Review

10.1586/14737175.7.2.195 © 2007 Future Drugs Ltd ISSN 1473-7175 195www.future-drugs.com

Pharmacotherapy of attention-deficit/hyperactivity disorder: nonstimulant medication approachesMohammad Reza Mohammadi and Shahin Akhondzadeh†

†Author for correspondenceTehran University of Medical Sciences, Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, South Kargar Street, Tehran 13337, IranTel.: +98 215 541 2222Fax: +98 215 541 9113s.akhond@neda.net

KEYWORDS: ADHD, alternative medicine, attention-deficit/hyperactivity disorder, etiology, nonstimulants, pharmacotherapy

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common chronic health conditions and mental disorders affecting school-aged children. Prevalence with a conservative estimate is reported to be 3–5% of this population. Boys are approximately three-times more likely to be diagnosed than girls. The diagnosis refers to a family of related chronic neurobiological disorders that interfere with an individual’s capacity to regulate activity level, inhibit behavior and attend to tasks in developmentally appropriate ways. Signs and symptoms of ADHD are typically present during the preschool period or in the early elementary school years, and the diagnosis requires that difficulties were present at or before age 7 years and create problems or impairment in at least two areas of the child’s life (e.g., at school, on the playground, on the bus, at home or socially with peers). Stimulants are the first-line medication in the psychopharmacological treatment of ADHD. Between 10 and 30% of those affected with ADHD may not respond to stimulants or may not be able to tolerate associated side effects, such as appetite suppression, sleep disturbance, mood difficulties or exacerbation of comorbid tic disorders. In such instances, or when families are unwilling to consider a stimulant, nonstimulant medications may be appealing. Several nonstimulant medications that affect noradrenergic and/or dopaminergic pathways have demonstrated efficacy in the treatment of ADHD, although effect sizes are comparable with methylphenidate, fewer data have accumulated regarding the safety profile of nonstimulants in general. This review focuses on etiology, assessment and treatment of ADHD, in particular alternative treatment approaches with various nonstimulant agents, especially atomoxetine.

Expert Rev. Neurotherapeutics 7(2), 195–201 (2007)

Attention-deficit/hyperactivity disorder (ADHD)is the most common mental disorder in child-hood. In recent years, ADHD has been a sub-ject of great public attention and concern [1,2].The prevalence of ADHD is difficult to estab-lish owing to differences in diagnostic criteriaover the past several decades, differences inperception of symptoms between informantsand cultural differences. In the USA, however,the estimated prevalence of ADHD amongchildren is 8–10% [1,2]. Once considered achildhood disease, it is now known thatapproximately 40–70% of children withADHD will have their symptoms persist that

into adolescence and adulthood. ADHD ischaracterized by various symptoms of inatten-tion and/or hyperactivity and impulsivity. Theeffects of ADHD are life encompassing and arenot limited to the 8-h long school day. Usually,a number of symptoms that caused impair-ment are present before the age of 7 years.Classification of what constitutes ADHD haschanged dramatically over the last 20 years,with each successive revision of the Diagnosticand Statistical Manual of Mental Disorders(DSM), the diagnostic criteria used todescribe the disorder. Current DSM-IV classi-fication for combined-type ADHD requires a

CONTENTS

Epidemiology

Diagnostic criteria

Assessment

Etiology

Treatment

Alternative medicine

Expert commentary

Five-year view

Key issues

References

Affiliations

Mohammadi & Akhondzadeh

196 Expert Rev. Neurotherapeutics 7(2), (2007)

minimum of six out of nine symptoms of inattention, and aminimum of six out of nine symptoms of hyperactivity/impul-sivity. In addition, some impairment from the symptoms ispresent in two or more settings (e.g., at home and at school)and clear evidence of significant impairment in social, school orwork functioning. The DSM-IV also allows the classification oftwo subtype disorders: predominantly inattentive, where thechild only meets criteria for inattention; and predominantlyhyperactive–impulsive, where only the hyperactive–impulsivecriteria are met [3–5]. Effective treatment depends on appropri-ate diagnosis of ADHD. A comprehensive medical evaluationof the child must be conducted to establish a correct diagnosisof ADHD and to rule out other potential causes of the symp-toms. ADHD can be reliably diagnosed when appropriateguidelines are used [6–10].

EpidemiologyPrevalence estimates vary according to the method of ascertain-ment, diagnostic system and associated criteria (e.g., situationalvs pervasive and degree of impairment) measures used, infor-mants and the population sampled. The DSM-IV-TR estimatesthe prevalence in school-aged children to be 3–5% [11]. In acommunity survey in upstate New York (NY, USA), researchersfound ADHD (DSM-III-R) in 8.5% of girls and 17.1% ofboys aged 10–13 years, 6.5% of girls and 11.4% of boys aged14–16 years and 6.2% of girls and 5.8% of boys aged17–20 years. Children with ADHD are the most common cat-egory of referrals to child and adolescent psychiatric health ser-vices. In elementary school-aged children, the ratio of boys togirls suffering from ADHD is typically 2:1 to as high as 9:1 inclinical settings, but approximates 4:1 in community epidemio-logical surveys [12]. Teachers identify fewer girls than boys withADHD symptoms. The male:female ratio ranges from 4:1 forthe predominantly hyperactive–impulsive type, to 2:1 for thepredominantly inattentive type. Interestingly, even among chil-dren rated by teachers as meeting criteria for any subtype ofADHD, fewer girls than boys receive an ADHD diagnosis orstimulant treatment [13–15].

Diagnostic criteria There are two groups of nine symptoms each: inattention andhyperactivity–impulsivity (subdivided into two groups).Inattention includes failing to give close attention to details ormaking careless mistakes, difficulty sustaining attention, not lis-tening, not following through, difficulty organizing, avoidanceor dislike of sustained mental effort, losing things and beingeasily distracted and forgetful. Hyperactivity includes six symp-toms: being fidgety, out of seat, running or climbing excessively,difficulty playing quietly, on the go or as if driven by a motorand talking excessively. The three impulsivity symptom criteriaare: blurting out answers, difficulty awaiting turn and ofteninterrupting or intruding on others [6–8]. ADHD is divided intothree types according to the presence or absence of six or moresymptoms in each symptom group. These types are predomi-nantly inattentive, predominantly hyperactive–impulsive and

combined (both sets of symptoms). At least some symptomsmust have been present before the age of 7 years. The behaviorsused to meet the criteria must be inconsistent with the patient’sdevelopmental level and intellectual ability and have beenpresent for at least 6 months. Functional impairment must bepresent in two or more settings, with clinically significantimpairment in social, academic or occupational functioning. Bydefinition, the diagnosis of ADHD cannot be made if thesymptoms occur exclusively in the presence of a pervasive devel-opmental disorder, schizophrenia or other psychotic disorder, orif they are better accounted for by another psychiatric disorder.Signs of ADHD may not be observable when the patient is inhighly structured or novel settings, engaged in an interestingactivity, receiving one-to-one attention or supervision, or in asituation with frequent rewards for appropriate behavior. Con-versely, symptoms typically worsen in situations that areunstructured, minimally supervised, boring, or require sus-tained attention or mental effort. Core deficits include impair-ment in rule-governed behavior across a variety of settings andrelative difficulty for age in inhibiting impulsive response tointernal wishes or needs or external stimuli [6–8,10].

Assessment The parent interview is the core of the assessment process. It isoften difficult to confirm a diagnosis of ADHD by interviewwith the child or adolescent alone, since some children andmost adolescents with ADHD are able to maintain attentionand behavioral control while in the office setting. Many lackinsight into their own difficulties and are not willing or able toreport them accurately. Both parent and child interviews areused to rule out other psychiatric or environmental causes ofsymptoms. Structured interviews of parents may be useful inassuring coverage of ADHD symptoms, or a DSM-IV symp-tom checklist may be used. Standardized interviews of childrenand adolescents are less useful for ADHD symptoms, but mayaid in discovering alternative or comorbid diagnoses. Queriesabout family history of ADHD, other psychiatric disorders andpsychosocial adversity (e.g., poverty, parental psychopathologyor absence, or family conflict) are especially important owing totheir relationship to prognosis [5,16,17].

Etiology The causes of ADHD are unknown. Most children withADHD have no evidence of gross structural damage in theCNS. ADHD does appear to run in families with approxi-mately a third of affected children having a first–degree relativewith a history of ADHD [5,17]. Recent functional magnetic res-onance imaging brain studies indicate that the disorder may becaused by atypical functioning in the frontal lobes, basal gan-glia, corpus callosum and cerebellar vermis. Pharmacologicalstudies have also implicated dysregulation of frontal–subcorti-cal–cerebellar catecholaminergic circuits in the pathophysiol-ogy of the disorder. Central catecholaminergic neurotransmis-sion systems appear to be involved in the pathophysiology ofADHD. Effective medication treatments for ADHD appear to

Nonstimulant medication approaches for ADHD

www.future-drugs.com 197

modulate dopaminergic and noradrenergic neurotransmissionin the prefrontal cortex. As a group, children with ADHDshow differences from unaffected children in the volumes ofspecific brain regions in imaging studies (i.e., frontal lobes,temporal gray matter, caudate nucleus and cerebellum). Thecause of such differences is unknown and brain imaging is notuseful as a diagnostic tool if used to differentiate youths withADHD from those without. Traumatic brain injury has beenassociated with ADHD, but probably accounts for the dis-order in only a small percentage of affected children. Environ-mental factors may also be relevant. Exposure to maternaltobacco or alcohol use in utero may increase the risk of ADHDin offspring. Exposure to lead early in life has also been associ-ated with ADHD. Although up to 5% of children withADHD may respond to dietary manipulations for food aller-gies, there is little evidence that exposure to refined sugar orfood additives are responsible for ADHD in most affectedchildren [18–21].

TreatmentThe three treatments that have been validated as being signifi-cantly effective for ADHD are medication management,behavioral therapy and a combination of the two approaches [22].

Medication managementStimulant medications

Psychostimulant medications are the drugs of first choice in themedication of ADHD. Approximately 70% of the childrentreated show improvement in primary ADHD symptoms and incomorbidity such as conduct disorder, although the benefits maynot hold beyond 2 years [22]. Currently, methylphenidate andamphetamine are the drugs of choice [23,24].

Methylphenidate is the most widely used and best-studiedstimulant medication. Dextroamphetamine (D-amphetamine)and mixed amphetamine salts (D- and L-amphetamine) are alsoquite commonly used and have been reasonably wellstudied [25]. Amphetamine preparations are approximatelytwice as potent as methylphenidate. Recent reports of suddendeath in a handful of youths treated with amphetamine saltshave generated understandable concern. It appears that themajority of reported cases occurred in youths with pre-existingstructural cardiac abnormalities, but a few cases were not asso-ciated with such findings. At present, existing knowledgeshould be shared with patients and families, and a careful his-tory of pre-existing cardiac problems, ‘drop attacks’ or a familyhistory of sudden death should be explored prior to initiatingtreatment with amphetamine salts. Pemoline use has been dis-couraged by reports of rare, but potentially fatal, hepatoxicityin association with its use. Approximately 70% of youths withADHD will respond to the first stimulant taken and at least80% will respond to one stimulant if the medications are triedsystematically [23,26]. Consequently, given the current state ofknowledge it has been recommended that children who fail torespond to one stimulant should be tried on another. Approxi-mately 40% of youths with ADHD will respond equally well to

methylphenidate or amphetamine preparations, and approxi-mately a third will respond better either to methylphenidate oran amphetamine-based preparation [27,28].

Standard preparations of methylphenidate or amphetamineare relatively short-acting, with durations of action rangingfrom 3 to 6 h, and thus requiring administration two or threetimes per day. The development of new stimulant formula-tions that allow a rapid onset of action and a longer durationof effect have been important developments in the treatmentof ADHD, since their use can eliminate the need for multipledoses of short acting stimulant across the day, and avoid dos-ing during school. These preparations can be employed as ini-tial stimulant treatment for ADHD, eliminating the need tobegin with a short-acting preparation followed by conversionto a longer-acting preparation [29].

Nonstimulant medications

Between 10 and 30% of those affected with ADHD may notrespond to stimulants or may not be able to tolerate associ-ated side effects, such as appetite suppression, sleep distur-bance, mood difficulties or exacerbation of comorbid tic dis-orders [30]. In such instances, or when families are unwilling toconsider a stimulant, nonstimulant medications may beappealing. Several nonstimulant medications that affect nora-drenergic and/or dopaminergic pathways have demonstratedefficacy in the treatment of ADHD. Although effect sizes areprobably somewhat comparable with methylphenidate in tri-als, fewer data have accumulated regarding the safety profileof nonstimulants in general. Nevertheless, this group includesdrugs with noradrenergic, dopaminergic and serotoninergicproperties (such as venlafaxine, monoamine oxidase inhibitorsMAOIs; e.g., selegiline and moclobemide), buspirone, cholin-ergic drugs (such as donepezil), carbamazepine, neurolepticsand theophylline [30–32].

The US FDA approved atomoxetine (Stattera®, Eli Lilly andCo.) in November 2002 as a new nonstimulant treatment forADHD. Atomoxetine is a highly selective norepinephrinereuptake inhibitor that is the best studied and the only non-stimulant medication approved by the FDA for the treatmentof ADHD in both youths and adults [24,33,34]. Unlike the stim-ulant medications, atomoxetine does not appear to have abusepotential and is not a controlled substance. Atomoxetineincreases concentrations of norepinephrine and dopamine inthe prefrontal cortex, where dopamine is primarily inactivatedby the presynaptic norepinephrine transporter, but not inother brain regions such as the striatum and nucleus accum-bens, which may explain the drug’s lack of abuse potential [30].Several studies have demonstrated the efficacy of atomoxetinefor ADHD at total daily doses ranging from 1 to1.8 mg/kg/day, with the drug producing improvements inADHD symptoms, as well as in family and social functioningin both short- and longer-term trials lasting as long as 2 years.The drug is generally started at 0.5 mg/kg/day, then increasedafter 3 or 4 days, if tolerated, to approximately 1.2 mg/kg/day.The maximum recommended dosage in youths is

Mohammadi & Akhondzadeh

198 Expert Rev. Neurotherapeutics 7(2), (2007)

1.4 mg/kg/day or 100 mg, whichever is less. Unlike stimulants,which tend to show effects on core ADHD symptoms virtuallyimmediately, patience is required when using atomoxetine, assome patients may still be showing improvements for1–2 months after achieving the recommended dosage [24,33,34].The drug is reasonably well tolerated, with few serious safetyconcerns until two recent case reports of atomoxetine-associ-ated hepatotoxicity. Other than slight increases in pulse andblood pressure, cardiovascular effects are not generally clini-cally significant. Common side effects include weight loss,poor appetite, nausea, insomnia, fatigue, dizziness and irrita-bility. Urinary retention and sexual dysfunction have beenreported in adults. Atomoxetine is metabolized primarily bycytochrome P450 (CYP)2D6, making approximately 7% ofthe Caucasian population who are poor metabolizers poten-tially more vulnerable to experiencing side effects on typicaldosages, and making it necessary to consider dosage adjust-ments when using atomoxetine in combination with CYP2D6inhibitors such as fluoxetine [24,33,34].

Venlafaxine, an antidepressant with both serotonergic andnoradrenergic properties, has been investigated as a possibletreatment alternative in ADHD. It has no significant affinityfor muscarinic, cholinergic, histaminic, or α-1-adrenergicreceptors and a relatively short half life, and is given in divideddoses [30]. Some small open-label studies suggest that venlafax-ine may be an effective medication (50–75% response rate incompleters; 25% drop-out owing to side effects) in treatingthe core symptoms of ADHD in children, adolescents andadults [35]. Side effects include irritability, insomnia and gas-trointestinal disturbance. While two open-label studies of flu-oxetine in a total of 51 children and adolescents with ADHDsuggested that fluoxetine may be beneficial in the treatment ofADHD, the effectiveness of selective serotonin-reuptakeinhibitors (SSRIs) in the treatment of core ADHD symptomsis not supported by clinical experience. With a lack of compar-ison trials, the role of the SSRIs in ADHD remains, at best,unclear [24]. A small number of studies with MAOIs suggestedthat irreversible and reversible MAOIs may improve ADHDsymptoms. The mechanism of MAOIs in reducing ADHDsymptoms is probably related to their ability to block themetabolism of noradrenaline and dopamine. However, the useof irreversible MAOIs (e.g., phenelzine and tranylcypromine)is strongly limited by their potential for hypertensive crises, byproblems with dietary violations (tyramine-containing foods)and drug interactions. Reversible MAOIs (e.g., moclobemideand selegiline) need to be further evaluated. Buspirone has ahigh affinity to pre- and postsynaptic serotonin (5-hydrox-ytryptamine [5-HT])1A receptors, as well as a modest effect onthe dopaminergic system, plus α-adrenergic activity [30–32]. Anopen-label clinical trial of 12 children with ADHD treatedwith buspirone 0.5 mg/kg/day (range: 15–30 mg/day) in twodivided doses suggested that it helps to improve hyperactivity,impulsivity and oppositionality. However, results from arecent multisite, controlled clinical trial of transdermal bus-pirone failed to separate it from placebo in a large sample of

children with ADHD [30]. A recent multicenter, open-label,short-term dose-titration study suggested that GW320659, achemically novel inhibitor of noradrenaline and dopaminereuptake, may have clinically relevant efficacy in treatingsymptoms of ADHD. Bupropion and the α-adrenergic ago-nists, clonidine and guanfacine, have also proven to beefficacious in the treatment of ADHD.

A meta-analysis of clinical trials involving clonidine forADHD treatment suggested that clonidine is effective as a sec-ond-line therapy, although the effect size of clonidine is lowerthan that of the psychostimulants. This study also indicatedthat there was a high rate of side effects associated with cloni-dine treatment, the most common of which were sedation, irri-tability, sleep disturbance, blood pressure drop, hypotension,dry mouth and dizziness [36].

Guanfacine is less sedating and has a longer duration ofaction than clonidine, which may make it more convenient touse with children and adolescents. A randomized, placebo-con-trolled study of guanfacine in 34 children with tic disorders andADHD suggested that guanfacine is well tolerated whenadministered three times daily. Improvements in behavior weresimilar to, or better than, those reported for other nonstimulanttrials, but they were lower than improvement levels observedwith psychostimulant use [37].

It has been demonstrated that bupropion is effective inimproving ADHD symptoms [30]. Generally, bupropionappears to be less effective than stimulants [30], but more stud-ies are needed. A double-blind, crossover study in 15 patientswith ADHD (7–17 years old) found that methylphenidate(mean dose 0.7 mg/kg/day) and bupropion (mean dose3.3 mg/kg/day) were both effective and not different in theiroverall efficacy as medications for ADHD. Bupropionappears to be well tolerated in most children and adolescents.Bupropion’s side effects include irritability, insomnia, drowsi-ness, fatigue, headache, dry mouth, sweating, constipation,nausea and dermatological reactions. While it does not havethe cardiovascular risks associated with the tricyclic anti-depressants or the substance abuse potential of the stimulants,concerns remain over an increased risk of seizures. Therefore,regular control examinations of the electroencephalographyare recommended [38].

Modafinil is structurally different from the psychostimulantsand has been reported as being effective in improving thesymptoms of ADHD. It has been suggested that a higher doseof modafinil may be needed in children than that used fortreatment of narcolepsy. A recent double-blind clinical trialfound that modafinil significantly improved symptoms ofADHD both at school and at home and was well tolerated bychildren and adolescents. Abrupt discontinuation of modafinilwas not associated with symptoms of withdrawal or withrebound of symptoms of ADHD [39].

In recent years, evidence has emerged that nicotinic dysregula-tion may contribute to the pathophysiology of ADHD. Centralnicotinic activation stimulates the release of several neuro-transmitters, including dopamine, noradrenaline, acetylcholine,

Nonstimulant medication approaches for ADHD

www.future-drugs.com 199

5-HT, γ-aminobutyric acid (GABA) and endorphins, and hasbeen shown to improve vigilance, attention and executive func-tion, probably by its noradrenergic or dopaminergic effects [31].Although controlled clinical trials in children, adolescents andadults with ADHD have indicated that nicotinic receptor mod-ulation may be a potentially useful strategy for the treatment ofADHD, the therapeutic uses of nicotine are limited owing toside effects. Nausea, stomach ache, itching under patch and diz-ziness are the most frequently reported adverse effects associatedwith transdermal nicotine [40]. Other cholinergic drugs, such asacetylcholinesterase inhibitors (donepezil) as well as a novel nic-otinic analog (ABT-418), have also been used in treatingADHD. ABT-418, a novel cholinergic activating agent withstructural similarities to nicotine, has been found to be a poten-tially useful agent for the treatment of adults with ADHD in adouble-blind, placebo controlled, randomized, crossover study.At a dose of 75 mg daily, the response rate was significantlyhigher than under placebo (40 vs 13%). Treatment with ABT-418 was relatively well tolerated; dizziness and nausea were themost frequently reported adverse effects [31].

Alternative medicineApproximately 70% of children treated show improvement inprimary ADHD symptoms, and in comorbidity such as conductdisorder, although the benefits may not hold beyond 2 years[41]. Despite the well-established efficacy and safety of stimu-lants for ADHD, alternative medicines are still needed for sev-eral reasons [41]. Approximately 30% of children and adolescentswith ADHD may not respond to stimulants or may be unable totolerate potential adverse events, such as decreased appetite,mood lability and sleep disturbances. Although stimulants donot increase the risk for later substance abuse in ADHD, con-cerns have been raised over special prescription rules and a poten-tial for abuse by persons other than the ADHD subjects [42,43].Herbal medicines have been shown to ameliorate ADHD-relatedbehaviors in individuals without this disorder [41–44]. For exam-ple, Ginkgo biloba is somewhat effective for cognition impair-ment disorders such as dementia. A review of 40 controlled trials

found at least a partial positive outcome in nearly all subjectswho had cerebral insufficiency (e.g., difficulties of concentrationand memory). This finding may help to provide support forusing Ginkgo in children with ADHD, especially those who areprimarily inattentive. Moreover, Ginkgo improves cerebrovascu-lar blood flow and attention may help to reduce hyperactivityowing to boredom and lack of focus [43]. A recent study demon-strated that Passiflora incarnata may be a novel therapeutic agentfor the treatment of ADHD. In addition, a tolerable side effectprofile may be considered as one of the advantages of Passiflora inthe treatment of ADHD [45].

Expert commentaryADHD is a common neurobehavioral disorder of childhood andadolescents. It is characterized by symptoms of inattention and/orhyperactivity/impulsivity that have persisted for at least 6 months.It is diagnosed by parent/child interview, medical evaluation withcomplete medical history and physical examination; other testingor consultation may be warranted when the presence of focal signsor clinical findings is suggestive of neurological condition. Treat-ment generally includes medication management, in particular,the use of stimulants. There is evidence to support that a combi-nation of medical management and behavior management iseffective for the treatment of ADHD. Stimulants are a highly efficacious and safe treatment forADHD and have been the mainstay for over 60 years. How-ever, treatment with atomoxetine or other nonstimulant drugsshould be considered as an alternative in cases of: limited or noresponse to stimulants; when the subject and/or their familydoes not accept a stimulant treatment; comorbid disorders suchas tic disorder (and possibly anxiety or depression); or when thechild is at an elevated risk of side effects with the stimulantsused. Moreover, complementary and alternative medicines maybe tried more often in children with ADHD than with otherconditions since it is a chronic problem which affects multipledomains of functioning (academic, social and behavioral)resulting in much frustration for families who understandablyoften search hard for solutions.

Key issues

• Medications for the treatment of attention-deficit/hyperactivity disorder should only be initiated by psychiatrists or pediatricians who have special training.

• Psychiatrists should measure and record the child’s height, weight, blood pressure and pulse as a baseline prior to starting any medication.

• First-line medications include: – Methylphenidate (Ritalin®, Equasym®, Equasym XL™ and Concerta® XL) – Dexamphetamine (Dexadrine™).

• Second line medications include: – Atomoxetine (Strattera®) – Antidepressants (e.g., tricyclic antidepressants) and monoamine oxidase inhibitors such as selegiline – Clonidine – Herbal medicine (e.g., Ginkgo and Passiflora).

Mohammadi & Akhondzadeh

200 Expert Rev. Neurotherapeutics 7(2), (2007)

Five-year view Transdermal patch systems have proved to be both effectiveand innovative in the delivery of medications for a widerange of diseases. The first transdermal patch system forADHD uses methylphenidate and is suggested for once-a-day use in children aged 6–12 years. At present, a new drugapplication for this methylphenidate transdermal system isunder review with the US FDA. The methylphenidate trans-dermal system is a different treatment strategy and the results

are promising so far. Despite the promising results for the useof nonstimulant drugs in the treatment of ADHD, morelarge scale, randomized clinical trials with placebo and stimu-lant controls are needed to better define the role of alterna-tive pharmacological medications in the treatment ofADHD. Polypharmacy with stimulant and nonstimulantmedication including herbal medicines should be investi-gated in controlled clinical trials as specific subgroups mayhave differential responses.

References

1 National Institutes of Health Consensus Development Conference Statement. Diagnosis and treatment of attention-deficit/hyperactivity disorder (ADHD). J. Am. Acad. Child Adolesc. Psychiatry 39, 182–193 (2000).

2 Scahill L. Epidemiology of ADHD in school-age children. Child Adolesc. Psychiatry Clin. North Am. 9, 541–555 (2000).

3 Barkley RA. Attention-deficit hyperactivity disorder. Scientific Am. 8, 44–52 (1998).

4 Fox AM, Mahoney WJ. Children with School Problems. Canadian Paediatric Society, Ottawa, Canada (1998).

5 American Academy of Pediatrics, Committee on Quality Improvement. Diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder. Pediatrics 105, 1158–1170 (2000).

6 Barkley RA. Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment (2nd Edition). Guilford Press, NY, USA (1998).

7 Goldman L, Genel M, Bezman R, Slanetz P. Diagnosis and treatment of attention deficit/hyperactivity disorder in children and adolescents. JAMA 279, 1100–1107 (1998).

8 Mercuglioano M. What is attention-deficit/ hyperactivity disorder? Pediatric Clin. N. Am. 46, 831–843 (1999).

9 Spencer T, Biederman J, Wilens T. Attention-deficit/hyperactivity disorder and comorbidity. Pediatric Clin. N. Am. 46, 915–927 (1999).

10 Richard W, Root II, Robert J, Resnick J. An update on the diagnosis and treatment of attention-deficit/hyperactivity disorder in children. Prof. Psychol. Res. Pr. 34, 34–41 (2003).

11 Owens J, Hoza B. Diagnostic utility of DSM-IV-TR symptoms in the prediction of DSM-IV-TR ADHD subtypes and ODD. J. Atten. Dis. 7, 11–27 (2003).

12 Staller J, Faraone SV. Attention-deficit hyperactivity disorder in girls: epidemiology and management. CNS Drugs 20, 107–123 (2006).

13 Gaub M, Carlson CL. Gender differences in ADHD: a meta-analysis and critical review. J. Am. Acad. Child Adolesc. Psychiatry 36, 1036–1045 (1997).

14 Biederman J, Faraone S, Mick E, Williamson S. Clinical correlates of ADHD in females: findings from a large group of girls ascertained from pediatric and psychiatric referral sources. J. Am. Acad. Child Adolesc. Psychiatry 38, 966–975 (1999).

15 Nadeau K, Littman EB, Quinn PQ. Understanding Girls with Attention Deficit Hyperactivity Disorder. Bruner/Mazel, NY, USA (2000).

16 American Psychiatric Association. Diagnostic and Statistical Manual for Mental Disorders (4th Edition). American Psychiatric Association, Washington, USA (1994).

17 Tannock R. Attention deficit hyperactivity disorder: advances in cognitive, neurobiological, and genetic research. J. Child Psychol. Psychiatry 39, 65–99 (1998).

18 Pliszka SR, McCracken JT, Maas JW. Catecholamines in attention-deficit hyperactivity disorder: current perspectives. J. Am. Acad. Child Adolesc. Psychiatry 35, 264–272 (1996).

19 Waldman ID, Rowe DC, Abramowitz A, Kozel ST, Mohr JH, Sherman SL. Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity. Am. J. Hum. Genet. 63, 1767–1776 (1998).

20 Mick E, Biederman J, Faraone SV, Sayer J, Kleinman S. Case-control study of attention-deficit hyperactivity disorder and maternal smoking, alcohol use, and drug use during pregnancy. J. Am. Acad. Child Adolesc. Psychiatry 41, 378–385 (2002).

21 Linnet KM, Dalsgaard S, Obel C, Wisborg K, Henriksen TB, Rodriguez A. Maternal lifestyle factors in pregnancy risk of attention deficit hyperactivity disorder and associated behaviors: review of the current evidence. Am. J. Psychiatry 160, 1028–1040 (2003).

22 American Academy of Pediatrics. Subcommittee on Attention- Deficit/Hyperactivity Disorder and Committee on Quality Improvement. Treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics 108, 1033–1044 (2001).

23 MTA Cooperative Group. 14-month randomized clinical trial of treatment strategies for attention deficit hyperactivity disorder. Arch. Gen. Psychiatry 56, 1073–1086 (1999).

24 Greenhill L, Pliszka S, Dulcan MK. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J. Am. Acad. Child Adolesc. Psychiatry 41, S26–S49 (2002).

25 Angold AJ. Stimulant treatment for children: a community perspective. J. Am. Acad. Child Adolesc. Psychiatry 39, 975–984 (2000).

26 American Academy of Pediatrics, Committee on Quality Improvement. Clinical practice guidelines: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics 108, 1033–1044 (2001).

27 Biederman J. Practical considerations in stimulant drug selection for the attention-deficit/hyperactivity disorder patient – efficacy, potency, and titration. Today’s Therapeutic Trends 20, 311–328 (2002).

28 Findling RL, Dogin JW. Psychopharmacology of ADHD: children and adolescents. J. Clin. Psychiatry 59, 42–49 (1998).

29 Greenhill L, Shockey E, Halperin J, March J. Stimulants in Psychiatry (2nd Edition). Tasman A, Kay J, Lieberman JA (Eds). John Wiley & Sons, Ltd, Chichester, England, (2003).

30 Banaschewski T, Roessner V, Dittmann RW, Santosh PJ, Rothenberger A. Non-stimulant medications in the treatment of ADHD. Eur. Child Adolesc. Psychiatry 13, 102–116 (2004).

31 Akhondzadeh S, Tavakolian R, Davari-Ashtiani R, Arabgol F, Amini H. Selegiline in the treatment of attention deficit hyperactivity disorder in children: a double blind and randomized trial. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 841–845 (2003).

Nonstimulant medication approaches for ADHD

www.future-drugs.com 201

32 Mohammadi M, Kashani L, Akhondzadeh S, Sahimi Izadian E, Ohadinia S. Efficacy of theophylline compared to methylphenidate for the treatment of attention deficit hyperactivity disorder in children and adolescents: a double blind and randomized trial. J. Clin. Pharm. Ther. 29, 139–144 (2004).

33 MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal treatment Study of Children with ADHD. Arch. Gen. Psychiatry 56, 1073–1086 (1999).

34 Wernicke JF, Kratochvil CJ. Safety profile of atomoxetine in the treatment of children and adolescents with ADHD. J. Clin. Psychiatry 63, 50–55 (2002).

35 Olvera RL, Pliszka SR, Luh J, Tatum R. An open trial of venlafaxine in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. J. Child Adolesc. Psychopharmacol. 6, 241–250 (1996).

36 Connor DF, Fletcher KE, Swanson JM. A meta-analysis of clonidine for symptoms of attention-deficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 38, 1551–1559 (1999).

37 Scahill L, Chappell PB, Kim YS. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention-deficit/hyperactivity disorder. Am. J. Psychiatry 158, 1067–1074 (2001).

38 Conners CK, Casat CD, Gualtieri CT et al. Bupropion hydrochloride in attention deficit disorder with hyperactivity. J. Am. Acad. Child Adolesc. Psychiatry 35, 1314–1321 (1996).

39 Swanson JM, Greenhill LL, Lopez FA et al. Modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, fixed-dose study followed by abrupt discontinuation. J. Clin. Psychiatry 67, 137–147 (2006).

40 Shytle RD, Silver AA, Wilkinson BJ, Sanberg PR. A pilot controlled trial of transdermal nicotine in the treatment of attention deficit hyperactivity disorder. World J. Biol. Psychiatry 3, 150–155 (2002).

41 Garber SW, Garber MD, Spizman RF. Beyond Ritalin. Harper Collins, NY, USA (1997).

42 Gant C. Complementary medicine approaches to ADHD. Presentation to Annual Conference, American College of Advancement in Medicine (ACAM), Orlando, FL, May 1999; Laguna Hills, CA, ACAM, (1999).

43 Brue, AW, Oakland TD. Alternative treatments for attention deficit hyperactivity disorders: does evidence support their use. Altern. Ther. Med. 8, 68–74 (2002).

44 Pelham WE, Murphy HA. Attention deficit and conduct disorders. In: Pharmacological and Behavioral Treatment: An Integrative Approach. Herson M (Ed.). J Wiley & Sons, NY, USA, 108–148 (1986).

45 Akhondzadeh S, Mohammadi MR, Momeni F. Passiflora incarnata in treatment of attention-deficit hyperactivity disorder in children and adolescents. Therapy 2, 609–614 (2005).

Affiliations

• Mohammad Reza Mohammadi, MD

Tehran University of Medical Sciences, Psychiatric Research Center, Roozbeh Psychiatric Hospital,South Kargar Street, Tehran 13337, IranTel.: +98 215 541 2222Fax: +98 215 541 9113mohamadn@tums.ac.ir

• Shahin Akhondzadeh, PhD

Tehran University of Medical Sciences, Psychiatric Research Center,Roozbeh Psychiatric Hospital, South Kargar Street, Tehran 13337, IranTel.: +98 215 541 2222Fax: +98 215 541 9113s.akhond@neda.net