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. 2011 Dec 7;2011(12):CD009504. doi: 10.1002/14651858.CD009504

Bupropion for Attention Deficit Hyperactivity Disorder (ADHD) in adults

Wim Verbeeck 1,✉, Geertruida E Bekkering 2, Wim Van den Noortgate 3
PMCID: PMC6483732

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To examine the efficacy and safety of noradrenergic/dopaminergic reuptake inhibitors (DARI) for the treatment of adults with ADHD.

Background

Description of the condition

Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neurobiological condition, which persists throughout the lifespan, affecting an estimated 6% of adolescents and 3% to 4% of adults (Fayyad 2007). ADHD is characterised by problems of inattention, impulsivity and excessive activity, and is commonly associated with emotional instability, sleep problems, risk‐taking behaviour, accident proneness, delinquency, poor self‐esteem and co‐occurring mental illnesses such as mood, personality and substance use disorders (Asherson 2005). This kaleidoscopic scale of symptoms can culminate in substantial academic underachievement, as well as occupational, social and relational impairment (Vaughan 2008). The revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV‐TR; APA 2000) defines the most widely used criteria and includes three ADHD subtypes: (1) predominantly inattentive, (2) predominantly hyperactive/impulsive and (3) combined.

Evidence from genetic, neuroimaging and neuropsychological studies suggest that a number of biological and environmental factors (Voeller 2004; Biederman 2005; Dopheide 2009), each of small individual effect, interact to produce the condition, which is characterised by cognitive and behavioural deficits (Sonuga‐Barke 2005).

Putative environmental risk factors related to ADHD can be categorised as biological factors (for example, fetal exposure to toxins or smoking) or adverse psychosocial factors (for example, low socioeconomic status, marital discord), but it is unclear which mechanisms underlie these relations (Banerjee 2007).

Neurobiological studies highlight that dysregulation of largely dopaminergic (Wang 2004) and noradrenergic systems of the frontostriatal circuit appear operant in ADHD (Bush 2005; Ashton 2006; Wilens 2006), leading to its key manifestations. However, even a dopamine/noradrenaline hypothesis of ADHD may be oversimplified since we may be observing merely the correlates of a process and not the cause.

At a clinical, genetic, neuroanatomical and neuropsychological level, marked disparities have been found between subgroups, indicating that ADHD is best conceptualised as a heterogeneous disorder with complex aetiology (Nutt 2007; Steinhausen 2009).

Despite the rapidly expanding body of preclinical research on the neurobiological underpinnings of ADHD, the exact aetiological processes are complex and not fully understood. As with most psychiatric disorders, there is no single diagnostic test to identify ADHD in adulthood. It therefore remains a clinical diagnosis, based on a comprehensive, multifaceted assessment of history and current symptoms and impairments, using clinical examination, rating scales, screening instruments, semi‐structured diagnostic interviews and other tools, as indicated (Kooij 2010).

Description of the intervention

Most of the effective pharmacological treatments for ADHD facilitate catecholamine transmission, either as agonists or as reuptake inhibitors (Faraone 1998; Wender 2001; Berridge 2006; Faraone 2006; Young 2006; Nutt 2007). They can be divided into psychostimulants and nonstimulants.

Psychostimulants

Despite the fact that psychostimulant medications are the mainstay of treatment, with a solid track record of safety and efficacy (Faraone 2004; Spencer 2005), they are either not effective, or tolerated, in approximately 30% to 50% of all adults with ADHD (Biederman 2006). Acute dose‐related psychiatric side effects include nervousness, insomnia, psychosis and agitation; somatic side effects include anorexia, weight loss, nausea, headaches and elevated blood pressure and heart rate (Ashton 2006). Their reinforcing or euphorigenic effects mean there is a potential for abuse and diversion (Leonard 2004; Wolraich 2004). Psychostimulants are contraindicated in patients who use monoamine oxidase (MAO) inhibitors, who have a history of illicit drug use or abuse, or who suffer from "glaucoma, symptomatic cardiovascular diseases, hyperthyroidism and hypertension" (Greenhill 2002). In addition to various medical contraindications, the presence of one or more comorbid psychiatric conditions may represent a relative contraindication to using stimulants (Newcorn 2008). Moreover, adults with ADHD demonstrate a higher rate of emotional dysregulation, which may be exacerbated through the use of psychostimulants. Finally, some patients simply will not accept treatment with a psychostimulant (Himpel 2005).

Nonstimulants

As stimulant medications are not effective or are poorly tolerated in a subset of patients with ADHD, efforts have been made to to expand the current pharmacopoeia to alternative approaches for ADHD (Pliszka 2003). The majority of nonstimulant compounds target noradrenaline, although there may also be primary and secondary effects on dopamine and other neurotransmitters and neuromodulators (Newcorn 2008). In addition to these catecholaminergic agents, the nonstimulants also harbour a variety of investigational drugs that have an effect on various other neurotransmitter systems, including cholinomimetics, histaminergic agonists, modafinil and ampakines, the latter affecting the glutamatergic system. The dopamine and adrenaline reuptake inhibitors (DARI) constitute the focus of this review, amongst which bupropion is the only agent that is clinically available. Bupropion is registered as an antidepressant and it is used as an aid to stop smoking. Given its impact on the catecholaminergic system, bupropion has been used off‐label to treat ADHD (Wilens 2005). Two studies (Wilens 2001; Wilens 2005) report a therapeutic effect after several weeks, with the largest improvement occurring up to the six‐week endpoint, suggesting an apparent delayed onset of action in adults with ADHD. Reimherr 2005 also recommends a six‐week duration for "short‐term, double‐blind studies with bupropion".

How the intervention might work

Bupropion is an aminoketone antidepressant and non‐competitive antagonism of nicotinic acetylcholine receptors (Gobbi 2003). Its mechanism of action most likely involves reuptake inhibition of the catecholamines dopamine and noradrenaline, a profile similar to the presumed action of psychostimulants. The powerful influences that catecholamines have on the brain circuits that appear to be altered in ADHD are mediated through stimulation of dopamine 1 (D1) and noradrenergic 2a receptors, respectively (Arnsten 2005). Bupropion is rapidly absorbed into the gastrointestinal tract following oral administration, with peak plasma levels occurring after two hours. Its mean elimination half‐life is approximately 14 hours.

Studies have demonstrated similar bioavailability for immediate release, sustained release (SR) and extended release (XR) bupropion, but information regarding their efficacy and the occurrence of adverse effects is scarce. There is a small dose‐dependent elevated risk of drug‐induced seizures, whereby the incidence of a convulsion rises significantly at dosages higher than 450 mg a day, the highest recommended dose (Spencer 2004). A few patients taking the drug develop anxiety, some develop headaches (Rostain 2008), and exacerbation of tics has also been reported (Popper 1997). The potential increase in blood pressure is usually small and only of concern in patients with marginal or high blood pressure. On the other hand, bupropion shows little impact on weight and sexual function (Wilens 2004; Demyttenaere 2008). The dose‐related side effects are mediated via the catecholamines transmitters. The mechanism of idiosyncratic side effects is unknown.

There is some evidence that bupropion may be a first‐line medication in the treatment of ADHD in patients with a dual diagnosis of mood or substance use disorders (Solhkhah 2005). Data regarding the most effective formulation and dosing of bupropion are lacking. It is also unclear whether there is a differential response rate to bupropion, according to the patient's ADHD subtype. Depression is often comorbid with ADHD and can influence ADHD symptoms, suggesting that bupropion, which is an antidepressant, may reduce ADHD symptoms only in the presence of depression.

Why it is important to do this review

The high ADHD prevalence rate, incomplete response and/or adverse drug reactions to stimulants, as well as the risk of stimulant abuse, mean that pharmacotherapeutic alternatives to stimulants, such as bupropion, should be explored.

Although buproprion is widely used as a treatment for ADHD, data from randomised controlled trials regarding its effectiveness are lacking (Reimherr 2005). It is of both clinical and research interest to document the efficacy of buproprion for ADHD, as it might generate new avenues of research that inform us of the aetiology of ADHD (Reimherr 2005).

It is likely that there is a differential response to stimulant and nonstimulant drugs in adults with ADHD, with some patients responding preferentially to, or tolerating, one treatment over another (Newcorn 2008a). A major challenge for the future is to develop strategies to identify a priori those patients who will respond preferentially to a stimulant or nonstimulant drug. At present, there is a paucity of empirical evidence to guide such treatment selection.

Nonstimulants do not produce euphoria and so may be used in patients with a history of illicit drug use and abuse (Young 2006), and through their alternative mechanism of action, new options are added to the therapeutic armamentarium.

Treating ADHD is challenging given the heterogeneity of symptoms and comorbidity that accompany the disorder. As psychostimulants are relatively contraindicated in ADHD patients with a dual diagnosis of, for example, depression, anxiety and substance misuse, it is vital to explore nonstimulant treatment options.

When proper symptom control and functional improvement cannot be met by licensed medicines, clinicians resort to off‐label use (Nutt 2007). This is the case with bupropion for adults with ADHD. It is important to examine the benefits and harms of off‐label use of bupropion, which is the purpose of this review.

A systematic review may reduce the uncertainty that remains regarding recommended optimum prescribing hierarchies, as they vary between different guideline committees (Peterson 2008).

Objectives

To examine the efficacy and safety of noradrenergic/dopaminergic reuptake inhibitors (DARI) for the treatment of adults with ADHD.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled clinical trials. We will include acute studies (less than 24 hours), as well as short‐ (less than six weeks), medium‐ and long‐term studies (more than six months). These will be analysed via subgroup analysis and/or meta‐regression.

Types of participants

Adults, aged 18 or older, diagnosed with ADHD according to formal standardised diagnostic criteria (Utah criteria, DSM IV‐TR, ICD 10). All ADHD subtypes are included. We will not exclude comorbid psychiatric conditions.

Types of interventions

Any formulation of bupropion (bupropion, bupropion XR, bupropion SR) at any dose compared with placebo. We will not exclude studies with adjuvant interventions if they are provided to both arms of the study.

Types of outcome measures

We will include the primary outcomes in a 'Summary of findings' table.

Primary outcomes

  1. Efficacy outcomes

    1. Change in the severity from baseline of ADHD symptoms assessed by a standardised instrument (patient or investigator rated).

    2. Proportion of patients achieving a significant clinical improvement. Significant improvement is defined as a reduction of at least 30% in the severity of ADHD symptoms or a Clinical Global Impression (CGI) Improvement scale score of 1 or 2.

  2. Adverse events

    1. Proportion of patients withdrawn due to any event (somatic or psychiatric).

Secondary outcomes

  1. Efficacy outcomes

    1. Clinical impression measured by the CGI severity of illness scale.

    2. Global level of functioning.

    3. Social adjustment as measured by a social adjustment scale.

    4. Depressive symptoms assessed by standardised instrument.

    5. Anxiety assessed by standardised instrument.

  2. 2. Adverse events

    1. Proportion of patients withdrawn due to any somatic adverse event.

    2. Proportion of patients withdrawn due to any psychiatric adverse event.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, Science Citation Index, Social Science Citation Index, Conference Proceedings Citation Index, and LILACS.

In addition, we will search the following trial registers for completed studies: the Netherlands Trial Register, Current Controlled Trials metaRegister of Controlled Trials (mRCT) and ClinicalTrials.gov register. We will search for theses and dissertations in the Networked Digital Library of Theses and Dissertations and DART ‐ Europe E‐theses Portal.

We will use the following MEDLINE search strategy, which includes controlled vocabulary and free text terms. We will modify this strategy as necessary for other databases We will not impose any language restrictions and will seek translations of relevant studies.

1 "attention deficit and disruptive behavior disorders"/ or attention deficit disorder with hyperactivity/ or conduct disorder/ 2 ADHD.tw. 3 ADDH.tw. 4 ADHS.tw. 5 "AD/HD".tw. 6 ((attention$ or behav$) adj3 (defic$ or dysfunc$ or disorder$)).tw. 7 ((disrupt$ adj3 disorder$) or (disrupt$ adj3 behav$) or (defian$ adj3 disorder$) or (defian$ adj3 behav$)).tw. 8 (impulsiv$ or inattentiv$ or inattention$).tw. 9 hyperkinesis/ 10 hyperkine$.tw. 11 (minimal adj3 brain adj3 (disorder$ or dysfunct$ or damage$)).tw. 12 hyperactiv$.tw. 13 or/1‐12 14 Bupropion$.tw. 15 Propiophenones/ 16 Antidepressive Agents/ 17 Antidepressive Agents, Second‐Generation/ 18 Bupropion/ 19 bupropion$.tw. 20 amfebutamone$.tw. 21 zyban$.tw. 22 wellbutrin$.tw. 23 wellbatrin$.tw. 24 quomem$.tw. 25 zyntabac$.tw. 26 radafaxine$.tw. 27 ((new or second) adj generation adj (anti‐depress$ or antidepress$)).tw. 28 ((atypical or a‐typical) adj (anti‐depress$ or antidepress$)).tw. 29 or/14‐28 30 exp Adult/ 31 Male/ 32 female/ 33 (adult$ or man or men or woman or women or female$ or male$).tw. 34 or/30‐33 35 randomized controlled trial.pt. 36 controlled clinical trial.pt. 37 randomi#ed.ab. 38 placebo$.ab. 39 drug therapy.fs. 40 randomly.ab. 41 trial.ab. 42 groups.ab. 43 or/35‐42 44 exp animals/ not humans.sh. 45 43 not 44 46 13 and 29 and 34 and 45

Searching other resources

We will search the reference lists of all relevant papers for further studies. In addition, we will contact colleagues, experts and pharmaceutical companies in the field to ascertain if there are any unpublished studies.

Data collection and analysis

Selection of studies

Two review authors (WV, GEB) will screen titles and abstracts of all identified studies. The same two review authors will retrieve a copy of the article of those studies deemed to be relevant for full‐text assessment.

Data extraction and management

Two review authors working independently (WV, GEB) will extract data using a piloted data extraction sheet (see Appendix 1). Any disagreements will be resolved by consensus. In case of missing information or in case of unpublished trials, we will mail the respective author to request missing data.

Assessment of risk of bias in included studies

Two review authors (WV and GEB) will independently assess the risk of bias within each included study based on the following domains, with ratings of low, high or unclear (Higgins 2008). 1. Sequence generation: was the allocation concealment sequence adequately generated? Description: we will describe the method used to generate the allocation sequence in detail so as to assess whether it should have produced comparable groups.

2. Allocation concealment: was allocation adequately concealed? Description: we will describe the method used to conceal allocation sequence in sufficient detail to assess whether intervention schedules could have been foreseen in advance of, or during, recruitment.

3. Blinding: was knowledge of the allocated intervention adequately prevented during the study? Description: we will describe any measures used to blind participants, personnel and outcome assessors so as to assess knowledge of any group as to which intervention a given participant might have received.

4. Incomplete outcome data: were incomplete outcome data adequately addressed? Description: we will extract and report data on attrition and exclusions as well the numbers involved (compared with total randomised), reasons for attrition/exclusion where reported or obtained from investigators, and any re‐inclusions in analyses we performed.

5. Selective outcome reporting: are reports of the study free of suggestion of selective outcome reporting? Description: we will make attempts to assess the possibility of selective outcome reporting by investigators (review authors' judgement).

6. Other sources of bias: Concerns regarding risk of bias not addressed in the above domains will be stated.

For each study we will note whether or not the study was funded by the pharmaceutical industry and report this in the 'Characteristics of included studies' table.

Measures of treatment effect

Continuous data

For continuous outcomes (for example, change in severity of ADHD symptoms) that are measured identically across studies, we will summarise data by calculating a mean difference (MD) and 95% confidence interval (CI). If the same continuous outcome is measured differently across studies, we may calculate an overall standardised mean difference (SMD) and 95% CI (Higgins 2008) using Hedge's g.

Dichotomous data

For dichotomous outcomes (for example, proportion of patients achieving a significant clinical improvement), we will summarise data by calculating risk ratio (RR) with 95% confidence interval (CI).

Multiple time points

We will classify outcomes of all studies based on time of measurement from randomisation: acute (less than 24 hours), short‐term (less than six weeks), medium‐term (six weeks to six months) and long‐term (more than six months). Within each time period, we will include the latest outcome in the meta‐analysis. We will carry out separate meta‐analysis according to the respective study durations.

Unit of analysis issues

Cross‐over trials

We will include cross‐over trials; however, because of the risk of carry‐over effects, we will only use data from the first period and treat them as parallel‐group trials. We will specify whether a study adhered to standard washout procedures. In terms of anti‐ADHD treatment with stimulants, one week washout should suffice, taking the elimination half‐life of stimulant drugs into consideration. If bupropion proves to show an effect, we will use a sensitivity analysis to evaluate whether this effect still shows if only studies with a longer washout are taken into consideration. If the total number of retrieved studies permits (at least five cross‐over trials), we will evaluate whether the effect is associated with prior interventions.

Multiple‐arm trials

We will carry out pair‐wise comparisons, selecting 'placebo' versus 'bupropion' as being relevant to this systematic review.

Dealing with missing data

In the first instance, we will contact authors to supply data missing from included studies. If authors are not able or not willing to supply the data, we will impute missing standard deviations by replacement values. The replacement value will be the mean of the standard deviations of other studies in that analysis that use the same dependent variable. We will use sensitivity analysis to assess how sensitive conclusions are to these replacements. Missing means will not be replaced.

Assessment of heterogeneity

We will assess statistical heterogeneity by examining the I2 statistic (Higgins 2003), a quantity which describes approximately the proportion of variation in point estimates that is due to heterogeneity rather than sampling error. In addition, we will employ a Chi2 test of homogeneity to determine the strength of evidence that heterogeneity is genuine.

Assessment of reporting biases

We will draw funnel plots (estimated treatment effects against their standard error) if sufficient studies are found. Asymmetry could be due to publication bias, but can also be due to a relationship between trial size and effect size. In the event that a relationship is found, we will examine clinical diversity of the studies (Egger 1997).

Data synthesis

We plan to perform meta‐analyses when there are at least two studies reporting on similar interventions in the way of dosage, frequency and duration, and when suitable data are presented. We expect fewer than 10 studies in the analyses. Therefore we will use a fixed‐effect model to pool the results because when there are few studies, random‐effects models are at risk of wrongly estimating the variance of studies (Van den Noortgate 2003). When meta‐analysis is not possible, we will describe the results and conclusions, without combining the results quantitatively.

Subgroup analysis and investigation of heterogeneity

If data permit, we will conduct two subgroup analyses:

  1. type of drug release formulation: immediate release, sustained release (SR) and extended release (XR); and

  2. dose: above versus below median dose.

We will assess clinical heterogeneity by comparing the distribution of important participant factors between studies (such as treatment type, co‐interventions, patient characteristics, ADHD subtype). We will discuss the impact of these on the findings.

When there are more than 10 studies included in the analyses, we will investigate statistical heterogeneity using meta‐regression (Higgins 2008). This regression will include the variables type of drug release formulation and drug dose.

Sensitivity analysis

We will conduct sensitivity analyses to determine whether findings are sensitive to restricting the analyses to studies judged to be at low risk of bias. In these analyses, we will restrict the analysis to:

  1. only studies with low risk of selection bias (associated with sequence generation and allocation concealment);

  2. only studies without financial support from the pharmaceutical industry;

  3. only studies where the presence of a comorbid disorder is an inclusion criterion; and

  4. if possible, we will perform a sensitivity analysis to assess the impact of studies that used non‐standardised instrument(s) to measure efficacy.

In addition, we will perform sensitivity analyses to assess the sensitivity of findings to any imputed data (see also 'Dealing with missing data').

Acknowledgements

We acknowledge with gratitude the comments of Professor Geraldine Macdonald, Cochrane Developmental, Psychosocial and Learning Problems Group (CDPLPG) Co‐ordinating Editor, to help develop this protocol.

Appendices

Appendix 1. Data to be extracted from included studies

Study description and funding:

Author Year of publication Country of study Authors affiliated with pharmaceutical industry (yes, no, unclear) Study funded by industry (yes, no, unclear) Study ID Source of data (report, correspondence with authors, individual patient data (IPD))

Methods:

Adequate sequence generation (yes, no, unclear) Adequate allocation concealment (yes, no, unclear) Adequate blinding of patients/clinicians/therapists/assessors (yes, no, unclear) Incomplete outcome data (yes, no, unclear) Selective outcome reporting (yes, no, unclear) Design (cross‐over/parallel groups; single/multi‐site) Were comorbid psychiatric disorders an exclusion criterion? (yes, no, unclear) Duration of intervention (from randomisation to treatment completion) Number of patients randomised Was an intention‐to‐treat (ITT) analysis performed? (yes, no, unclear)

Participants:

Inclusion/exclusion criteria (NR) Gender (% male) (NR) Age (mean, standard deviation (SD)) (NR) Race (% Caucasian) (NR) Setting: primary care, specialised ADHD clinic (NR) Employment status (% unemployed/per group) (NR) Prior ADHD treatment (yes/no), with psychostimulants (yes/no) (NR) Type of ADHD (% with inattentive subtype, % hyperactive/impulsive subtype, % combined subtype/per group) (NR) Comorbid conditions (% with comorbid psychiatric disorders/per group) (NR)

(NR) denotes not reported

Intervention:

Number of patients randomised Number of patients analysed Type of bupropion (SR, XR, regular) Dose (mean, SD) Was compliance assessed? (yes, no, unclear) Was compliance adequate? (yes, no, unclear) Were adjunctive psychological interventions, including coaching, provided? (yes, no, unclear)

Control:

Number of patients randomised Number of patients analysed Type of treatment (placebo, no treatment, treatment as usual) Description of treatment Were adjunctive psychological interventions, including coaching, provided? (yes, no, unclear)

Outcomes:

Achievement of significant clinical improvement (% of patients achieving a significant improvement) ADHD severity score Clinical Global Impression (% patients achieving at least a CGI of 1 or 2 at study conclusion) Clinical Global Impression ‐ Improvement (% of patients achieving a CGI ‐ Improvement score of 1 or 2 at study conclusion) Global functioning (mean SD) score at study conclusion Depressive symptoms assessed by standardised instrument (mean, SD) Anxiety symptoms assessed by standardised instrument (mean, SD) Number of patients withdrawn due to adverse events (number of patients withdrawn due to any adverse event, % participants withdrawn due to any somatic event, % of patients withdrawn due to any psychiatric event) Retention (% of participants who completed the study) Severity of side effects (mean SD score at study completion)

Results:

Number of participants allocated to each group

For each outcome of interest:

  • sample size;

  • missing participants;

  • summary data for each intervention group (2 x 2 table for dichotomous data; means and SDs for continuous data);

  • subgroup analysis (type of drug release formulation (immediate, SR, XR); dose: above versus below median dose).

Miscellaneous:

Correspondence required.

What's new

Date Event Description
8 September 2017 Amended Minor edits to text.
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Contributions of authors

Wim Verbeeck ‐ first review author, leading all stages of the review. Geertruida E Bekkering ‐ second review author, methodological and statistical support. Wim Van den Noortgate ‐ contributed methodological and statistical support.

Sources of support

Internal sources

  • None, Other.

External sources

  • None, Other.

Declarations of interest

Wim Verbeeck ‐ none known. Geertruida E Bekkering ‐ none known. Wim Van den Noortgate ‐ none known.

Edited (no change to conclusions)

References

Additional references

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders ‐ DSM‐IV‐TR. 4th Edition. Washington, DC: American Psychiatric Association, 2000. [Google Scholar]
  2. Arnsten AF, Li BM. Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biological Psychiatry 2005;57(11):1377‐84. [PUBMED: 15950011] [DOI] [PubMed] [Google Scholar]
  3. Asherson P. Clinical assessment and treatment of attention deficit hyperactivity disorder in adults. Expert Review of Neurotherapeutics 2005;5(4):525‐39. [DOI] [PubMed] [Google Scholar]
  4. Ashton H, Gallagher P, Moore B. The adult psychiatrist's dilemma: psychostimulant use in attention deficit/hyperactivity disorder. Journal of Psychopharmacology 2006;20(5):602‐10. [DOI] [PubMed] [Google Scholar]
  5. Banerjee T, Middleton F, Faraone S. Environmental risk factors for attention‐deficit hyperactivity disorder. Acta Paediatrica 2007;96(9):1269‐74. [DOI] [PubMed] [Google Scholar]
  6. Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AF, Kelley AE, Schmeichel B, et al. Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biological Psychiatry 2006;60(10):1111‐20. [PUBMED: 16806100] [DOI] [PubMed] [Google Scholar]
  7. Biederman J, Faraone SV. Attention‐deficit hyperactivity disorder. Lancet 2005;366(9481):237‐48. [PUBMED: 16023516] [DOI] [PubMed] [Google Scholar]
  8. Biederman J. Introduction: new developments in the treatment of attention‐deficit/hyperactivity disorder. Journal of Clinical Psychiatry 2006;67(Suppl 8):4‐6. [PubMed] [Google Scholar]
  9. Bush G, Valera EM, Seidman LJ. Functional neuroimaging of attention‐deficit/hyperactivity disorder: a review and suggested future directions. Biological Psychiatry 2005;57(11):1273‐84. [PUBMED: 15949999] [DOI] [PubMed] [Google Scholar]
  10. Demyttenaere K, Jaspers L. Review: bupropion and SSRI‐induced side effects. Journal of Psychopharmacology 2008;22(7):792‐804. [DOI] [PubMed] [Google Scholar]
  11. Dopheide JA, Pliszka SR. Attention‐deficit‐hyperactivity disorder: an update. Pharmacotherapy 2009;29(6):656‐79. [DOI] [PubMed] [Google Scholar]
  12. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphical test. BMJ 1997;315(7109):629‐34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Faraone SV, Biederman J. Neurobiology of attention‐deficit hyperactivity disorder. Biological Psychiatry 1998;44(10):951‐8. [PUBMED: 9821559] [DOI] [PubMed] [Google Scholar]
  14. Faraone SV, Spencer T, Aleardi M, Pagano C, Biederman J. Meta‐analysis of the efficacy of methylphenidate for treating adult attention‐deficit/hyperactivity disorder. Journal of Clinical Psychopharmacology 2004;24(1):24‐9. [DOI] [PubMed] [Google Scholar]
  15. Faraone SV, Biederman J, Spencer TJ, Aleardi M. Comparing the efficacy of medications for ADHD using meta‐analysis. Medscape General Medicine 2006;8(4):4. [PUBMED: 17415287] [PMC free article] [PubMed] [Google Scholar]
  16. Fayyad J, Graaf R, Kessler R, Alonso J, Angermeyer M, Demyttenaere K, et al. Cross‐national prevalence and correlates of adult attention‐deficit hyperactivity disorder. British Journal of Psychiatry 2007;190:402‐9. [DOI] [PubMed] [Google Scholar]
  17. Gobbi G, Slater S, Boucher N, Debonnel G, Blier P. Neurochemical and psychotropic effects of bupropion in healthy male subjects. Journal of Clinical Psychopharmacology 2003;23(3):233‐9. [DOI] [PubMed] [Google Scholar]
  18. Greenhill LL, Pliszka S, Dulcan MK, Bernet W, Arnold V, Beitchman J, et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. Journal of the American Academy of Child and Adolescent Psychiatry 2002;41(Suppl 2):26S‐49S. [DOI] [PubMed] [Google Scholar]
  19. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327(7414):557‐60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions. Chichester, UK: John Wiley & Sons, 2008. [Google Scholar]
  21. Himpel S, Banaschewski T, Heise CA, Rothenberger A. The safety of nonstimulant agents for the treatment of attention‐deficit hyperactivity disorder. Expert Opinion on Drug Safety 2005;4(2):311‐21. [DOI] [PubMed] [Google Scholar]
  22. Kooij SJ, 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;10:67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Leonard BE, McCartan D, White J, King DJ. Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects. Human Psychopharmacology 2004;19(3):151‐80. [DOI] [PubMed] [Google Scholar]
  24. Newcorn JH. Nonstimulants and emerging treatments in adults with ADHD. CNS Spectrums 2008;13(9 Suppl 13):12‐6. [PubMed] [Google Scholar]
  25. 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. American Journal of Psychiatry 2008;165(6):721‐30. [DOI] [PubMed] [Google Scholar]
  26. Nutt DJ, Fone K, Asherson P, Bramble D, Hill P, Matthews K, et al. Evidence‐based guidelines for management of attention‐deficit/hyperactivity disorder in adolescents in transition to adult services and in adults: recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology 2007;21(1):10‐41. [DOI] [PubMed] [Google Scholar]
  27. 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 2008;197(1):1‐11. [DOI] [PubMed] [Google Scholar]
  28. Pliszka SR. Non‐stimulant treatment of attention‐deficit/hyperactivity disorder. CNS Spectrums 2003;8(4):253‐8. [DOI] [PubMed] [Google Scholar]
  29. Popper CW. Antidepressants in the treatment of ADHD. Journal of Clinical Psychiatry 1997;58(Suppl 14):14‐29. [PubMed] [Google Scholar]
  30. Reimherr FW, Hedges DW, Strong RE, Marchant BK, Williams ED. Bupropion SR in adults with ADHD: a short‐term, placebo‐controlled trial. Neuropsychiatric Disease and Treatment 2005;1(3):245‐51. [PUBMED: 18568102] [PMC free article] [PubMed] [Google Scholar]
  31. Rostain AL. ADHD in adults: evidence‐based recommendations for management. Postgraduate Medicine 2008;20(3):27‐38. [PUBMED: PMID:18824823] [DOI] [PubMed] [Google Scholar]
  32. Solhkhah R, Wilens TE, Daly J, Prince JB, Patten SL, Biederman J. Bupropion SR for the treatment of substance‐abusing outpatient adolescents with attention‐deficit/hyperactivity disorder and mood disorders. Journal of Child and Adolescent Psychopharmacology 2005;15(5):777‐86. [PUBMED: 16262594] [DOI] [PubMed] [Google Scholar]
  33. Sonuga‐Barke EJ. Causal models of attention‐deficit/hyperactivity disorder: from common simple deficits to multiple developmental pathways. Biological Psychiatry 2005;57(11):1231‐8. [DOI] [PubMed] [Google Scholar]
  34. Spencer T, Biederman J, Wilens T. Nonstimulant treatment of adult attention‐deficit/hyperactivity disorder. Psychiatric Clinics of North America 2004;27(2):373‐83. [PUBMED: 15064003] [DOI] [PubMed] [Google Scholar]
  35. Spencer T, Biederman J, Wilens T, Doyle R, Surman C, Prince J, et al. A large, double‐blind, randomized clinical trial of methylphenidate in the treatment of adults with attention‐deficit/hyperactivity disorder. Biological Psychiatry 2005;57(5):456‐63. [PUBMED: 15737659] [DOI] [PubMed] [Google Scholar]
  36. Steinhausen HC. The heterogeneity of causes and courses of attention‐deficit/hyperactivity disorder. Acta Psychiatrica Scandinavica 2009;120(5):392‐9. [DOI] [PubMed] [Google Scholar]
  37. Noortgate W, Onghena P. Multilevel meta‐analysis: a comparison with traditional meta‐analytical procedures. Educational and Psychological Measurement 2003;63(5):765‐90. [Google Scholar]
  38. Vaughan BS, Wetzel MW, Kratochvil CJ. Beyond the 'typical' patient: treating attention‐deficit/hyperactivity disorder in preschoolers and adults. International Review of Psychiatry 2008;20(2):143‐9. [DOI] [PubMed] [Google Scholar]
  39. Voeller KK. Attention‐deficit hyperactivity disorder (ADHD). Journal of Child Neurology 2004;19(10):798‐814. [PUBMED: 15559895] [DOI] [PubMed] [Google Scholar]
  40. Wang M, Vijayraghavan S, Goldman‐Rakic PS. Selective D2 receptor actions on the functional circuitry of working memory. Science 2004;303(5659):853‐6. [PUBMED: 14764884] [DOI] [PubMed] [Google Scholar]
  41. Wender PH, Wolf LE, Wasserstein J. Adults with ADHD. An overview. Annals of the New York Academy of Sciences 2001;931:1‐16. [PUBMED: 11462736] [PubMed] [Google Scholar]
  42. Wilens T, Spencer J, Biederman J, Girard K, Doyle R, Prince J, et al. A controlled clinical trial of bupropion for Attention Deficit Hyperactivity Disorder in adults. American Journal of Psychiatry 2001;158:282‐8. [DOI] [PubMed] [Google Scholar]
  43. Wilens TE, Dodson W. A clinical perspective of attention‐deficit/hyperactivity disorder into adulthood. Journal of Clinical Psychiatry 2004;65(10):1301‐13. [DOI] [PubMed] [Google Scholar]
  44. Wilens TE, Haight BR, Horrigan JP, Hudziak JJ, Rosenthal NE, Connor DF, et al. Bupropion XL in adults with attention‐deficit/hyperactivity disorder: a randomized, placebo‐controlled study. Biological Psychiatry 2005;57(7):793‐801. [PUBMED: 15820237] [DOI] [PubMed] [Google Scholar]
  45. Wilens TE. Mechanism of action of agents used in attention‐deficit/hyperactivity disorder. Journal of Clinical Psychiatry 2006;67(Suppl 8):32‐8. [PubMed] [Google Scholar]
  46. Wolraich ML, Doffing MA. Pharmacokinetic considerations in the treatment of attention‐deficit hyperactivity disorder with methylphenidate. CNS Drugs 2004;18(4):243‐50. [DOI] [PubMed] [Google Scholar]
  47. Young JL. Treatment of adult ADHD and comorbid disorders. CNS Spectrums 2006;11(10 Suppl 11):10‐2. [DOI] [PubMed] [Google Scholar]

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