esteem Inventory * Results were calculated from data provided in the articles according to the predefined protocol

Pharmacological and Non-pharmacological Therapies for Adults with 113 Attention-Deficit/Hyperactivity Disorder

APPENDIX 9: Psychotherapeutic Interventions for the Treatment of ADHD in Adults Hirvikoski T, Waaler E, Alfredsson J, Pihlgren C, Holmstrom A, Johnson A, et al. Reduced ADHD symptoms in adults with ADHD after structured skills training group: Results from a randomized controlled trial. Behaviour Research & Therapy. 2011 Mar;49(3):175-85.

Dialectical Behavioural Therapy (DBT)

Fourteen sessions of two-hour group therapy (four to eight patients per group) were chaired by two clinical psychologists. The sessions covered the following themes: clarification of ADHD symptoms; neurobiology and mindfulness; homework; dysfunctional behaviour/behaviour analysis; emotion regulation; depression/medication in ADHD; impulse control; stress management; chaos and control; dependency (e.g., substance abuse and other risk behaviours); ADHD in relationships/self-respect; and retrospect and outlook.

Control group

Fourteen sessions of two-hour group therapy in the form of a loosely structured discussion, supported by two clinical psychologists. Participants chose and discussed an ADHD-related theme at each session.

Virta M, Salakari A, Antila M, Chydenius E, Partinen M, Kaski M, et al. Short cognitive behavioral therapy and cognitive training for adults with ADHD - a randomized controlled pilot study. Neuropsychiatric Disease & Treatment [Internet]. 2010 [cited 2011 Mar 29];6:443-53. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938293/pdf/ndt-6-443.pdf

Cognitive behavioural therapy (CBT)

Ten weekly sessions of one-hour therapy were led by a psychologist. The sessions were semi- structured to allow individual treatment, and covered the following areas: goals and symptoms of ADHD; attention; motivation and initiation of activities; organization and planning; stress management and relaxation; self-esteem; individually chosen topics (e.g., memory techniques, managing impulsivity); and continuation of the process and ending the rehabilitation.

Cognitive training (CT)

Twenty sessions (two per week) of one hour each were led by a psychologist. Participants completed tasks on a computer, and received immediate feedback, then discussed feedback with the psychologist. The tasks were as follows: continuous performance tasks; digit search; circle-letter sequences; continuous performance task and a simultaneous task; digit arrangement; alternating rules; digit-letter search; counting while reading; and circle sequences.

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Hypnotherapy

Ten weekly sessions of 40 to 60 minutes were led by a psychologist. Some sessions were individually tailored. The following themes were covered: stillness/calming; motivation to change; attention; initiation of activities; memory; self-esteem; individually chosen topics; andcontinuation of the process and ending the rehabilitation.

Control group

The control group did not receive any treatment.

Safren SA, Sprich S, Mimiaga MJ, Surman C, Knouse L, Groves M, et al. Cognitive behavioral therapy vs relaxation with educational support for medication-treated adults with ADHD and persistent symptoms: a randomized controlled trial. JAMA [Internet]. 2010 Aug 25 [cited 2011 Mar 29];304(8):875-80. Available from: http://jama.ama- assn.org/content/304/8/875.full.pdf+html

Cognitive behavioural therapy

Twelve group sessions of 50 minutes were led by clinical psychologists and postdoctoral-level clinical psychology fellows. Therapy was provided as three core modules and two optional modules, consisting of: psychoeducation about ADHD and training in organization and planning; skills to reduce distractibility; cognitive restructuring; skills to reduce procrastination; and a session with a family member.

Relaxation with education (Control group)

Twelve group sessions of 50 minutes were led by clinical psychologists and postdoctoral-level clinical psychology fellows. Therapy was provided as three core modules, consisting of: psychoeducation; progressive muscle relaxation; and application of relaxation to ADHD symptoms.

Solanto MV, Marks DJ, Wasserstein J, Mitchell K, Abikoff H, Alvir JM, et al. Efficacy of meta-cognitive therapy for adult ADHD. Am J Psychiatry. 2010 Aug;167(8):958-68.

Meta-cognitive therapy

Twelve weekly, two-hour group sessions led by the therapist covered the following themes: time- and task-management; implementation and maintenance for organizational systems; planning through use of flow-charting goals; and summarizing of strategies and areas for continued practice or improvement.

Pharmacological and Non-pharmacological Therapies for Adults with 115 Attention-Deficit/Hyperactivity Disorder

Supportive therapy (Control group)

Twelve weekly, two-hour group sessions led by the therapist used the following program structure: identification of personal goals for the program; discussion of weekly events, challenges, and accomplishments; and discussion of specific psychoeducational themes identified by group members.

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