Psychopharmacologic Treatments for the Assessment and Treatment of Patients with ADHD

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Psychopharmacologic Treatments for the Assessment and Treatment of Patients with ADHD

This article reviews rational approaches to treating attention-deficit/hyperactivity disorder (ADHD) in preschool children, including pharmacological and nonpharmacological treatments. Implications for clinical practice are discussed.

Data Sources
We searched MEDLINE, PsychINFO, Cumulative Index to Nursing & Allied Health, Educational Resources Information Center, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects for relevant literature published in English from 1967 to 2007 on preschool ADHD. We also reviewed the references cited in identified reports. Psychopharmacologic Treatments for the Assessment and Treatment of Patients with ADHD.

Study Selection
Studies were reviewed if the sample included at least some children younger than 6 years of age or attending kindergarten, the study participants had a diagnosis of ADHD or equivalent symptoms, received intervention aimed at ADHD symptoms, and included a relevant outcome measure.

Data Extraction
Studies were reviewed for type of intervention and outcome relevant to ADHD and were rated for the level of evidence for adequacy of the data to inform clinical practice.

Conclusions
The current level of evidence for adequacy of empirical data to inform clinical practice for short-term treatment of ADHD in preschool children is Level A for methylphenidate and Level B for parent behavior training, child training, and additive-free elimination diet.

Attention deficit/hyperactivity disorder (ADHD) frequently begins between 2 and 4 years of age (Connor 2002; Egger and Angold 2006). It is associated with significant impairment in terms of emotional distress for the preschool child and the caregivers (DuPaul et al. 2001), expulsion from daycare or early education settings (Blackman 1999), demands on the caregiver’s time, exclusion from family events, and accident proneness and other safety concerns (Lahey et al. 2004; Rappley et al. 1999). Children with ADHD have comorbid mental health and chronic health problems and are frequent users of the healthcare system (Rappley et al. 2002). As shown by several prospective longitudinal follow up studies, behavior problems in preschool children persist to school-age years and continue to be associated with significant impairment (Campbell and Ewing 1990; Campbell et al. 2000; Egeland et al. 1990; Fischer et al. 1984; Lahey et al. 2004; Lavigne et al. 1998; McGee et al. 1991; Richman et al. 1982). In a recent study, 79.2% of the preschool children who met full diagnostic criteria for ADHD and 34.5% of the preschool children who met criteria in one situation only at initial assessment continued to meet full ADHD diagnostic criteria and exhibited global academic and social impairment three years later (Lahey et al. 2004). Psychopharmacologic Treatments for the Assessment and Treatment of Patients with ADHD.

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Impairment from ADHD and persistence of problems at later ages underscores the need for early intervention in preschool children with ADHD (Beckwith 2000; Bierman et al. 2007; Campbell 2002; Conduct Problems Prevention Research Group 1999; Elliot et al. 2002; Petras et al. 2008; Shure et al. 2001). Recently, the Preschool Psychopharmacology Working Group (PPWG) reviewed pharmacological treatment studies in preschool children and proposed treatment algorithms for preschool psychiatric disorders (Gleason et al. 2007), however the nonpharmacological treatments for ADHD were not reviewed in detail. The primary objective of this paper is to review rational approaches to pharmacological and nonpharmacological treatment of ADHD in preschoolers and the implications for clinical practice. For the purposes of this paper, we define preschool age as prior to starting formal schooling, i.e., first grade. Hence, we reviewed studies that included children in kindergarten and/or younger than 6 years of age. The Food and Drug Administration (FDA) provides additional demarcation for children younger than 6 years. Most of the pharmacological agents for treatment of ADHD are approved by the FDA only for children older than 6 years (with the exception of amphetamines), and the FDA considers their use in children younger than 6 years as “off-label.”

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Methods and Review
We searched MEDLINE, PsychlNFO, Cumulative Index to Nursing & Allied Health, Educational Resources Information Center, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects for relevant literature on treatment of preschool ADHD. We also reviewed the references cited in identified reports to locate other relevant studies. Due to limited literature in this area, we reviewed both controlled and non-controlled studies. The reviewed studies met the following inclusion criteria: Published in English in the past 40 years (between 1967 to 2007); included at least some children younger than 6 years of age and/or attending kindergarten who had a diagnosis of ADHD; or exhibited behavior problems that are part of the ADHD diagnostic criteria, involved intervention aimed at ADHD symptoms, and included an outcome measure to monitor ADHD symptoms. To determine the level of evidence to inform clinical practice, we adapted the International Psychopharmacology Algorithm Project criteria (Jobson and Potter 1995) previously used by Judice and Mayes (2003) to categorize psychopharmacology treatments in preschool children. Psychopharmacologic Treatments for the Assessment and Treatment of Patients with ADHD. Since most of the reviewed child training studies were single case design experiments (state of current evidence for child training studies), based on the Task Force on Promotion and Dissemination of Psychological Procedures guidelines (Task Force on Psychological Intervention Guidelines 1995) previously used by Chorpita et al. (2002) to assess efficacy of psychosocial treatment studies in children and adolescents, we modified the criteria to include single case design experiments in addition to randomized controlled trials.

A treatment was considered to have evidence at Level A, if it demonstrated a significant difference on an ADHD outcome variable in a sample of preschoolers with a Diagnostic and Statistical Manual (DSM) diagnosis of ADHD in at least two randomized controlled trials (RCT) or two series of single case design experiments comparing randomly assigned active treatment to a comparison treatment or placebo. A treatment was considered to have evidence at Level B, if it demonstrated a significant difference on an ADHD outcome variable in a sample of preschoolers with a DSM diagnosis of ADHD in one RCT, two or more RCTs with mixed results, or one series of single case design experiments comparing randomly assigned active treatment to a comparison treatment or placebo. Level C was assigned to a treatment to indicate that data were based on uncontrolled trials, case reports, retrospective chart reviews, or informed clinical opinion.

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Treatment of Preschool Attention-Deficit/Hyperactivity Disorder
Here we review the current available evidence for psychopharmacological and nonpsychopharmacological interventions (psychosocial and alternative treatments) and clinical implications for preschool children with ADHD. Prior to starting any treatment, it is important to conduct a comprehensive assessment that is contextually relevant and takes into account the rapid developmental changes occurring during preschool years. Because a comprehensive discussion of the assessment process for diagnosing ADHD in preschool children is beyond the scope of this paper, the reader is referred to several excellent reviews addressing preschool nosology, diagnosis, and assessment (Angold et al. 2004; Campbell 2002; Carter et al. 2004; Egger and Angold 2006; Emde et al. 1993; Task Force on Research Diagnostic Criteria: Infancy and Preschool 2003). In general, a multi-method and multi-informant evaluation extending over multiple appointments to assess symptomatology and impairment in multiple environments and caregiving contexts is recommended (Carter et al. 2004; Gleason et al. 2007). A combination of diagnostic interviews and parent and teacher rating scales, with psychometric data in preschoolers, are commonly employed to aid in the diagnostic and assessment process. Examples of the parent and teacher rating scales include Conners’ Rating Scales-Revised (CRS-R) (Conners 2001), Swanson, Nolan and Pelham (SNAP) rating scale (Swanson 1992), Child Behavior Checklist-1½ (CBCL-1½) (Achenbach and Rescorla 2000), and ADHD Rating Scale (ADHD-RS) (DuPaul 1998; Gimpel and Kuhn 2000). Psychopharmacologic Treatments for the Assessment and Treatment of Patients with ADHD. The Preschool Age Psychiatric Assessment (PAPA) (Egger et al. 2006) is a reliable and valid semi-structured diagnostic parent-interview that is widely used in research studies of preschool pathology. However, clinical settings may find the cost and length of the PAPA training and administration to be a barrier for its use in routine clinical practice. Nonetheless, adequate history, mental status examination, and collateral information are important for developing an appropriate treatment plan that addresses the biopsychosocial issues specific to each family.

Psychopharmacological treatment
There are several challenges to psychopharmacological treatment of preschool children with ADHD. Preschool age is a period of continued rapid neuronal maturation including synaptic remodeling and construction. Cortical synaptic density reaches its maximum at age 3 and is substantially modified by the pruning process from ages 3 to 7 years (Huttenlocher 1990). Cerebral metabolic rate peaks between 3 and 4 years of age (Chugani 1987). Aminergic systems play an important role in neurogenesis, neuronal migration, axonal outgrowth, and synaptogenesis (Coyle 1997) and are also the targets of action for many psychopharmacological agents as indicated by studies in preclinical models. Thus, clinicians are faced with a dilemma. On one hand, whether it is prudent to recommend exposing the rapidly developing brain of a preschool child to psychopharmacological agents. On the other hand, clinicians also need to consider the consequences of an untreated disorder. Early exposure to adverse environmental circumstances and stress has been shown to result in long-lasting impact on the brain and emotional regulation of animals and humans (Graham et al. 1999; Matthews 2002; Nemeroff 2004).

Information about the use of psychopharmacological agents for treatment of ADHD is available mostly for school age children. In school age children, psychostimulants are the mainstay of treatment for ADHD; nonstimulant psychopharmacological agents are frequently recommended as a second-line treatment if a school age child’s ADHD symptoms do not adequately respond to stimulants (Dulcan and Benson 1997). Recently, a nonstimulant psychopharmacological agent, atomoxetine, has been shown to be a safe and effective treatment of ADHD in school age children (Kratochvil et al. 2004; Michelson et al. 2001). Comparatively, there is limited information on the use of psychopharmacological agents for treatment of ADHD in preschool children. Psychopharmacologic Treatments for the Assessment and Treatment of Patients with ADHD. No pharmacokinetic and dose finding studies to identify dosage and frequency of drug administration in preschool children are available. Until recently, clinicians were left to extrapolate findings from older children to preschool children. However, medications used in older children may have specific toxicities in preschool children (Wigal et al. 2006), and there may be differences in efficacy in preschool children compared to school age children (Greenhill et al. 2006). Additionally, extrapolation to preschool children of data collected in older children is not always possible due to differences in development.

There are over 250 published studies of psychopharmacological agents in school age children with ADHD (Wilens et al. 2002). In contrast, there are a total of 24 published reports (blinded and open-label studies) on the use of psychopharmacological agents involving over 495 preschool children with ADHD. Of the 24 published reports (Tables 1 and ​and2),2), 20 published reports are on the use of stimulants, 2 published case reports on the use of α2 agonists, 1 published case report on the use of atomoxetine, and 1 published case report on the use of fluoxetine in preschool children with ADHD.

Table 1.
Published Blinded Studies of Stimulant Treatment of Attention-Deficit/Hyperactivity Disorder in Preschool Children

Authors Age Range (Mean ± SD) N/n < 6 years Procedure for ADHD Diagnosis Intervention Medication/Dose Study Design/Duration Outcome Assessment (for ADHD and disruptive behaviors) Study Outcome Side Effects/Safety
Conners, 1975 <6 years (57.7 ± 13.2 months) 59/59 Clinical interview, parent questionnaire (MPH 11.8 mg/day (1.5 mg/kg/day) Double-blind, 2 parallel groups (MPH, placebo)/6 weeks Parent Behavior Rating Scale, Global Clinical Improvement Rating, measures of vigilance, seat activity & impulsivity Significant clinical improvement (93% improved on MPH, 11.5% improved on placebo) as rated by the physician on the Global Clinical Improvement Rating, significant reduction in restlessness and disruptive behavior as rated by the parents on the Parent Behavior Rating Scale. Measures of vigilance, seat activity & impulsivity did not show significant difference between MPH and placebo Minimal side effects, trend towards elevated blood pressure in the MPH group
Schleifer et al., 1975 40–58 months (49 ± months1) 26/26 Clinical interview MPH 2.5–30 mg/day on a qd or bid schedule Double-blind, crossover (placebo & MPH “optimal dose”)/4–6 weeks Nursery school observation, Hyperactivity Rating Scale measures of reflectivity-impulsivity, field independence and motor impulsivity Improvement based on caregiver report, no improvement on nursery school observation or psychological measures Dysphoria, social withdrawal, poor appetite, difficulty getting to sleep
Barkely et al., 1984 48–119 months (60.8 ± 7.6 months) 54/18 Clinical interview, Conners’ Rating Scale-Parent (CRS-P), WWPARS MPH 0.15 mg/kg bid, 1.5 mg/kg bid Double-blind, crossover (placebo & 2 MPH doses)/3 weeks Mother-child interaction Significant improvement in child compliance and off-task behavior with MPH, “normalizing” effect of MPH on mother-child interactions More frequent side effects on high MPH dose than low dose or placebo
Barkley et al., 1985 5–9 years (89 months1) 60/12 Psychiatric assessment, CRS-P, Werry Weiss Peters Activity Rating Scale (WWPARS), Home Situations Questionnaire (HSQ) MPH 0.3 mg/kg bid. 0.7 mg/kg bid Double-blind, crossover (placebo & 2 MPH doses)/4 weeks Mother-child interaction during free play and task periods Child compliance and length of sustained compliance improved with the higher dose during the task period, drug effects did not differ during free play or across age levels Greater number of side effects on MPH compared to placebo
Cunningham et al., 1985 4–6 years (68 months1) 42/12 Clinical diagnosis CRS-P Single dose of MPH 0.15 mg/kg, 0.50 mg/kg Double-blind, crossover (placebo & 2 MPH doses)/4 sessions Videotaped observations during freeplay, co-operative task, and simulated school setting ↓ actometer readings & ↑ on-task behavior during the simulated school setting, linear dose response, optimal ↓ in controlling and domineering interactions observed at 0.15 mg/kg dose with no incremental benefit on 0.50 mg/kg dose Side effects were not monitored
Barkley, 1988 31–59 months (46.8 ± 6.7 months) 27/27 Clinical interview, CRS-P, WWPARS, HSQ MPH 0.15 mg/kg bid, 1.5 mg/kg bid Triple-blind, crossover (placebo & 2 MPH doses)/3 weeks Mother-child interaction ↑ rates of compliance and length of sustained compliance with maternal commands, and on task behavior on higher dose during the task period Trend for more frequent side effects on MPH compared to placebo
Barkley, at al., 1988 5–12 years (8.5 ± 2.3 years) 23/not specified Semistructured parent interview, CRS-P or CRS- Teacher (CRS-T) MPH 0.3 mg/kg bid, 0.5 mg/kg bid Double-blind, crossover (placebo & 2 MPH doses)/3 weeks Gordon Diagnostic System (GDS) for vigilance and impulse control, playroom observation during a restricted academic situation, CRS-P, CRS- T, HSQ, School Situations Questionnaire (SSQ) 80% of the children responded positivly to MPH on parent and teacher ratings of hyperactivity and disruptive behaviors, and ↓ off-task and hyperacctivity ratings during playroom observation (restricted academic situation). Significant main drug effects for 16 of the 31 outcome measures, mostly on teacher ratings and observations during the restricted academic situation, both doses were equally effective No difference in the number or severity of side effects. Two children discontinued the study due to development of tics in response to the medication and were excluded from the study analysis
Speltz et al., 19882 51 months 1/1 Clinical interview, CRS-T Dextroamphet-amine (DEX) 2.5 mg bid DEX 5 mg bid and Day Program Double-blind time series (placebo & 2 DEX doses in counter- balanced order)/11 weeks Daily observations of 15-minute work periods and 20-minute free play for frequency of on-task behavior, and teacher ratings of aggressive and disruptive behaviors and reports of side effects ↓ off-task and aggressive behavior on DEX compared to placebo Behavior gains maintained at follow up 2 years later ↓ whining, listlessness, solitary play, stomachache ↓ appetite, more frequent during 5 mg bid dose
Fischer & Newby, 1991 2–17 years (8.9 ± 2.9 years) 161/not specified Semistructured parent interview, CRS-P, CRS-T, Child Behavior Checklist (CBCL), Teacher Rating Form (TRF) MPH 0.2 mg/kg & 0.4 mg/kg BID Double-blind crossover (placebo & 2 MPH doses)/3 weeks CRS-P, CRS-T, HSQ SSQ, reaction time, GDS viligance task Significant positive medication response on parent and teacher ratings of hyperactivity and laboratory measures of viligance and off-task behaviors, higher dose was most effective No side effects reported
Mayes et al., 19943 2–13 years (7.1 years1) 69/14 Clinical interview MPH 7.5–30 mg/day on a tid schedule Double-blind, ABA (placebo & MPH “optimal dose”)/3 weeks Conners’ 10-item ADHD Parent Rating Scale 79.4% improved on MPH based parent ratings on the Conners’ scale 50.7% experienced side effects irritability, ↓ appetite, lethargy
Musten et al., 1997; Firestone et al., 1998 48–70 months (58.1 ± 8.2 months) 31/31 Diagnostic Interview for Children and Adults-Parents (DICA-P), Swanson, Nolan and Pelham checklist (SNAP), CRS-P, attention task MPH 0.3 mg/kg bid, 0.5 mg/kg bid Double-blind, crossover (placebo & 2 MPH doses)/3 weeks Parent-child interaction tasks, CRS-P, GDS Delay and Vigilance Tasks ↑ attention and on-task during laboratory observation, ↓ impulsivitiy and hyperactivity as rated by parents on the CRS-P, no improved in compliance to parent requests 10% experienced severe side effects: social withdrawal, sadness, ↑ number & ↑ severity of side effects with the higher dose
Handen et al., 19994 48–71 months (58.9 ± 8.2 months) 11/11 Clinical interview, Preschool Behavior Questionaire (PBQ), CRS-P MPH 0.3 mg/kg/dose & 0.6 mg/kg/dose qd to tid Double-blind, crossover (placebo & 2 MPH doses)/3 weeks CRS-T, PBQ, direct behavior observation 72.7% improved on MPH based on at-least 40% reduction in teacher ratings of hyperactivity and inattention, significant improvement on clinic-based observations of activity level and level and compliance, more improvement on the higher dose 45% experienced side effects (social withdrawal and irritability); side effects more frequent at the higher dose
Short et al., 2004 <6 years (63 months1) 28/28 Diagnostic Interview Schedule for Children-Parent (DISC-P) or clinical interview, Conners’ Abbreviated Symptoms Questionnaire (CASQ), ADHD Rating Scale (ADHD-RS) MPH 5 mg, 10 mg, 15 mg bid or mixed amphetamine salts (MAS; Adderall) 5 mg, 10 mg & 15 mg qd Double-blind, crossover (placebo & 2 or 3 MPH or MAS doses)/3–4 weeks ASQ ADHD-RS, HSQ Improved parent and teacher ratings of ADHD on either stimulant by at least 1 SD in 82% of the children and by 2 SD in 50% of the children. Clinical ratings of normalized behavior on best dose in 82% of the children ↓ appetite, crying & rebound effects
Chacko et al., 2005 5–6 years (6.1 ± 0.57 months) 36/14 Structured parent interview, parent and teacher Disruptive Behavior Disorder rating scales MPH 0.3 mg/kg & 0.6 mg/kg bid and Behavior Modification System in a Summer Treatment Program Double-blind, crossover (placebo & 2 MPH doses)/8 weeks Point system, classroom rules, productivity and accuracy of class work Improved classroom behavior for following rules and noncompliance and class work completion on both MPH doses compared to placebo, little incremental improvement in classroom measures on the higher MPH dose compared to the lower MPH dose. 28% children improved with classroom behavioral intervention & showed no incremental benefit of MPH ↓ appetite
Greenhill et al., 2006 3–5.5 years (53 ± 8 months) 165/165 Clinical assessment for DSM-IV diagnosis of ADHD, unanimous consensus by the panel of investigators, CRS-P, CRS-T MPH 1.25 mg, 2.5 mg, 5.0 mg, 7.5 mg tid Double-blind, crossover (placebo & 4 MPH doses) after 10 weeks of parent training/5 weeks Swanson, Kotkin, Atkins, M-Flynn, and Pelham (SKAMP), Conners, Loney and Milch (CLAM) rating scales Significant ↓ in parent- and teacher-rated ADHD symptoms on the 3 higher doses ↓ appetite stomachache, and sleep difficulties, ↑ rates of social withdrawal and lethargy, ↑ growth velocity, 8.3% discontinued due to MPH side effects
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1SD not provided.
2Individualized weekly parent training sessions, classroom behavior management program and social skills training group were also administered concurrently.
3Included inpatient or outpatient preschool and school age children with autism, other developmental disorders or no developmental disorders. Psychopharmacologic Treatments for the Assessment and Treatment of Patients with ADHD.
4Included preschool children with mental retardation.
ADHD = attention-deficity/hyperactivity disorder; MPH = methylphenidate.

Table 2.
Published Open-Label Studies of Stimulant Treatment of Attention-Deficit/Hyperactivity Disorder in Prechool Children

Authors Age Range (Mean ± SD) N/n < 6 years Diagnostic Procedure for Eligibility Medication/Dose Study Design/Duration Outcome Assessment (for ADHD and disruptive behaviors) Study Outcome Side Effects/Safety
Cohen et al., 1981 Kindergarten aged1 24/24 Clinical interview, Connors’ Rating Scale-Teacher (CRS-T) MPH 10–30 mg/day Three randomized parallel groups (MPH, Cognitive Behavior Management [CBM], and CBM + MPH), open-label treatment/10 weeks Cognitive and motor impulsivity tasks, parent and teacher behavior rating scales, classroom observation No treatment effect in any of the groups 4 of the 14 (29%) children on MPH stopped medication due to side effects and were reassigned to either CBT or no treatment
Alessandri & Scharmm, 1991 50 months 1/1 Clinical interview, Connors’ Rating Scale-Parent (CRS-P) DEX 2.5 mg bid Open-label A-B-A-B reversal design/16 weeks Blinded ratings of off-task behavior, level of cognitive play and social participation during structured activity and unstructured play; teacher rated PBQ, CRS-T ↓ off-task behavior, ↑ attention, ↑ developmentally appropriate goal-directed, organized and symbolic play, & improved social functioning on direct observation ratings of behavior during structured activity and unstructured play ↑ solitary & parallel play
Byrne et al., 1998 62 months1 8/8 Clinical interview, Continuous Performance Test for Preschoolers—Visual (CPTP-V), CPT-Auditory (A), CRS-P, CBCL MPH 15–20 mg/day or DEX 7.5–15 mg/day on qd-tid schedule Open-label/5 months CPTP-V, CPT-A, CRS-P, Child Behavior Check-list (CBCL) ↑ attention & social relations, ↓ problem behaviors No information
Stiefel & Dossetor, 1998 5 years 1/1 Clinical interview DEX 5 mg bid Open-label/4 years Clinical assessment Improved behavior Initial problem with reduced appetite and getting to sleep ameliorated with time
Ghuman et al., 2001 40–70 months (56.4 ± (9.6 months) 27/27 Clinical interview MPH 0.55 mg/kg/day or DEX 0.43 mg/kg qd-qid Chart review/24 months Clinical Global Impressions-Severity (CGI-S) and CGI-Improvement 74% experienced improvement at 3 months and 70% at 12 and 24 months 63% experienced side effects; poor appetite, stomachache, irritability, dysphoria, sleep disturbance, headache, dull/tired; 11% stopped stimulants due to side effects
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1Mean age not provided.
MPH = methylphenidate; DEX = dextroamphetamine.

Psychostimulant studies
Of the 20 published studies on the use of stimulants in preschool children, 12 double-blind group treatment studies (one parallel groups, 10 crossover and 1 ABA design) included 417 preschool children treated with methylphenidate (MPH). Two double-blind MPH/placebo crossover studies included both preschool and older children, but did not specify the number of preschool participants (Barkley 1988; Fischer and Newby 1991); and one blinded time series treated one preschool child with dextroamphetamine (Speltz et al. 1988). Psychopharmacologic Treatments for the Assessment and Treatment of Patients with ADHD. The remaining five published reports are open-label studies or case reports involving a total of 61 preschool children treated with MPH or dextroamphetamine (Alessandri and Schramm 1991; Byrne et al. 1998; Cohen et al. 1981; Ghuman et al. 2001; Stiefel and Dossetor 1998).

Twelve of the fifteen blinded MPH studies treated typically developing preschool children with ADHD; seven studies included only preschool children (Barkley 1988; Conners 1975; Firestone et al. 1998; Greenhill et al. 2006; Musten et al. 1997; Schleifer et al. 1975; Short et al. 2004; Speltz et al. 1988), while the other six studies included both preschool and older children (Barkley et al. 1988; 1985; 1984; Chacko et al. 2005; Cunningham et al. 1985; Fischer and Newby 1991). Of the other two studies, one included a mixture of inpatient or outpatient preschool and school age children with ADHD who were either typically developing or had autism or other developmental disorders (Mayes et al. 1994), and the one remaining blinded study treated preschool children with developmental disorders (Handen et al. 1999). The diagnostic procedure used most frequently included a combination of clinical interview and dimensional rating scales. With the exception of the recent PATS study, sample size was small ranging from 11–59, duration of the psychostimulant trials ranged from 3–9 weeks, and stimulant dose ranged from 0.15–0.6 mg/kg. Mixed outcomes were reported for efficacy. Based on direct observation of the preschool children’s nursery school behavior, one study reported no improvement with MPH compared to placebo (Schleifer et al. 1975). Positive response to MPH was reported by other investigators in 80%–83% of typically developing preschool children (Conners 1975; Greenhill et al. 2006; Short et al. 2004) and 71%–73% of preschool children with developmental disorders (Handen et al. 1999). Data on side effect profile in preschool children was also divergent. Rates of side effects ranged from minimal or clinically negligible (Conners 1975) to 89% in typically developing preschool children (Schleifer et al. 1975) and 45%–50% in preschool children with developmental disorders (Handen et al. 1999; Mayes et al. 1994). Dysphoria, crying, whining, irritability, and solitary play were more frequently reported in preschool children than seen in older children.

The 6-site PATS study randomized 165 preschool children (3–5.5 years) diagnosed with ADHD in a placebo-controlled, double-blind crossover design, to one week each of 4 MPH doses (1.25 mg, 2.5 mg, 5 mg and 7.5 mg TID) and placebo. With the exception of the lowest MPH dose, improvements in parent- and teacher-rated ADHD symptoms were reported with MPH compared to placebo; the 7.5 mg TID dose was found to be the most effective. The effect sizes (Cohen’s d) in the intent-to-treat sample ranged from 0.4–0.8 and were smaller than those reported for school age children treated with MPH (Greenhill et al. 2006).Psychopharmacologic Treatments for the Assessment and Treatment of Patients with ADHD. Interestingly, secondary analyses of the PATS efficacy data showed that preschoolers with ADHD with no or one comorbid disorder (primarily oppositional defiant disorder [ODD]) had treatment responses (Cohen’s d = 0.89 and 1.00, respectively) at the same level as found in school age children (Ghuman et al. 2007). Preschoolers with 2 comorbid disorders had moderate treatment response (Cohen’s d = 0.56) and preschoolers with 3 or more comorbid disorders did not respond to MPH (Ghuman et al. 2007). However, caution is needed in the generalization of the findings as there were only 15 preschoolers (9% of the sample) with 3 or more comorbid disorders compared to 150 preschoolers with two comorbid disorders (n = 34, 21% of the sample), one comorbid disorder (n = 69, 42% of the sample) or no comorbid disorders (n = 47, 28% of the sample). In addition to decreased appetite, stomach ache, and sleep difficulties usually seen in school age children, increased rates of social withdrawal and lethargy were reported especially at higher doses. A higher discontinuation rate (8.3%) due to MPH side effects was reported in the PATS study than the 0.5% discontinuation rate in the National Institute of Mental Health (NIMH) Multimodal Treatment of ADHD (MTA) study with school-age ADHD children (Wigal et al. 2006). Compared with the Center for Disease Control (CDC) norms, the preschool children with ADHD in the PATS were 2.0 cm taller and 1.8 kg heavier at baseline. A 20% less than expected annual height gain (−1.38 cm/year) and 55% less than expected annual weight gain (−1.32 kg/year) was reported for the children who continued MPH for a year in the open-label follow up phase (Swanson et al. 2006). Decrease in weight velocity was evident at the end of the 5-week double-blind crossover phase. Most preschoolers with ADHD were able to maintain improvement over 10 months of open-label follow up treatment (Vitiello et al. 2007).

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Two of the open-label stimulant studies were prospective open-label treatment trials, two were case reports, and one was a retrospective chart review. Positive response to stimulants (MPH or dextroamphetamine) was reported in four of the open-label studies; one prospective treatment trial reported no treatment effect and reported a 30% discontinuation rate due to MPH adverse effects (Cohen et al. 1981).

Non-stimulant studies
The two published case reports of open-label treatment with α2 agonists in 5 preschool children with ADHD reported improvement in hyperactive and impulsive behavior (Cesena et al. 1995; Lee 1997), one published case report of open-label treatment with atomoxetine in 10 preschool children reported improvement in hyperactive, impulsive and inattentive symptoms (Kratochvil et al. 2007), and one published case report of open-label treatment with fluoxetine in one preschool child with ADHD reported improvement in attention span. Psychopharmacologic Treatments for the Assessment and Treatment of Patients with ADHD.