Dose Adjustment of Stimulants for Children with Attention-Deficit/Hyperactivity Disorder: A Retrospective Chart Review of the Impact of Exceeding Recommended Doses.

BACKGROUND: When children with attention-deficit/hyperactivity disorder (ADHD) are treated with stimulant medication, the dose is established clinically by dose adjustment over time. Little is known about children who are not adequately treated when they reach a designated maximum dose, or the consequences of exceeding this dose. OBJECTIVE: The aim of this study was to determine the characteristics of and side effects observed in children optimised to high dose (HD) versus regular dose (RD) stimulants. METHOD: Children treated by one paediatrician (AP) in Western Sydney, Australia with HD stimulants (n = 52) were identified using an electronic database; controls on RD stimulant (n = 118) were matched by prescription date with the cases' first HD prescription. HD was defined as methylphenidate > 2 mg/kg/day or > 108 mg/day; dexamphetamine > 1 mg/kg/day or > 50 mg/day; lisdexamfetamine > 70 mg/day. In all children, the dose was adjusted over time to optimise the clinical response. Clinical characteristics, anthropometric measures, reported side effects and reasons for dose changes were extracted from the clinical charts by LR, VS and CS. The HD and RD cohorts were compared using chi-square for categorical data and t tests for continuous data. RESULTS: The HD cohort included more boys (88% vs 75%, p = 0.041) and more oppositional defiant disorder (83% vs 55%, p = 0.001). They started stimulants younger (6.40 ± 1.67 vs 8.28 ± 2.77 years, p < 0.001) and had more growth attenuation (Δ height z-score - 0.41 ± 0.55 vs - 0.09 ± 0.58, p = 0.001; Δ weight z-score - 0.56 ± 0.82 vs - 0.18 ± 0.66, p = 0.002). The growth attenuation mainly occurred before the dose reached the HD range. Diminishing stimulant effectiveness was the commonest reason for a dose increase in either cohort, the most prominent recurring symptoms being persistent anger/aggression in the HD and poor concentration in the RD cohort. The commonest reason for dose reduction in the HD cohort was that a dose increase gave no added benefit; dose reduction or change of drug due to subdued/depressed behaviour was more frequent in RD children. Apart from growth attenuation, no serious complications were reported in the HD group. CONCLUSIONS: In this preliminary study, dose adjustment over time in some patients meant using higher doses than those generally recommended. These children experienced more growth attenuation but recorded no other significant treatment complications. Determining the dose purely on clinical grounds by careful dose adjustment over time appears reasonable, but more data on this issue is required to clarify the efficacy and tolerability of exceeding the recommended doses of stimulants when treating ADHD.

Stimulant prescribing for attention deficit hyperactivity disorder (ADHD): what guides clinicians in their choice of an upper limit for dose titration?

OBJECTIVE: There is little evidence to support the current stimulant dose upper limit restrictions in the treatment of attention deficit hyperactivity disorder (ADHD). Within Australasia, there is inconsistency in dose maxima in different jurisdictions. Clinician experience in this area may be worth gauging when trying to improve the understanding of optimal maximal dosing. Our objective was to survey prescribers' experience of whether the current stimulant maximum doses ever conflict with dose optimisation and how such conflicts are managed. METHOD: We conducted an anonymous online survey of health professionals treating children, adolescents and adults with ADHD. RESULTS: Responses were received from 128 prescribers, mainly paediatricians (52%) and adult psychiatrists (39%). The designated maximum dose of stimulant was a constraint to dose optimisation experienced by 91% for the Product Information maxima and 82% for their respective state/territory regulations maxima. When clinically indicated, 72% would exceed the designated maxima, either with or without obtaining a second opinion or applying for special authority. Of the remaining 28%, the majority (16%) would opt for polypharmacy, with only two accepting a suboptimal dose. CONCLUSION: The current stimulant dose maxima act as a constraint to stimulant dose optimisation and may promote undertreatment and polypharmacy.

Evaluation of Methylphenidate Safety and Maximum-Dose Titration Rationale in Attention-Deficit/Hyperactivity Disorder: A Meta-analysis.

Importance: Evidence on the titration of stimulant medications for attention-deficit/hyperactivity disorder (ADHD) is lacking. However, this lack of evidence has not prevented medication guidelines from specifying apparently arbitrary dose limitations, which could discourage clinicians from titrating methylphenidate to higher and, perhaps for some patients, more efficacious doses. Objective: To determine the evidence on dose titration and adverse events associated with dose titration of stimulants for ADHD. Data Sources: MEDLINE from 1946, Embase from 1974, and PsycINFO from 1806 through April 1, 2019, were searched to identify relevant articles. Study Selection: The inclusion criteria were that (1) the study was conducted on children up to 18 years of age; (2) children had a diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, or hyperkinetic disorder according to the International Classification of Diseases codes; and (3) the dose of methylphenidate was determined by titration. Data Extraction and Synthesis: The PRISMA guidelines for abstracting data and assessing data quality and validity were followed. Quality assessment was undertaken using the Jadad scoring system. Statistical analysis was undertaken using a random-effects model. Main Outcomes and Measures: The outcomes of interest were (1) the doses used in published clinical trials, (2) the clinical justification given by researchers for their selected dose range, and (3) the adverse effects associated with methylphenidate when the dose is established by titration. Results: A total of 11 randomized clinical trials and 38 cohort studies were analyzed. The randomized clinical trials involved 1304 participants treated with methylphenidate and 887 controls; the 38 cohort studies included 5524 participants. Maximum doses of methylphenidate ranged from 0.8 to 1.8 mg/kg/d. Some studies detailed their method of titration, including starting dose, titration interval, increment dose, and maximum dose. Not all of these studies reported justification for the chosen dose range. Common adverse effects of methylphenidate included insomnia (odds ratio, 4.66; 95% CI, 1.99-10.92; P < .001), anorexia (5.11 higher than for those who took placebo; 95% CI, 1.99-13.14; P < .001), abdominal pain (1.9 times more likely; 95% CI, 0.77-4.77; P = .16), and headache (14% of participants; 95% CI, 10%-20%; P < .001). Conclusions and Relevance: A range of maximum doses for methylphenidate was recommended in clinical studies; no discernable scientific justification for any particular dose was given. Reports of life-threatening adverse events were absent; further studies of the efficacy, tolerability, and safety of methylphenidate titrated purely on clinical grounds, without reference to any set maximum dose, are needed.

Perinatal Outcomes of Women Diagnosed with Attention-Deficit/Hyperactivity Disorder: An Australian Population-Based Cohort Study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is common and may require treatment in adulthood. We aimed to investigate the treatment patterns and perinatal outcomes of women with any history of stimulant treatment for ADHD. METHODS: We used health records of the New South Wales (NSW, Australia) population to compare perinatal outcomes of women treated with stimulants (dexamphetamine or methylphenidate) for ADHD from 1982 to 2012 who gave birth between 1994 and 2012, with perinatal outcomes of women with no known ADHD or stimulant treatment (comparison cohort). Five comparison women, matched by maternal age and infant year of birth, were selected for each treated woman. Pregnancy outcome odds ratios in the two groups were adjusted for confounders including maternal age and smoking. RESULTS: Of 5056 women treated for ADHD with stimulant medication, 3351 (66.3%) had stimulant treatment documented before the index pregnancy but not within 1 year before the expected date of delivery, 175 (3.5%) had stimulant treatment before and possibly during pregnancy (stimulant prescription within the 12 months directly before the expected date of the index birth and earlier), and 1530 (30.2%) had no stimulant treatment until after the index pregnancy. Treatment for ADHD at any time (before, before and during and only after the index pregnancy) was associated with reduced likelihood of spontaneous labour-odds ratios (ORs) 0.7 [0.7, 0.8], 0.7 [0.5, 0.9], and 0.7 [0.7, 0.8], respectively-and increased risk of caesarean delivery (1.2 [1.1, 1.3], 1.3 [0.9, 1.8], 1.3 [1.1, 1.4]); active neonatal resuscitation (1.2 [1.0, 1.3], 1.7 [1.1, 2.7], 1.3 [1.0, 1.7]); and neonatal admission > 4 h (1.2 [1.1, 1.3], 1.7 [1.2, 2.4], 1.2 [1.0, 1.4]). Treatment before or before and during pregnancy was, in addition, associated with increased risk of pre-eclampsia (1.2 [1.0, 1.4], 1.5 [0.8, 2.6]); preterm birth < 37 weeks (1.2 [1.0, 1.3], 1.4 [0.9, 2.3]); and 1-min Apgar < 7 (1.2 [1.1, 1.3], 2.0 [1.4, 2.9]). Stimulant prescribing was low during pregnancy (3.5% of women received such a prescription) and dropped during the 12 months before the due date from an average of 24.7 prescriptions per month in the first 6 months to 4.5 per month in the final 6 months. CONCLUSIONS: Compared with no treatment, ADHD stimulant treatment at any time was associated with small increases in the risk of some adverse pregnancy outcomes; treatment before, or before and during pregnancy, was associated with additional adverse outcomes, even after a treatment-free period of several years. None of these associations can be confidently attributed to stimulant treatment; in all cases ADHD per se or correlates of it could be responsible for the association.

Transition in ADHD: attention to the lifespan.

OBJECTIVES: This paper reviews the importance of transition to adult services for young people with ADHD. METHOD: Different models are described and evidence sought for their effectiveness in clinical practice. RESULTS: Models of care for children with ADHD include specialised mental health services, individual paediatricians and child and adolescent psychiatrists. Although it might be expected that transition would be to equivalent adult teams or specialists, studies have shown that transition may not run smoothly, and the adult services are frequently inadequate. This may result in attrition from treatment or discharge to the general practitioner. CONCLUSIONS: Adult mental health services for transitioning young people with ADHD are under-resourced. The way forward may be a generic ADHD specialist or service, treating ADHD across the lifespan and avoiding the need for transition.

Stimulants for the Control of Hedonic Appetite.

The focus of this paper is treatment of obesity in relation to the management of hedonic appetite. Obesity is a complex condition which may be potentiated by excessive reward seeking in combination with executive functioning deficits that impair cognitive control of behavior. Stimulant medications address both reward deficiency and enhance motivation, as well as suppressing appetite. They have long been recognized to be effective for treating obesity. However, stimulants can be abused for their euphoric effect. They induce euphoria via the same neural pathway that underlies their therapeutic effect in obesity. For this reason they have generally not been endorsed for use in obesity. Among the stimulants, only phentermine (either alone or in combination with topiramate) and bupropion (which has stimulant-like properties and is used in combination with naltrexone), are approved by the United States Food and Drug Administration (FDA) for obesity, although dexamphetamine and methylpenidate are approved and widely used for treating attention deficit hyperactivity disorder (ADHD) in adults and children. Experience gained over many years in the treatment of ADHD demonstrates that with careful dose titration, stimulants can be used safely. In obesity, improvement in mood and executive functioning could assist with the lifestyle changes necessary for weight control, acting synergistically with appetite suppression. The obesity crisis has reached the stage that strong consideration should be given to adequate utilization of this effective and inexpensive class of drug.

Stimulant medication effects on growth and bone age in children with attention-deficit/hyperactivity disorder: a prospective cohort study.

Stimulant medication is known to cause transient weight loss and slowing down of growth, but whether it delays physical maturation is unclear. We studied growth and bone age over the first 3 years of treatment in children with attention-deficit/hyperactivity disorder (patients) compared with healthy siblings (controls). Bone age was estimated blindly by two independent radiologists using Tanner and Whitehouse version 3. Dexamphetamine or methylphenidate was titrated and continued when clinically indicated. Forty out of 73 patients, together with 22 controls, completed the study. There were no significant growth differences between the two groups at baseline. Despite slower growth on treatment [5.1 cm/year, 95% confidence interval (CI): 4.7-5.5, vs. 6.3 cm/year, 95% CI: 5.7-6.8, P=0.002; and 2.7 kg/year, 95% CI: 2.1-3.3, vs. 4.4 kg/year, 95% CI: 3.5-5.3, P=0.005], the patients showed no significant maturational delay (RUS score: 49 U/year, 95% CI: 44-55, vs. 55 U/year, 95% CI: 47-63, P=0.27). A subgroup of patients underwent serial biochemistry and dual-energy X-ray absorptiometry, recording a significant reduction in fat (5.61±3.56-4.22±3.09 kg, P<0.001) and leptin (3.88±2.87-2.57±1.94 ng/ml, P=0.017). The pattern of change in height z-score over time was modified by the dose of medication (P for interaction=0.024). We found no medication effect on the rate of maturation, which was instead predicted by baseline leptin (P=0.035 controlling for age and sex).

Piloting a new approach to the treatment of obesity using dexamphetamine.

BACKGROUND AND AIMS: There is a clear need for a new approach to the treatment of obesity, which is inexpensive and is effective for establishing lifestyle change. We conducted a pilot study to evaluate whether dexamphetamine can be used safely, combined with diet and exercise, for treating obesity. Our ultimate aim is to develop a 6-month treatment program for establishing the lifestyle changes necessary for weight control, utilizing dexamphetamine for its psychotropic effect on motivation. We viewed the anorexigenic effect as an additional advantage for promoting initial weight loss. METHODS: Obese adults were treated with dexamphetamine for 6 months (maximum of 30 mg twice daily), diet, and exercise. Weight, electrocardiogram, echocardiogram, and blood pressure were monitored. RESULTS: Twelve out of 14 completed 6 months treatment. Weight loss by intention to treat was 10.6 kg (95% CI 5.8-15.5, p < 0.001). The mean weight gain in the 6 months after ceasing dexamphetamine was 4.5 kg (95% CI 1.9-7.2, p = 0.003), leaving a mean weight loss at 12 months from baseline of 7.0 kg (95% CI -13.4 to -0.6, p = 0.03). All reported favorable increases in energy and alertness. Dose-limiting symptoms were mood changes (2) and insomnia (2). None had drug craving on ceasing dexamphetamine, and there were no cardiac complications. Among the seven women, there was a significant correlation for those who lost most weight on treatment to have the least regain in the following 6 months (r = 0.88, p = 0.009). CONCLUSION: Our treatment with dexamphetamine, diet, and exercise was well tolerated and effective for initial weight loss. Future research will focus on identifying baseline predictive variables associated with long-term weight control.

Growth and pubertal development of adolescent boys on stimulant medication for attention deficit hyperactivity disorder.

OBJECTIVE: To investigate the growth and pubertal attainment of boys with attention deficit hyperactivity disorder (ADHD) on stimulant medication. DESIGN, SETTING AND PARTICIPANTS: Longitudinal study of boys aged 12.00-15.99 years at recruitment in 2005-2011, with stimulant-treated ADHD for at least 3 years, attending three paediatric practices (subjects), compared with longitudinal data from 174 boys from the Nepean longitudinal study (controls). MAIN OUTCOME MEASURES: Subjects' growth parameters before treatment were compared with controls aged 7 or 8 years; growth parameters and longitudinal changes on treatment to ages 12.00-13.99 and 14.00-15.99 years were compared with controls reviewed at 13 and 15 years of age, respectively. The subjects' pubertal staging and height velocity were related to their treatment history. RESULTS: Sixty-five subjects were recruited; mean duration of treatment was 6.3 ± 1.9 years. At baseline, their growth parameters were not significantly different from those of the controls after adjusting for age. Compared with the controls, after adjusting for current age and baseline growth parameter z score, subjects aged 12.00-13.99 years had significantly lower weight and body mass index (P < 0.01), and those aged 14.00-15.99 years had significantly lower height and weight (P < 0.05). At 12.00-13.99 years of age, the subjects were comparable to the controls in their pubertal development adjusted for age, but those aged 14.00-15.99 years reported significant delay (mean Tanner stage, 3.6 for subjects v 4.0 for controls; P < 0.05). The dose of medication was inversely correlated with the height velocity from baseline to 14.00-15.99 years of age (P < 0.05). CONCLUSIONS: Prolonged treatment (more than 3 years) with stimulant medication was associated with a slower rate of physical development during puberty. To maintain adequate height velocity during puberty, we recommend keeping the dose as low as possible.

Time to redefine the diagnosis of oppositional defiant disorder.

Oppositional defiant disorder (ODD) is a common and difficult problem that is regularly seen in general paediatric practice. Although classified as an independent diagnosis, ODD very commonly coexists with attention-deficit/hyperactivity disorder (ADHD) but in contrast to the latter, there are few studies that deal specifically with ODD and there is a lack of formal management guidelines. However, if ODD was included as a subtype of ADHD, this exclusion would not be sustainable. This would make guidelines more helpful and relevant for Australian paediatricians who currently have little support beyond their own clinical experience in dealing with this often very disabling condition.

Prior treatment with stimulant medication: a much neglected confounder of studies of growth in children with attention-deficit/hyperactivity disorder.

Abstract Evidence is provided that growth is an accurate indicator of prior treatment with stimulant medication. This is of utmost importance when interpreting clinical studies on attention-deficit/hyperactivity disorder (ADHD), as pretreated cohorts are likely to include fewer nonresponders and fewer individuals with intolerable side effects. In this respect, growth patterns are an excellent tool to identify pretreatment and thus address selection bias.