Clinical Psychopharmacology Seminar
Original Authors: Paul Perry, Ph.D, BCPP, Sam Kuperman,
M.D.
Latest Revisers: Mitchell Barnett, PharmD, MS
Creation Date: 1996
Last Revision Date: May 2005
Peer Review Status: Internally Peer Reviewed
Critics of ADHD include the Church of Scientology, newspaper reporters, talk show hosts, some US Drug Enforcement Agency officials, conservative legislators, and a few physicians and psychologists. With few exceptions, these critics have never been involved in the management and treatment of children, adolescents or adults with ADHD. Safer (2000) summarizes the objections of the ADHD faultfinders into seven following criticisms.
The data do not support these assertions. Safer (2000) counters these claims by noting the following data.
The effectiveness of stimulants in improving academic performance is widely misunderstood. Often times parent's pressure clinicians into writing stimulant prescriptions for "a lets see if it helps" trial. If the drug does help they assume a diagnosis of ADHD. Sostek et al (1980) showed that stimulant medication improves vigilance performance (attention/concentration) in both normal and hyperactive children. This is an extraordinarily important clinical observation that points out the fallacy of making a diagnosis via treatment response. It also explains why other commonly used dopamine agonists such as caffeine and nicotine also benefit concentration and the ability to study.
Prevalence. The ADHD diagnostic criteria were modified in 1994 with DSM-IV. The new criteria were subtyped as hyperactive-impulsive, inattentive or combined. Wolraich et al (1998) estimated the effect of the reclassification of the criteria by interviewing 214 teachers from 10 schools in Nashville, Tennessee. They estimated the prevalence rates of ADHD in 4,323 children (kindergarten through 5th grade). Table 1 presents the rates for the three ADHD subtypes based first on symptoms only and then the rates based on symptoms in children whose academic and behavioral problems were in the lower 5th percentile for the group.
Comorbidity. ADHD is characterized by consistent impaired attention impulsivity, and excessive motor activity in two or more settings e.g., home, school, physician's office etc. There is a high rate of comorbidity between ADHD and conduct disorder, oppositional defiant disorder, depression, and anxiety disorders. Additionally, symptoms of ADHD can be found in cases of learning disabilities, language disorders and mental retardation. Thus comorbidity raises the questions as to whether the presence of another disorder alters the likelihood of a positive drug response? Family histories of the first degree relatives find increased rates of ADHD, poly-substance dependence, antisocial personality disorder, depression and anxiety disorders. Additionally, there is a 25% concordance rate for ADHD exists among the probands' first-degree relatives (Weiss and Hechtman 1986). Children with ADHD are at an increased risk of having antisocial behavior, depression and poly-substance abuse problems occurring when they are adults. The ADHD problems persist into adulthood in approximately 10-60% of the patients (Wilens et al 1995). There have been nine reports published in which cohorts of children with ADHD were reexamined 4-16 years later to determine the level of retained ADHD. The rate of ADHD declined by 50% approximately every 5 years. Therefore it is estimated; assuming the adult ADHD prevalence rate is 0.8% at age 20 it would decline to 0.05% at age 40 (Hill et al 1996). Adults with ADHD are usually self-sufficient, but they have poorer academic performance, poorer job performance, and lower socioeconomic status than siblings do. They have frequent divorces, job changes, change of residence, and car accidents. Most report a high level of subjective distress (79%) and interpersonal problems (75%) (Fargason and Ford 1994).
Differential Diagnosis. ADHD should not be diagnosed until head injuries, petit mal seizures, cerebral infection, substance abuse, hyperthyroidism; anxiety disorders and mood disorders have been excluded. Of the diagnoses, anxiety disorders and mood disorders are most commonly misdiagnosed as ADHD. The ADHD workup should include teacher and parent child ratings, e.g., Iowa Connors; a physical examination; lead screening; neurologic examination; antenatal, perinatal, social, family, school and medical history; developmental milestones, cognitive testing that includes an IQ test and a reading test; and psychometric tests that quantifies errors of omission (inattention) and errors of commission (hyperactivity/impulsivity).
Neurochemistry. Various abnormal neurochemical findings for ADHD have been reported. A decrease in norepinephrine’s major metabolite, MHPG, has been argued to support a norepinephrine deficiency hypothesis, whereas low levels of dopamine’s major metabolite, homovanillic acid (HVA) are postulated to support a dopamine deficiency hypothesis (Cohen et al 1977). Additionally, an excess of platelet MAO has been observed. Young et al (1980) demonstrated an age-related decrease in MAO in the platelets of normal children. However, the decrease in MAO activity was not observed in children with ADHD. The brain maps of ADHD children show an excess of theta (slow wave) activity in the frontal lobe, which may relate to a decrease in glucose metabolism in this area and suggest dysregulation of arousal and attention (Zametkin et al 1990). The neurochemical changes are hypothesized to have a genetic basis that is likely polygenic in nature. The candidate genes that may be involved in ADHD include three categories 1) genes coding for various neurotransmitter functions, i.e, dopamine-transporter receptor (DAT1), dopamine-4 receptor (DRD4), dopamine-5 receptor (DRD5), synaptosome-associated protein of 25 kDA (SNAP25); 2) genes coding for catalyzing dopamine biosynthesis, i.e., tyrosine hydroxylase (chromosome 11p15.5), dihydroxyphenalanine (DOPA) decarboxylase (chromosome 7p11), dopamine-beta-hydroxylase (chromosome 9q34); 3) genes coding for the metabolism of cathecholamines, i.e., COMT, MAO; and 4) other genes, i.e, glutamate receptor inotropic NMDA 2A (GRIN2A) (chromosome 16p13), serotonin transporter gene (Voeller 2004).
Pharmacotherapy. While CNS stimulant medications currently are the drugs of choice, tricyclic antidepressants are also useful. Stimulants (norepinephrine or dopamine agonists) have been shown to help the symptoms of ADHD. Patients, teachers, and clinicians rate 75% of children with ADHD to be improved on stimulants, compared to 18% of placebo-treated children (Green 1992). Approximately 20-25% of those who respond poorly to one medication will respond positively to another (Dulcan 1990). Importantly, the psychopharmacology literature provides no agreement about how much improvement is required for a child to qualify as a “clinical responder.” Stimulants tend to decrease physical activity, particularly during times when children are expected to be less active such as during school. They decrease vocalizations,and noise, and disruptive activity, and improve handwriting. Stimulants improve compliance with adults’ commands, improve attention span and short-term memory and reduce distractibility and impulsivity. The studies reviewed in this section include those that were double-blind controlled studies that investigated the efficacy of stimulants, antidepressants, and clonidine in the treatment of ADHD. Dopamine agonists such as L-DOPA, piribidal, amantadine are not effective.
Monitoring. The Iowa group utilizes the Iowa-Connors Teacher's Scale Revised for monitoring of children and adolescents both at home and at school. The scale consists of ten items scored as not at all (0), a little bit (1), pretty much (2) or very much (3). They are divided into two symptom clusters, the Attention Factor and the Conduct Factor. The five items of the Attention Factor consist of (1) fidgeting, (2) hums and makes other odd noises, (3) excitable (impulsive), (4) inattentive, (easily distracted), and (5) fails to finish thing he starts. The five items of the Conduct Factor consist of (1) quarrelsome, (2) acts "smart", (3) temper outburst (explosive, unpredictable behavior), (4) defiant, and (5) uncooperative. This is a user-friendly monitoring scale that requires minimal time to score.
Stimulants
Efficacy - Children/Adolescents.
The study by Huestis et al (1975) contrasted the effectiveness of MPH, dextroamphetamine (DAS) and caffeine to placebo in the treatment of MBD. Subjects consisted of 12 boys and 6 girls with a mean age of 8.5 years who met the criteria for MBD. Following a two-week placebo or vitamin capsule lead-in period, a randomized crossover treatment paradigm was utilized. Subjects received two capsules in the morning and one capsule at noon of caffeine 80 mg, DAS 5 mg, or MPH 10 mg capsules for 3 three-week treatment periods. However, the amount of medication for each subject was individualized during the three-week period. Each subject received at least 300 mg/d of caffeine for at least one week while the mean dose for DAS was 20 mg/d (5-25 mg/d) and MPH 40 mg/d (30-60 mg/d). Two psychiatrists carried out weekly assessments of mean target symptoms. Parents and teachers took part in weekly rating using the Davids’ Hyperkinetic Rating Scale (DHRS). Parents also took part in weekly symptom checklists, while teachers rated behaviors. The results indicated that both DAS and MPH were significantly more effective than placebo and caffeine, but were not statistically different from each other.
Arnold et al (1978) conducted a double-blind placebo controlled comparison of MPH, DAS, and caffeine in 29 children (22 males and 7 females) with MBD. Using a randomized crossover design, patients received approximately MPH 30 mg/d, DAS 15 mg/d and caffeine 240 mg/d with two-thirds of the dose being given in the morning and the other third at noon. Each treatment was given for three weeks. The teacher rating Davids’ Hyperkinetic Rating Scale found that both MPH and DAS both reduced hyperkinetic behavior and improved the poor -school work parameter in contrast to caffeine and placebo. There was no difference in effectiveness between MPH and DAS. The parent rated problem list also found MPH and DAS equally effective and both were more effective than either caffeine or placebo. Twenty-six of the 29 children responded to the stimulants, 12 best to DAS, 10 best to MPH, and one best to caffeine. The only significant adverse drug reactions as rated by the parents were that DAS actually reduced “tummy ache” complaints, while both DAS and MPH decreased appetite.
A common misperception involving the use of stimulants in reducing hyperactivity was that the drugs impaired social functioning by reducing spontaneity and the child’s decision-making ability. However, Whalen et al (1987) have shown just the opposite finding that doses of MPH 0.6 mg/kg or 0.3 mg/kg improve social behavior in school. They defined the effects of MPH on the natural behaviors and unstructured activities utilizing a group of 24 children with either ADD or ADHD (DSM-III). Though social difficulties are not part of the DSM-III criteria, it is well known that these children have problems interacting with their peers. This study looked at 24 children (three girls and twenty-one boys) between ages of 6 and 11 years. In random order, each subject received two consecutive days of placebo, 0.3 mg/kg/d MPH and 0.6 mg/kg/d MPH. This sequence was repeated a second time with the same randomized order. The measured behaviors were classified as either appropriate social, negative social, or non-social behavior. Appropriate social behavior included conversing, initiating social contact or participating on an ongoing game. Negative social behavior included rule breaking, non-compliance, disruption, teasing, verbal aggression and physical aggression. Nonsocial behavior included solitary play, daydreaming, and bystanding. For the data analyses, children were split into a younger group (mean = 7-8 years, n=12) and an older group (mean = 9-11 years, n=12). Both groups experienced a decrease in negative social behavior while receiving low dose MPH. Only the younger group showed a further improvement in their negative social behavior when the dose was increased from 0.3 to 0.6 mg/kg/d. The occurrence rates of non-social behaviors remained unchanged while on either placebo or MPH. The authors concluded that disruptive behaviors (negative-social behavior) could be reduced successfully without decreasing overall sociability (appropriate social behavior).
Klorman et al (1990) examined the effects on 48 previously untreated adolescents diagnosed with DSM-III attention deficit disorder (ADD). Forty-two were male and 6 were female with an age range of 12-18 years (mean = 14 years). All patients had a Wechsler IQ > 80 with a mean score of 109. The subjects received three consecutive weeks each of MPH and placebo in random order and under blind conditions. The dose of MPH was based on body weight. Subjects weighing under 37.5 kg received 7.5 mg in the morning and at noon in the first week, 10 mg in the second week and 10 mg twice daily plus 5 mg at 4 PM in the third week. Those in the range of 37.5 kg and 54.5 kg received 10 mg twice daily in week one, 12.5 mg twice daily in week two and 12.5 mg twice daily plus 7.5 mg at 4 PM in week three. Those weighing more than 54.5 kg received 12.5 mg twice daily in the first week, 15 mg twice daily during week two and 15 mg twice daily plus 10 mg at 4 PM during week three. For reported side effects, dosages were lowered. Three females in the active phase required dose lowering. Parents and teachers on a weekly basis using the Conners Hyperactivity Questionnaire and the Iowa Inattention and Aggression Scales took measurements. At the end of each phase, aggression and hyperactivity was rated on the Time on Task Scale (TOTS). At this time the occurrence of side effects were also assessed. Throughout the trial, weights were taken and subjects’ moods were analyzed using the Nowles Mood Scale. Mood ratings focused on factors known to be sensitive to the effects of stimulants: vigor, elation, urgency, fatigue and concentration. Patients’ behavior was significantly better during MPH than during placebo. Both teachers and parents estimated an equivalent degree of benefit for the MPH treatment. Parents reported significant improvement with MPH treatment based on the Conners Questionnaire, the Inattention-Overactivity Scale, and the Aggressions Scale. Similar results were seen from the teacher’s ratings, which indicted significant improvement on the Conners Questionnaire. With respect to the TOTS scale, both parents and teachers reported significant improvement with MPH treatment. Patients had more adverse effect complaints during MPH treatment than placebo. Increased rates of appetite loss, dry mouth, and shakiness were found. The patients’ mood parameters of concentration, fatigue, elation, and vigor were better while receiving MPH rather than placebo. In summary, MPH significantly reduced teachers’ and parents’ ratings of hyperactivity, inattention, and oppositionality. The patients rating themselves improved and reported elevated subjective mood during stimulant therapy. Treatment benefits were comparable for patients with and without concurrent conduct or oppositional disorder as those with and without past or present depressive disorders.
Pelham et al (1990) studied 22 children (8-13 years) with a diagnosis of ADHD (DSM-III-R). Using a double-blind, placebo-controlled crossover design subjects received in random order for 3-6 days each, placebo, MPH 10 mg bid, sustained release MPH 20 mg q AM, pemoline 56.25 mg q AM, and sustained release DAS 10 mg q AM. Dependent measures included evaluations of social behavior during group recreational activities, classroom performance, and performance on a continuous performance task. Although all four medications were effective 10 of the 15 responders were ultimately placed on either DAS spansules or pemoline. The short treatment periods obviate the criticism of pemoline that claim 3 to 6 weeks of treatment must elapse before its therapeutic effect is observed.
Methylphenidate has been shown to be effective in 4-6 year old children as measured in a double-blind, placebo-controlled trial by Musten et al 1997. Significant improvements were seen in attention and impulsivity as measured by cognitive tasks for both doses of 0.3 and 0.5 mg/kg/dose of methylphenidate versus placebo (no difference between doses). Parent ratings of child behavior were also significantly improved, although children had no change in complying with parental requests. There was a significant amount of intolerability with the 0.5mg dose versus the 0.3mg dose.
Children/Adolescents Efficacy Conclusions. There are a total of 7 double-blind placebo controlled ADHD efficacy studies, 7 involving methylphenidate, 3 dextroamphetamine, 3 caffeine, and 1 pemoline (Gittelman-Klein 1987, Green 1992, Greenhill 1992). A total of 152 patients were studied. Methylphenidate, dextroamphetamine, and pemoline appear equally effective in treating ADHD. The 3 psychostimulants were found to be more effective than caffeine and placebo. A summary of the studies is presented in Table 1. It can be concluded from these studies the following:
Stimulants - Efficacy -- Adults. There are 6 controlled trials assessing the efficacy of stimulants in adults (Wood et al 1976, Wender et al 1981, Mattes et al 1984, Wender et al 1985, Gualtieri et al 1985, Spencer et al 1995). The trials are profiled in Table 2. In contrast to the robust response in children and adolescents, the data suggest a more equivocal response rate that varies from 25% (Mattes et al 1984) to 78% (Spencer et al 1995) (mean = 52%). There was no difference in the response rate between methylphenidate (56%) and pemoline (50%). The wide variability in the response rate often times appears to be a function of often times subtherapeutic doses, high rates of comorbidity, and differing methods of defining ADHD and treatment response. Spencer et al (1995) had the most robust response (MPH = 78% and placebo = 4%) using present day ADHD criteria and more aggressive doses of 0.5, 0.75, and 1 mg/kg/d. Although there was a positive correlation between dose (mg/kg/d) and response there was no correlation between MPH plasma concentrations and response.
Stimulant -- Dosage.
A reasonable dosing strategy is to gradually titrate a single morning dose to assess an effective cognitive dose and subsequently repeat this dose for the second dose and if necessary the third daily dose. Because of the anorexigenic effects of the stimulants doses should be administered after meals. Food in the stomach does not appear to alter the kinetics or behavioral effects of the medication. MPH and DAS are both short-acting drugs with an onset of action within 30-60 min and a peak clinical effect usually seen between 1-3 hr after administration. Thus multiple daily dosing is generally required unless sustained release tablets or capsules are utilized. The sustained release products (Dexedrine spansules and Ritalin SR) produce their peak levels at the times that vary widely between 1 to 5 hours. Although more expensive they may be useful in some children in whom a once daily dosage formulation is required. The two drugs have a rapid onset of clinical effect once a therapeutic dose is attained. However, most clinicians and patients feel they are less effective than the regular release formulations. Tachyphlaxis was hypothesized to account for the reduced effects, ie.the patients were becoming tolerant to the same blood level being present constantly throughout the day as opposed to being exposed to peak and trough levels during the day with the non-sustained release formulations (Swanson et al 2003). The most recently marketed MPD sustained release formulation, Concerta, may worth a trial since the drug delivery system produces MPD blood levels over a 12 hour period with an 18 mg/d dose that are reasonably similar to dosing MPD 5 mg po tid (Swanson et al 2003). Using a double-blind three-way crossover design, 64 children (6-12 yo) were administered methylphenidate 5mg po tid, Concerta 18 mg po q d, and placebo for one week. Using the Iowa Conners Attention Factor rating (maximum = 15), to assess efficacy, it was observed that both Concerta and methylphenidate produced similar improvement of the Iowa Conners Attention Factor versus placebo. Based on average wholesale prices, 30 days of Concerta 18 mg/d po costs the pharmacy $66 whereas Ritalin 5 mg po tid cost $38 and generic MPD $26. Pemoline is another stimulant with a long half-life suitable for once daily dosing. Finally Adderall (3:1 mixture of d and l amphetamine) may be used as a long-acting stimulant for children for whom midday dosing is a problem (Pelham et al 1999a).
The sustained-release formulations of MPH and DAS have a greater delay in the onset of action, and their effect often does not last as long as would a second dose of the non-sustained release formulations. The duration of action of sustained release medications may be suitable for mild case of ADHD or when compliance is a problem. However, their clinical efficacy is not always predictable. DAS spansules are more reliable in their effectiveness than sustained-release MPH.
The usual starting dose of pemoline is 37.5 mg q AM. The dose is titrated upward at a rate of 18.75 mg/wk to a maximum dose of 112.5 mg/d. The average child generally requires a dose between 56.25 to 75 mg/d. The slower onset of action of pemoline is more likely a function of the slow titration period recommended by the manufacturer. Thus some clinicians increase the dose every 3rd day to speed up the process. Collier et al (1985) evaluated pemoline’s pharmacokinetic parameters in 21 ADHD children 5-12 yo). The mean beta elimination half-life was 7.0 ± 1.8 h with a Cmax of 2.4 ± 0.6 hours. A 6 month follow-up of 15 subjects in which 89% of the children responded required a pemoline dose that ranged from 37.5 to 131.25 mg/d (3.0 ± 0.9 mg/kg/d). Sallee et al (1992) have found that if the blood level exceeds 2 mcg/ml clinically measurable effects are more rapidly apparent. . The effect of pemoline on neuroprocessing was apparent within the first 2 hours after administration. However, recent FDA recommendations for frequently LFT monitoring has made use of this medication difficult (see infrequent ADRsbelow).
Although stimulants produce their effect rapidly it may take upwards of 4 to 8 weeks to adequately titrate the patient to the optimum dose. Thus in general an adequate trial of medication is generally regarded in the neighborhood of 4-8 weeks.
Stimulant - Tolerance (Greenhill 1992). In humans, tolerance develops to the anorectic, hyperthermic, cardiovascular, and mood elevating effects of DAS usually within 1 to 8 weeks. Tolerance to the effects of MPH on heart rate occurs within a few weeks. However, this is not true of the effects of stimulants on narcolepsy nor is it true of the psychostimulants' effects on ADHD. The majority of short-term (2-3 months) studies of stimulants do not observe the occurrence of tolerance. Despite the clinical observation that tolerance does indeed occur, controlled studies have been unable to substantiate this claim. It has been suggested that about 40% of ADHD patients require a small increase in their dose during the first year of treatment. A prospective 23-month fixed dose MPH study (Gualtieri et al 1981) was unable to identify any loss of efficacy as long as detectable blood levels of MPH were obvious. The most parsimonious explanation for supposed tolerance stimulants is poor compliance.
Stimulant - Drug Interactions (Greenhill 1992)
MAOIs and Psychostimulants. Zametkin and Rapoport (1985) despite their positive findings in a controlled trial do not recommend using MAOIs for ADHD because of the possibility of this interaction. They worry that if the parent runs out of MAOI medication they make unwittingly give the child some left over DAS or MPH and thereby cause a hypertensive crisis.
Theophylline and Psychostimulants. The combination of these medications results in increases in tachycardia, dizziness, palpitations, weakness, and agitation. Instead it is suggested to request that the pediatrician or allergist switch the child to a beta-agonist inhaler such as albuterol (Proventil, Ventolin) (Green 1992).
Methylphenidate can inhibit the metabolism of the following drugs thereby causing significant increases in their blood levels: TCA, fluoxetine, phenytoin, coumarin, and phenylbutazone (Green 1992).
Methylphenidate and Clonidine. There was 1995 public radio report that suggested the possibility of an association between sudden deaths and the combined use of methylphenidate and clonidine. An examination of the three deaths suggested the association to be coincidental (Popper et al 1995). The first case was a 7 yo male who had been taking two drugs for a year. He complained of abdominal pain and suddenly died of a cardiac arrest. The autopsy found extensive fibrotic scarring of the heart as a result of severe perinatal hypoxia when the child was born prematurely. An 8 yo female treated with the methylphenidate and clonidine for 2 years and 3 months respectively died following suddenly during surgery. The girl appears to have reacted twice to the anesthesia first during angiography and then during surgery to repair a damaged finger. No methylphenidate or clonidine was found at autopsy suggesting the drugs were discontinued prior to surgery. The third case involved a 9 yo male with ADHD, OCD, Tourette's, mild mental retardation, and fetal alcohol syndrome that was being treated with methylphenidate 60 mg/d, clonidine 0.8 mg/d, fluoxetine 100 mg/d and promethazine 25 mg/d. The cause of death was attributed to intentional drug overdose. The FDA reviewed these cases as well as its Med Watch database and concluded there was no convincing evidence that there was an interaction between the two drugs.
Stimulant - Adverse Effects
ADRs are relative infrequent with the stimulants. The only ADRs that occur more commonly than with placebo are anxiety, staring, disinterest, sadness, decreased appetite, stomachaches, and insomnia. Less than 4% of children discontinue stimulants because of ADRs. GI ADRs are usually managed by taking the medication with food or by switching to a sustained-release MPH or DAS. Temporary dose reductions usually can resolve most of these ADRs.
Insomnia. Initial insomnia is purported to result from late afternoon or evening administration. Thus many physicians prospectively manage this ADR by not using a late afternoon stimulant dose or substituting clonidine for the late afternoon or evening dose. Polysomnographic studies are unable to detect any differences in sleep parameters in ADHD children treated with late afternoon doses of stimulants and controls. However, subjectively parents report being awakened in the middle of the night more often by ADHD children than non-ADHD children. However, this is actually thought to be a result of nature of ADHD children in that they are less inhibited about waking their parents. Kent (1995) has demonstrated that late afternoon dosing is feasible and beneficial in these patients. In addition to their regular morning and noon doses of medication using a double-blind crossover design at 4 PM he administered 12 ADHD (DSM-III-R) patients (5-110 yo) MPH 15 mg, 10 mg, or placebo for 12 days. MPH markedly improved behavior versus placebo. Sleep latencies were similar for MPH and placebo. The MPH 10 mg resulted in the children feeling less tired in the morning versus either placebo or the 15 mg dose. Thus tid dosing of stimulants appears to be a reasonable
Growth Retardation. MPH has statistically significant effects on growth velocity, i.e. ~ 3 cm. However, the height deficits evident in early and mid adolescents are not present in late adolescents. Additionally, the deficit is not a function of stimulant use. The effect appears to be mediated by ADHD and not its treatment (Spencer et al 1996). These findings are consistent with the ADHD dysmaturation hypothesis that proposes that the pathological manifestations of ADHD in some children may represent developmental lags that will eventually be outgrown. Thus the practice of drug holidays during the weekends and summers to compensate for this effect are unnecessary and counterproductive because of the effect on the child's inadequate socialization when off medication.
Tics. Stimulants supposedly precipitate or exacerbate tics in children in approximately 1.3% to 60% of ADHD patients (Lipkin et al 1994). Onset may occur within 1 week to 24 months after the stimulant administration. It is reported that usually after initial worsening of the tics, continued treatment and/or adjustment of the dose of the stimulant medication, a return to the baseline severity or improvement will occur in most cases (Rapoport and Castellanos 1992). It is rare to see the tics persist after discontinuation of the medication. The veracity of this ADR has been repeatedly questioned over the years. Two controlled trials one by Gadow et al (1995) and the other by Castellanos et al (1997) demonstrates why this is the case. Thirty-four prepubertal children with ADHD and tic disorder received placebo and MPH 0.1, 0.3 and 0.5 mg/kg for 2 weeks each. MPH suppressed the ADHD symptoms and did not alter the severity of the tics. However, it did have a weak effect on the frequency of motor (increase) and vocal (decrease) tics (Gadow et al 1995). Twenty children with concomitant ADHD and Tourette's disorder (1 patient with chronic motor tics) participated in a 9-week double-blind, placebo-controlled crossover trial of methylphenidate, dextroamphetamine and placebo (3 weeks each) (Castellanos et al 1997). Methylphenidate doses (weekly) in those >30kg were 15, 25, 45 mg/dose bid, dextroamphetamine doses were 7.5, 15, 22.5 mg/dose bid. For those ²30 kg weekly doses were 12.5, 20 and 35 mg bid, weekly dextroamphetamine doses were 5, 12.5 and 20 mg bid. Ratings on the lowest dose of either methylphenidate or dextroamphetamine were compared; there was no significant effect of either on tic severity rating. Those that received medium stimulant doses were not significant, although methylphenidate produced tic severity ratings that were 21% greater than placebo. Those on high doses of dextroamphetamine had a significant increase (+25%) in tic severity versus placebo (p<0.05). Those on methylphenidate had a decrease in tic severity by 4%. The Tourette's Syndrome (TS) Study Group (2002) contrasted the effect of methylphenidate, clonidine, and the combination of the two to placebo in the treatment of 136 children (7-14 yo) diagnosed with ADHD and TS. Fourteen (20%) of the patients treated with methylphenidate reported worsening of tics, i.e., 8, methylphenidate alone versus 6 combination treatment. This adverse event rate was similar to clonidine (26%) and placebo (22%). However, the tics reported for methylphenidate (35%) limited dose increases more often than for the combination (15%), clonidine (18%) or placebo (19%). The Group concluded that prior recommendations to avoid methylphenidate in these children because of concerns of worsening tics were unsupported by the trial.
Infrequent ADRs. Mood disturbances ranging from increased tearfulness to MDD have been associated with stimulant use in children. This could be related to another ADR often referred to as acute withdrawal or "rebound." Children presented with afternoon irritability, overtalkativeness, noncompliance, excitability, and insomnia 5-15 hours after the last dose of the psychostimulants. The addition of a late afternoon dose of clonidine for these patients may be beneficial. Other infrequent ADRs include headaches, abdominal discomfort, and increased lethargy and fatigue. Acute psychotic episodes secondary to psychostimulant use in ADHD are rarely reported in the literature. However, doses of approximately 300 mg and 150 mg of MPH and DAS respectively are required before children paranoid delusions or auditory or visual hallucinations.
Seizures. There is a warning that methylphenidate may lower the convulsive threshold in patients with a history of seizures, with prior EEG abnormalities in absence of seizures and very rarely, in the absence of history of seizures and no prior EEG evidence of seizures. Thirty children with epilepsy aged 6.4-16.4 (9.8±2.8) years with ADHD were studied to determine the safety and efficacy of methylphenidate (Gross-Tsur et al 1997). Fifteen children had complex partial seizures, 7 with primary tonic-clonic, 6 with absences, 2 with multiple seizure types. For 8 weeks patients received their regular regimen of antiepileptic, then 8 weeks of antiepileptic and methylphenidate (0.3 mg/kg) in the morning only. During the first 8 weeks (no methylphenidate), 25 children were seizure free and five had a maximum of two seizures a week. None of the seizure-free children had attacks while taking methylphenidate. Of the five with seizures during the first 8 weeks, three had an increase in attacks, whereas the other two showed no change. ADHD symptoms improved in 70% of the children during methylphenidate treatment as per parental report and performance on the continuous performance test.
Long-Term Use and Substance Abuse. There do not appear to be any adverse long-term behavioral effects resulting from chronic stimulant use. A group of adults who had taken MPH for 3 or more years as children were found to have fewer psychiatric problems, fewer car accidents, more independent lives, more were attending school, a more positive view of their childhood and were less aggressive than a similar group of formerly untreated hyperactive adults (Hechtman et al 1984). Biederman et al (1999) determined that the odds ratios for substance use disorder (SUDO) in 19 unmedicated ADHD (prevalence) was 6.3 (95% CI, 1.8-21.6) while in 56 medicated ADHD adolescents it was 0.15 (95% CI, 0.04-0.6). The raw prevalence rates were 33% in the unmedicated subjects, 13% in the medicated subjects and 10% in the controls. Thus untreated ADHD is a significant risk factor for substance abuse disorder in adolescence. Treated ADHD was associated with an 85% reduction in risk for substance abuse disorder in ADHD youth.
Long-Term Use and Substance Abuse. There do not appear to be any adverse long-term behavioral effects resulting from chronic stimulant use. A group of adults who had taken MPH for 3 or more years as children were found to have fewer psychiatric problems, fewer car accidents, more independent lives, more were attending school, a more positive view of their childhood and were less aggressive than a similar group of formerly untreated hyperactive adults (Hechtman et al 1984). Biederman et al (1999) determined that the odds ratios for substance use disorder (SUDO) in 19 unmedicated ADHD (prevalence) was 6.3 (95% CI, 1.8-21.6) while in 56 medicated ADHD adolescents it was 0.15 (95% CI, 0.04-0.6). The raw prevalence rates were 33% in the unmedicated subjects, 13% in the medicated subjects and 10% in the controls. Thus untreated ADHD is a significant risk factor for substance abuse disorder in adolescence. Treated ADHD was associated with an 85% reduction in risk for substance abuse disorder in ADHD youth. Wilens et al (2003) conducted a meta-analysis of the ADHD / substance abuse epidemiologic literature. There were 6 studies available for analysis. Four had follow-up into adulthood while 2 had follow-up into late adolescence. Overall there were 674 stimulant medicated subjects contrasted to 360 unmedicated subjects. The pooled odds ratio estimate of 1.9 (1.1-3.6, 95% CI) concluded that stimulant-treated patients with a diagnosis of ADHD were less likely to be diagnosed with substance use disorder. This finding was stronger in the patients followed up at adolescence (OR +5.8) than in patients followed up during adulthood (OR _= 1.4.).
Pemoline. There are two ADRs that are unique to pemoline. Pemoline has been associated with increases in LFTs. Of children taking pemoline for ADHD, 2% had elevations of AST or ALT with some children experiencing nausea, vomiting, lethargy, and malaise. The effect was transient and reversible (Anonymous 1975). There are 15 cases of pemoline liver toxicity 12 of which resulted either in death or liver transplantation within 4 weeks of the onset of the symptoms. The earliest onset of the signs and symptoms of liver after pemoline was started was 6 months. The risk of acute hepatic failure is estimated to be 4 to 17 times the rate expected in the general population. The manufacturer recommends checking the ALT (SGPT) at baseline and every two weeks. The drug should be discontinued if the ALT exceeds twice the upper limit of normal (Pizzuti 1999).
Reversible choreoathetoid movements and dyskinesias were reported in 4 children treated with pemoline for between 3 week and 3 months (Sallee et al 1989). Pemoline caused initial insomnia twice as often as compared to patients treated with DAS and MPH in the Pelham (1990) study.
Tricyclic Antidepressants
The use of antidepressants in the treatment of ADHD has spanned nearly 30 years originating with Krakowski’s amitriptyline study (1965). There may be an ADHD subgroup that responds better to the TCA than to stimulants. Logically this group experiences more depression and anxiety symptoms than the stimulant responders (Pliska 1987). A total of eight controlled studies are available for efficacy evaluation (see Tables 3 and 5). Gross (1973) and Rapoport et al (1974) conducted studies using the tricyclic antidepressants (TCA) imipramine. Zametkin et al (1985) studied the use of the monoamine oxidase inhibitors (MAOI), clorgyline and tranylcypromine in ADHD. Donnelly et al (1986) and Biederman et al (1989) studied the effects of desipramine and Casat et al (1986), Clay et al. (1987), Barrickman et al (1995); Conners et al (1996) studied the use of bupropion.
In a double-blind placebo controlled pilot study Krakowski (1965) evaluating the effectiveness of amitriptyline in the treatment of hyperactivity in 50 patients, 36 boys and 14 girls. The treatment subjects were selected based on history, psychiatric examination, which included psychological testing, a physical and neurological examination and an EEG. The patients were initially given a 20-30 mg/d of amitriptyline with dose being titrated to a maximum of 120 mg/d over 30 days. The daily amitriptyline dose ranged from 20-120 mg/d (mean = 40 mg/d). Eight children received psychotherapy and another child speech therapy during this study. Patients had bi-monthly follow-up visits, which included parent and patient clinical interviews and patient physical examinations. The patients’ ages were grouped into three age ranges: 3-5 years old (n=6), 6-12 years old (n=34), and 13-18 years old (n=10). Four patients dropped out of the study after one to two months, 12 after three to four months, eight during the fifth month, 14 after seven to eight months and 12 after nine months of treatment. Thirty-four patients were still in therapy when the manuscript was written. Amelioration of function or physical symptoms (pain, vomiting, fecal soiling and enuresis), scholastic improvement and improvement in social adaptability, improvement in finding of psychological testing, and the increased amenability to psychotherapy was also considered. Out of the 26 who received the placebo, 1 (4%) demonstrated an excellent improvement (no symptoms present, 1 (4%) good improvement (marked alleviation), 2 (8%) had slight improvement (insufficient clinical improvement) and the rest were considered to have no improvement of their symptoms. Of the 24 who received amitriptyline, 7 (29%) achieved a rating of excellent, 14 (58%) fell in the good category, and three (12%) had no improvement at all. Drowsiness was the most common adverse effect encountered in 15 patients although it remitted spontaneously or responded to a decrease in dose. The author concluded that TCA were viable medications to be utilized in the treatment of hyperkinetic children.
In the Gross (1973) study, 259 MBD patients, aged 2 to 18, were studied. He compared the effectiveness of DAS, MPH, and imipramine to placebo. Each patient received a one-week course of each drug, without a washout period between each drug. The reasoning for not using washout periods was that it had been found earlier that a washout was not really necessary, except for the imipramine, which had a longer half-life and therefore, it was the last one to be used. The initial weekly treatment dose is presented in table 4. Parents and selected teachers took notes on the patients’ behavior during the one week treatment trials. Based on the treatment week that produced the best treatment response, the medication was restarted and continued for a minimum of four months. MPH worked best for 66 patients (25%) while DAS and imipramine worked best in 54 (21%) patients each. Imipramine was equally effective as DAS or MPH in 27 (10%) of the patients and in combination with one or the other in 30 (12%) of the patients. Placebo worked the best in three (1%) cases. In 13 (5%) cases none of the drugs worked. The authors concluded that imipramine should be utilized in treatment refractory patients although the drug was not shown to be any less effective than the stimulants.
In the Rapoport et al. (1974) study, 76 boys were treated. Inclusion criteria included the symptoms of persistent distractibility or motor restlessness and impulsiveness that had to be present for two or more years, ages 6 to 12, IQ ≥ 80, and absence of known neurological disorder. Evaluation was done using the Conners rating scales for parents and teachers, and a parental four-day diary, which was later, scored by an independent rater. The Kagan Matching Familiar Figure test and a self-concept scale were also used. Additionally, a psychiatric playroom observation period was used for global assessment of activity and behavioral level was used for the psychologist’s global ratings of “attention” and “behavioral problems.” Baseline measurements were taken the week before the start of the study. The patients then were given either a placebo twice a day or a maximum of 30 mg MPH (mean = 20 mg/d) or 150 mg imipramine (mean = 80 mg/d) for six weeks. Both imipramine and MPH were found to be superior to placebo by all patient observers. The physicians’ global ratings after six weeks of treatment found that MPH and imipramine were more effective than placebo with MPH being more effective than imipramine. However, the psychologists’ global ratings did not show a significant difference in improvement between MPH and imipramine. Overall on all measures MPH appeared more effective than imipramine, which in turn was more effective than placebo. It was suggested that the imipramine dose might have been too low in this study. However, it is impossible to conclude from other studies whether this is indeed the case.
Garfinkel et al (1983) compared the clinical efficacy of MPH, desipramine, and clomipramine in a double-blind placebo-controlled crossover study of 12 boys (mean = 7.3 years, range = 5.9-11.6 years) diagnosed with ADD who required day hospital or inpatient treatment for severe impulsiveness, attention deficit, and aggression. The mean dosage of clomipramine was 85 mg/d and did not exceed 100 mg or 3.5 mg/kg/d for any subject. MPH was rated significantly better than the tricyclics in improving overall classroom functioning. Clomipramine was better than desipramine in reducing scores reflecting aggressiveness, impulsivity, and depressive—affective symptomatology.
In the Donnelly study (1986) 29 ADHD (DSM-III) males aged 6 to 12 were recruited. Inclusion criteria included a CTRS hyperactivity score two standard deviations above the mean, an IQ ≥ 80 measured by the WISC-R, and no neurologic disorder or major medical problem. Patients were randomly assigned to a 3-week regimen of one week of placebo followed by two weeks of either a placebo or desipramine. Seventeen boys received desipramine and twelve the placebo. The desipramine was given in a single morning dose of a 25 mg capsule at breakfast, with the dose increasing by 25 mg per day up to 100 mg per day. The placebo was given at the same time as one capsule on day 1, increasing by one capsule per day up to four capsules per day. Measurements were taken during the baseline, on day 3 and day 14. The measurements included side effect monitoring, blood pressure and heart rate monitoring, and desipramine plasma levels. The classroom behavior was rated on the abbreviated 10 item CTRS, sustained attention by a modified version of the Roosevelt CPT, and the Bushcke test for cognitive tasks. Desipramine treatment resulted in improvement in teacher rated hyperactivity and impulsiveness. However, attention and cognition did not improve with desipramine treatment. Blood pressure and heart rate increased in those patients that received desipramine. About a 10 mm Hg increase in the systolic and diastolic blood pressure in the supine position and pulse.
Biederman (1989) randomly administered either desipramine or placebo for six weeks in a parallel design study to 62 ADHD (DSM-III) diagnosed children (n=42, < 12 years old) and adolescents (n=20, ≥ 12 years old). The 31 patients who received desipramine were administered a mean dose ≤ 5.6 mg/kg/d that was given twice daily. There was a significant improvement in the Conners Abbreviated Parent and Teacher Questionnaire (CABRS) and clinical global impression (CGI) scores of the patients who were on desipramine over those taking the placebo. Of the desipramine treated patients, 68% were rated as very much or much improved as opposed to only 10% of the placebo patients who experienced a similar response. The side effects observed were mild. They consisted of dry mouth, decreased appetite, headache, tiredness and trouble sleeping. Additionally, the data was re-analyzed and found that the presence of conduct disorder, major depression, an anxiety disorder, or a family history of ADHD did not affect the likelihood of the patient responding to desipramine (Biederman et al 1993).
TCA - Dosing (Green 1992). Recommended TCA doses include amitriptyline, imipramine and desipramine 3-5 mg/kg/d; nortriptyline 2.5 mg/kg/d; and clomipramine 1.5-3.0 mg/kg/d and< 200 mg/d. When TCA are discontinued a 10-day taper is suggested in order to avoid cholinergic rebound which mimics a flu-like syndrome characterized by nausea, vomiting, diarrhea, abdominal discomfort, and lethargy.
TCA - Tolerance (Green 1992). Quinn and Rapoport (1975) conducted a 1-year follow-up study of 76 hyperactive boys treated with imipramine or MPH. They found that a significantly greater number of subjects discontinued imipramine because of either lack of benefit or ADRs. However, of the patients who remained on the MPH and imipramine both groups derived similar benefit from the drugs. It appears that tolerance develops to imipramine resulting in deterioration after initial improvement.
TCA - Adverse Effects (Green 1992). Because there have been six fatalities associated with desipramine administration in children, careful cardiac monitoring is imperative (Medical Letter 1990, Varley and McClellan 1997). A baseline EKG should be obtained, and then repeated at 3 mg/kg/d, and once the maintenance dose (≤ 5 mg/kg/d) is reached. With respect to the use of TCA in children and adolescents the American Heart Association recommends a baseline history and physical, a current medication history, and a baseline ECG within the following parameters of PR interval ≤ 200 ms, QRS duration ≤ 120 ms and QTc ≤ 460 ms (Gutgesell et al 1999). Follow-up ECGs and history are indicated after steady-state is achieved at a TCA dose of 3-5 mg/kg/d (1.5-2.5 for nortriptyline).
Schroeder et al reported that in 20 children aged 7-12 years desipramine (mean = 4.25 mg/kg/d, maximum = 5 mg/kg/d) the mean increase in heart rate was 21% while the increase in the QTc was 2.5%.
TCA ADHD Efficacy – Conclusions. There are 8 double-blind placebo-controlled antidepressant efficacy studies that have studied a total of 488 patients. Tricyclics are more effective than placebo in treating ADHD. Compared to the psychostimulants, imipramine and clomipramine were found to be less effective than methylphenidate while a third study found imipramine equal in effectiveness to methylphenidate and dextroamphetamine. A summary of the studies is presented in table 3.Monoamine Oxidase Inhibitors
Zametkin et al (1985) conducted a 12-week randomized, double-blind, cross-over study comparing the efficacy of the MAOIs, clorgyline (MAOI-A specific), and tranylcypromine, to DAS in 14 male ADHD (DSM-III) patients ranging in age from 8 to 12 years old. They were each given the placebo and DAS. Six boys received the clorgyline and eight received the tranylcypromine. A 2-week drug washout period obtained baseline CTRS scores. Following a one week placebo lead-in, patients were randomized to either 5 mg of one of the MAOIs twice daily or DAS 10 mg in the morning and 5 mg at noon for four weeks. Treatment was followed by a 2-week placebo washout period and then the treatments were crossover for the next four weeks. Platelet MAO activity inhibition was highly significant with the use of tranylcypromine, but not significant during the treatment with clorgyline. The tranylcypromine produced a significant improvement in the teacher ratings beginning after only one week of treatment. However, improvement was only seen in parent rated hyperactivity (PRH) in week four. Clorgyline also showed similar improvement in the teacher rating and on the CPT. Clorgyline only showed a trend in parent rated hyperactivity. DAS produced equivalent improvement in all the same areas as was observed with the MAOIs.
Trott et al (1992) administered moclobemide, a reversible inhibitor of monoamine oxidase-A, to 12 ADHD (DSM-III-R) diagnosed children between the ages of 6 and 13. All had previously discontinued treatment with methylphenidate at least 10 days prior to the start of therapy due to side-effects (9) or lack of efficacy (2). Moclobemide was titrated to a dose of 100 mg po bid over two weeks in the 4-week study. A 40% improvement in parental assessment of children’s behavior occurred among those who received moclobemide as outpatients, and a 31% improvement among the five in-patients. There was a general increase in concentration and attention span at the end of the trial, but mood changes and explosive behavior continued to be present at a low level. Seven of the 11 patients who completed the trial responded. The non-responders included the two MPH treatment failures and a subject with comorbid FAS and mental retardation. Brain mapping in 6 of the patients after moclobemide treatment showed an overall reduction in frontal lobe delta activity. Moclobemide was well tolerated by these patients, although two complained of mild gastrointestinal disturbances during the first week of therapy.
Conclusions. Thus there is one controlled efficacy study that compared the effectiveness of MAOIs to dextroamphetamine in the treatment of 22 ADHD patients. The study found that 10 mg/d MAOI doses were as effective DAS. However, the authors noted that they preferred not to utilize MAOIs to treat ADHD because of the possibility that the patient or parent might unwittingly utilize a psychostimulant if they run out of MAOI medication. MAOIs must be washed out for approximately 14 days before its is safe to administer a sympathomimetic amine such as DAS or MPH to a patient. The small size of the study and ADR considerations suggest that MAOIs be best regarded as third-line drugs in the treatment of ADHD.
Bupropion
Simeon et al (1986) conducted a single-blind open trial of bupropion in the management of ADHD. Seventeen white males of age 7-13, who met DSM-III criteria for ADHD. Following a 4-week placebo lead-in, patients were administered bupropion 50-150 mg/d (mean = 135 mg/d) based on response for 8 weeks. Fifteen patients completed the trial. Results were measured using behavioral rating scores, cognitive performance, CGI and Conner's Rating Scales for Parents, Teachers and Physicians. At the end of the trial all ratings and scales showed statistically significant improvement. Adverse effects were checked on a 60-item checklist. Eight patients reported transient nausea. The subsequent double-blind controlled trials have replicated this finding.
Casat et al (1987) investigated the potential efficacy of the antidepressant in the treatment of 30 children (6-12 years old) diagnosed with ADHD (DSM-III) who were either treatment refractory or treatment naive. Following a 2-week washout period, and using a single-blind design, the patients received either bupropion or placebo for 28 days. The bupropion dose was titrated from 3 mg/kg/d to 6 mg/kg/d over the 28-day treatment period. The dose was administered twice daily at 0700 and 1900. Treatment response assessment for both studies included the Conner's Parent Questionnaire; Conner's Teacher Questionnaire, the Brief Psychiatric Rating Scale (BPRS) and the CGI. Significant differences between the bupropion group and placebo group were noted on the CTQ (hyperactivity) and on the CGI (severity and improvement). No differences were found in the CPQ-hyperactivity, CPQ-conduct and in the CTQ-conduct.
Using the identical protocol, Clay et al (1988) studied 33 children (6-12 years old) diagnosed with ADHD (DSM-III). Following a 1-week placebo lead-in, and using a double-blind design, the patients received either bupropion or placebo for 28 days. Like the previous study, the bupropion dose was titrated from 3 mg/kg/d to 6 mg/kg/d but over the 21-day treatment period and then adjusted to the optimum dose for the last week of the study. Significant improvement was observed on the CGI in severity and improvement. The CPQ and the CTQ hyperactivity scores and total scores, where said to have had some improvement, but were not found to be significant.
Conners et al (1996) summarized the findings of the above multicenter study. Overall, there was a significant treatment effect for bupropion on day three for conduct problems and restless-impulsive behavior according to teacher ratings and by day 28 according to the parental ratings.
Barrickman et al (1995) using a double blind, crossover design compared the effectiveness of MPH to bupropion. Following a 14 day medication washout period, 15 ADHD subjects (7-17 years old) were randomized to either MPH or bupropion for six weeks, washed out for an additional 2 weeks, and then crossed-over to the opposite drug. MPH was titrated to the maximum effective dose of 0.4-1.3 mg/kg/d (mean 0.7 mg/kg/d) while bupropion was titrated to an effective dose ranging from 1.4-5.7 mg/kg/d (mean 3.3 mg/kg/d). Both MPH and bupropion produced significantly greater (p < 0.001) and equivalent improvement on the Iowa Conners Teachers Rating Scale according to both the subjects' parents and teachers. The same pattern of improvement was also noted for improvement on the Clinical Global Impression; the Kagan's Matching Familiar Figures Test; Continuous Performance Test; the Children's Depression Inventory; the Children's Manifest Anxiety Scale, and the Rey Auditory-Verbal Learning Test. In this trial bupropion and MPH were both effective and did not differ in their overall efficacy as treatments for ADHD. The only reported side effects of any consequences in either of the trials were two cases of an allergic rash that cleared on discontinuation of the drug. Cardiovascular parameters were not affected. There were no apparent effects on height and weight.
Not surprisingly, bupropion has been associated with the occurrence of tics. Four Tourette's patients with ADHD had their tics worsen when treated with bupropion (Spencer et al 1993).
Bupropion-Efficacy-Adults. In an open study of 19 adults Wender and Reimher et al (1990) administered bupropion for 6-8 weeks at a mean dose of 360 mg. Eight of fourteen had a marked response and six of fourteen had a moderate response. Ten subjects continued to have improvement at 1 year.
Bupropion Conclusions. It appears that bupropion is effective in the treatment of ADHD according to the findings of 4 double-blind placebo controlled trials that studied a total of 93 patients administered doses ranging between 3-6 mg/kg/d. The drug was found to be as effective as MPH. Thus it would appear that the drug would be a second line drug with the TCA in the ADHD treatment algorithm. Table 5 presents a summary of these trials.
Atomoxitene
Atomoxetine inhibits the presynaptic norepinephrine transporter. It has minimal affinity for other noradrenergic receptors or other neurotransmitter transporters. Clinical trials have shown that atomoxetine is superior to placebo in reducing the symptoms of ADHD in children, adolescents and adults. Two studies have documented that atomoxetine is more effective than placebo in the treatment of ADHD in children (Michelsen et al 2001), girls (7-13 yo) (Biederman et al 2002) and adults (Spencer et al 1998). Using a randomized open label design, Kratochvil et al (2002) compared the effectiveness of atomoxetine (n=184) and methylphenidate (n=44). Parent and clinician ratings concluded that both drugs equally improved inattention and hyperactivity-impulsive symptom clusters. Safety and tolerability outcome measures as well as discontinuation rates were similar between the drugs. For most patients the plasma elimination half-life for atomoxetine is 4 hours. Since the drug is metabolized primarily by CYPP4502D6 it is longer in poor metabolizers who have a genetic polymorphism for the enzyme. Despite the relatively short half-life, Michelson et al (2002) in a randomized placebo controlled trial in 168 children and adolescents were able to demonstrate that once daily dosing was feasible. The dosing schedule during the 6-week trial was 0.5 mg/kg/d for 3 days, 0.75 mg/kg/d for 4 days, and then depending on response 1 to 1.5 mg/kg/d for the remaining five weeks. The drug was administered as a single dose in the morning. Parental reports confirmed that the drug effects were sustained late into the day. The only reported significant adverse effects that occurred in more than 5% of patients on atomoxetine included transient (1-2 days) nausea (12%) and vomiting (15%) and asthenia (tiredness and fatigue at 11%).
Alpha-2 Agonists
Alpha-2 agonists appear to be useful for ADHD patients confounded by tic disorders, extreme hyperactivity, oppositional or conduct disorder, hyperarousal, or a poor response to stimulants. (Hunt 1990).
Clonidine is alpha-2 agonist that stimulates presynaptic adrenergic neurons to block the release of norepinephrine. Norepinephrine is known to enhance excitatory inputs, resulting in an increased level of alertness and arousal, and may contribute to the hyperexcitability associated with ADHD. Using a double crossover design, Hunt et al (1985) evaluated the effect of clonidine in young children diagnosed with ADHD (DSM-III). Two girls and eight boys aged 12 ± 0.5 years received a clonidine dose titrated to 4-5 mcg/kg/d for 8 weeks and placebo for 4 weeks. According to the Conners parent and teacher rating, the children treated with clonidine exhibited a significant decrease in hyperactivity, conduct problems and inattention compared with those treated with placebo. Teachers felt that the children on clonidine exerted purposeful effort at school, concentrated better on task activity, appeared more relaxed, and were better accepted by their peers. Clinicians reported significant improvement in 8/10 children. When switched from clonidine to placebo, behavior deteriorated substantially in all but one child. Overall, the study concluded that clonidine improved the ADHD symptom triad of inattentiveness, impulsivity, and hyperactivity as well as it improved peer relationship and self-esteem. The clinician findings reported mild to moderate improvement in hyperactivity in 90% and impulsivity in 70% of the patients. The primary ADR was sleepiness but this was a transient effect that disappeared after three weeks of treatment. Occasionally, light-headedness was reported after standing abruptly. One child with a history of depression became more tearful on therapy. The Tourette’s Syndrome (TS) Study Group (2002) contrasted the effect of methylphenidate (~26 mg/d), clonidine (~250 mcg/d), and the combination (methylphenidate ~26 mg/d + clonidine 280 mcg/d) of the two to placebo in the treatment of 136 children (7-14 yo) diagnosed with ADHD and TS. The Conners Abbreviated Symptom Questionnaire – Teachers showed both individual treatments equally effective versus placebo. However, the greatest improvement versus placebo occurred with the combination therapy. Clonidine primarily benefited the symptoms of impulsivity and hyperactivity while methylphenidate primarily benefited inattention.
Sedation and hypotension limit the usefulness of clonidine in the treatment of ADHD. However, guanfacine is an alpha-2 agonist that has a more desirable pharmacokinetic and ADR profile. The drug has an 18-hour half-life in adults and it is less sedating and causes less hypotension than clonidine. In an open trial Hunt et al (1995) administered guanfacine to 13 ADHD patients (4-20 years. The mean therapeutic dose was 3.2 mg/d (mean = 0.09 mg/kg/d) usually administered on a tid and HS schedule. The 31-item Conner’s Questionnaire demonstrated a 33% decrease in ADHD severity. On average the hyperactivity factor decreased 42%, the inattention factor decreased 37%, and the immaturity factor decreased 49%. No significant blood pressure changes were noted. ADRs reported included transient sedation for 2 weeks, a transient decrease in appetite, as well as transient headaches and stomachaches. A controlled trial is currently underway to assess the efficacy of the drug.
Conclusion. Thus there is one small controlled trial (n =10) that concluded that clonidine 4-5 mcg/kg/d was more effective than placebo in the treatment of ADHD. However, since clonidine has not been contrasted to stimulants in the treatment of ADHD, the drug would have to be considered a third-line drug.
Clonidine can be quite useful in ADHD patients with comorbid tic disorders. In a retrospective chart review of 24 ADHD patients with tics 23 (96%) demonstrated global improvement in their ADHD and 18 (75%) had improvement in tics (Steingard et al 1993). The mean daily dose of clonidine was 0.21 ± 0.02 mg/d (range = 0.05-0.5 mg/d).
Fluoxetine
Barrickman, et al (1991) examined the effectiveness of the SSRI, fluoxetine, for treating ADHD. Following a 2 week medication washout period, patients were administered a fluoxetine dose based on response that ranged from 20-60 mg/d (mean = 27 mg/d). Twenty-two subjects entered the trial with a mean age of 10.9 (range 7-15). All subjects met the DSM-III-R criteria for ADHD. Measurements included the Conner’s Abbreviated Parent and Teacher Questionnaire, CGI, I.Q. Scale, Kagan’s Matching Familiar Figures, Continuous Performance Task (CPT) and the Children’s Depression Inventory. The patients who completed the trial all improved. ADHD severity ratings dropped from 6.0 (severe) at pretreatment to 3.4 (mild-moderate) at post treatment. IQ measurements increased from 105 to 109 and this was found to be statistically significant. Teacher’s Conners scores decreased from 18 ± 5 to 14 ± 6 while Parent’s Conners scores decreased significantly from 23 ± 3 to 10 ± 5. However, in contrast to the data generated by the same research group for methylphenidate and bupropion the changes for fluoxetine on the Continuous Performance Test and Kagan’s Matching Familiar Figures test two objective tests of attention and were not significant (Barrickman et al 1995). The fluoxetine figures are probably exaggerated since they were obtained in an open study design. Some mild adverse effects were noted but resolved upon dose adjustment. Compliance in the 19 completers was excellent with only one patient missing a single dose. Summary of the study shows fluoxetine to be a potential alternative treatment for ADHD. This study needs to replicated, using methylphenidate as the comparison agent.
Conclusion. Thus there is one open trial (n = 22) that concluded that fluoxetine 27 mg/d was partially effective in the treatment of ADHD. However, since fluoxetine has not been contrasted to either placebo or stimulants in the treatment of ADHD, the drug would have to be considered a fourth-line drug.
Venlafaxine-Efficacy-Adults
Sixteen patients were enrolled in an open-label study of venlafaxine for eight weeks. Venlafaxine was titrated to a dose of 225 mg/day. Four of the sixteen patients discontinued within the first week due to sedation, agitation or nausea. The 25-item Wender Utah Rating Scale scores decreased an average of 48 percent (p²0.0001). There were four patients on concomitant medications (stimulants=2, trazodone=1, clonazepam=1) (Adler et al 1995).
Pharmacotherapy vs Behavioral Modification
The Multimodal Treatment Study of Children with ADHD (MTA) Cooperative Group posed the question of how do long-term medication and behavioral treatments compare with one another? A group of 579 ADHD-combined type (DSM-IV) children between 7 to 10 years were recruited and randomized to treatment (MTA Group 1999). The children were included even if they had comorbid diagnoses including conduct disorder, oppositional defiant disorder or a learning disability. The treatment groups included drugs, behavioral treatment, drugs plus behavioral treatment, or community treatment. The behavioral treatment was extremely complicated and financially impractical. It consisted of the teacher meeting with the child for 10-16 biweekly sessions to work on behavior management. Daily behavior report card sent home to parents. The behavioral treatment was tapered downward and eventually taken over by parents. Each family was involved in 27 group therapy meetings plus 8 individual family meetings. A teaching assistant worked on each child’s behavior 1 on 1 for 60 days. Each child had an 8-week, 5-day-per-week, 9 hours per day, intensive behavioral interventions administered by counselor/aid. Of the children receiving drugs 75% received methylphenidate, 10% received dextroamphetamine and 15% received pemoline, imipramine, clonidine, guanfacine or bupropion. It was concluded that medication management was more effective than behavioral treatment according to parents’ and teachers’ ratings of inattention, teachers’ ratings of hyperactivity-impulsivity. Combined treatment (drug plus BM) was the equal of medication management and more effective than behavioral treatment and community care according to parent- and teacher- reported ADHD symptoms. It was concluded that for ADHD symptoms drug alone was the most cost-effective treatment. Finally, behavior therapy only benefited children with comorbid diagnosis such as conduct disorder, oppositional defiant disorder or a learning disability
ADHD Conclusion
Based on these data, since MPD has been demonstrated to be effective in improving behavior, cognition, and sociability of children with ADHD, it is obvious that this is the treatment of choice. The choice of a second line drug includes the TCA, MAOI and bupropion. The six controlled TCA studies suggest these agents are effective but whether they improve the three spheres of behavior, cognition, and sociability as the stimulants do remains to be proven. The MAOIs improve behavior but their effect on sociability and cognition remains undefined. Like the TCA the bupropion data suggest that the drug is slightly less effective than the stimulants.
|
Table 1. ADHD Prevalence Rates based on DSM-IV criteria. |
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|---|---|---|---|
|
ADHD subtype |
DSM-IV symptoms |
DSM-IV symptoms + academic- behavioral problems |
Note |
|
Hyperactive-impulsive |
2.6% |
0.6% |
youngest, male, less academic impairment |
|
Inattentive |
8.8%, |
3.2% |
most common female subtype; older than combined or HI; less conduct DO and aggression, more academic impairment |
|
Combined |
4.7% |
2.9% |
most impaired overall behaviorally and academically |
|
Total |
16.1% |
6.8% |
|
|
Table 2. Double-blind controlled studies of stimulants in the treatment of adult ADHD. |
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|
Study |
Dose (mg/d) |
Population |
Results |
|
Wood et al 1976 |
MPH 0.4 mg/kg x 4 wk.
|
15 adults, mean = 28 yo |
73% response
|
|
Wender et al 1981 |
Pemoline 0.9 mg/kg x 6 wk.
|
51 adults, mean = 28 yo |
50 % in pts with childhood onset ADHD
|
|
Mattes et al 1984 |
MPH 0.7 mg/kg x 6 wk.
|
26 adults, mean = 32 yo |
25% response
|
|
Wender et al 1985 |
MPH 0.6 mg/kg x 5 wk.
|
37 adults, mean = 32 yo |
57% response
|
|
Gualtieri et al 1985 |
MPH 0.6 mg/kg x 2 wk.
|
8 adults, mean = 28 yo |
mild-moderate response
|
|
Spencer et al 1995 |
MPH 0.5, 0.75, 1.0 mg/kg/d x 7 wk.
|
23 adults, mean = 40 yo |
78% response |
|
Table 3. Controlled studies of tricyclic antidepressants in the treatment of ADHD. |
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|
Study |
Dose (mg/d) |
Population |
Results |
|
Krakowski et al 1965 |
AMT 20-120 mg/d
|
MBD 36 males,
|
AMT
|
|
Gross 1973 |
DAS 2.5-10 mg/d
|
259 MBD
|
Based on best tx response pts then put on that therapy for an additional 4 months MPH 25%
|
|
Rapoport et al 1974 |
MPH < 30 mg/d Å 20 mg/d IMP < 150 mg/d
|
76 hyperactive males,
|
MPH > IMP > placebo
|
|
Donnelly et al 1986 |
DSP > 100 mg/d |
ADHD29 males,
|
Classroom behavior improved, i.e., impulsivity and hyperactivity Cognition and attention did not improve
|
|
Biederman 1989 |
DSP < 5.6 mg/kg/d
|
MBD
|
DSP > placebo
|
|
Table 4. Dosing schedule for Gross (1973) study |
||||
|
Drug |
2-4 years old (mg/d) |
5-7 years old (mg/d) |
8-10 years old (mg/d) |
> or = 11 years old (mg/d) |
|
dextroamphetamine* |
2.5 |
5 |
7.5 |
10 |
|
methylphenidate* |
5 |
10 |
15 |
20 |
|
imipramine |
10 HS |
20 HS |
25 HS |
50 HS |
|
Table 5. Controlled studies of bupropion in the treatment of ADHD. |
|||
|
Study |
Dose (mg/d) |
Population |
Results |
|
Simeon et al 1985 |
BPR 135 mg/d x 8 weeks 4 wk placebo lead-in, |
ADHD |
BPR > placebo |
|
Casat et al 1987 |
BPR 3-6 mg/kg/d, |
ADHD |
BPR > placebo |
|
Clay et al 1988 |
BPR 3-6 mg/kg/d, |
ADHD |
BPR > placebo |
|
Barrickman et al (1995) |
BPR = 3.3 mg/kg/d |
ADHD |
BPR = MPH |
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