To stop or not to stop? How long should medication treatment of attention-deficit hyperactivity disorder be extended?

doi:10.1016/j.euroneuro.2011.03.008

European Neuropsychopharmacology

Volume 21, Issue 8, August 2011, Pages 584-599

https://doi.org/10.1016/j.euroneuro.2011.03.008 Get rights and content

Abstract

ADHD is a common neuropsychiatric disorder with a strong persistence over time. Medication is frequently used in the clinical management of ADHD. After response, medication is typically prescribed for months to years. It is unclear whether extended medication treatment provides long-term benefits and how long it should be continued. Furthermore, there is concern about the long-term safety of ADHD medication. The aim of this systematic review is to address these issues and provide recommendations about the decision to stop or not to stop ADHD medication. We performed a search in PubMed and focused on medication studies with a treatment longer than 12 weeks in subjects 6–18 years old.

Extended placebo-controlled double-blind parallel studies are not available. Placebo-controlled discontinuation studies and prospective long-term observational treatment studies provide evidence that medication management leads to a substantial reduction of ADHD symptoms and less impairment of functioning for a period of about 2 years. There is limited and inconsistent evidence for long-term advantage of medication treatment beyond symptom control, such as improved social functioning, academic achievement, employment status and less adverse psychiatric outcome. In terms of safety, long-term effects of medication on growth, blood pressure and heart rate are limited and the occurrence of suicidal, psychotic and manic symptoms is rare. Animal data about neurotoxic effects of psycho stimulants cannot be directly extrapolated to humans.

Therefore, clinical decisions about starting, continuing, and stopping of ADHD medication should be made on an individual basis. Medication free periods should be implemented at regular times to investigate the need for an ongoing benefit of medication. Unfounded assumptions about continuing benefit of medication use should be abandoned. Careful monitoring of side effects is necessary and must be able to detect early alarming signals.

Section snippets

Aims

ADHD medications are not only efficacious but also proven to be fairly safe in short clinical trials during 6–12 weeks of treatment. However, as ADHD is a rather chronic condition, medication treatment typically will be extended over a long period of time, up to several years. This calls for a critical review of the long-term efficacy and safety of ADHD medication. Are short-term treatment gains maintained in extended treatment? What is the safety outcome of long-term treatment? Does long-term

Methods

We performed an internet search of the literature published on PUBMED and this search was repeated in Google Scholar to verify the results. Articles published in the last two decades (1990–2010) were included using the keywords: ADHD, long term treatment, MTA study, relapse prevention, (dex)amphetamine, methylphenidate, clonidine, guanfacine, alpha adrenergic agonists, atomoxetine, bupropion, anti-depressives, and modafinil. We limited our search to papers published in English, in subjects 6–18

Long-term efficacy

Examining the long-term efficacy of ADHD medication by extended placebo-controlled double-blind parallel studies would be ethically impossible since it would require withholding treatments of proven efficacy for a long period of time. Thus, long-term efficacy has been studied using nonrandomized controlled designs in which for example historic controls, alternative treatments, treatment duration and within-subject withdrawal designs have been used (Schachar and Tannock, 1993). Of course, these

Role of comorbid disorders

It is the rule rather than the exception that ADHD is comorbid with other conditions, such as oppositional defiant disorder, conduct disorder, mood and anxiety disorder, tic disorder or learning problems. In case of comorbid ADHD more often a combination of treatment modalities will be indicated (Taylor et al., 2004). This may influence the need for long-term treatment with medication. However, extensive analysis of the MTA data failed to show a direct and decisive impact of the presence of

Long-term safety

Common short-term side effects of psychostimulant medication are insomnia, loss of appetite, irritability, gastro-intestinal problems, and headaches (Greenhill et al., 2002), and those on atomoxetine decreased appetite, vomiting, nausea, dyspepsia and somnolence (Michelson et al., 2001). Most of the side effects, like headache, irritability, proneness to cry or gastro-intestinal problems tend to subside over time or can possibly be avoided or diminished with lowering the dose. Even sleep

Conclusions and recommendations

ADHD medications have shown to lead to powerful short-term effects in reducing the key symptoms of ADHD in numerous well-controlled clinical trials. These effects however seemed to be short-lived, and disappear when medication is discontinued. The data from the atomoxetine discontinuation study suggests however that at least for some patients the effects of atomoxetine do not always fade away when medication is stopped (Buitelaar et al., 2007). Since ADHD is a chronic condition with a strong

Role of the funding source

None.

Contributors

All authors performed literature searches and contributed equally to the writing of the manuscript.

Conflict of interest

Jan K Buitelaar has been, in the past 3 years, a consultant to / member of advisory board of / and/or speaker for Janssen Cilag BV, Eli Lilly, Organon/Shering Plough, UCB, Shire, Medice, and Servier. He is not an employee or a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, and royalties.

Gigi HH van de Loo-Neus has been in the past 3 years a consultant to / member of advisory board of / and/or speaker for Janssen

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Cited by (81)

Discontinuation of methylphenidate after long-term exposure in nonhuman primates
2023, Neurotoxicology and Teratology
Attention-deficit hyperactivity disorder (ADHD) is a common human neurobehavioral disorder that usually begins in early childhood. Methylphenidate (MPH) has been used extensively as a first-line medicine for the treatment of ADHD. Since ADHD is often diagnosed in early childhood and can persist for the entire lifespan, individuals may take MPH for many years. Given that in the course of one's lifetime a person may stop taking MPH for periods of time, or may implement lifestyle changes that may reduce the need for MPH entirely, it is important to understand how cessation of MPH affects the adult brain following long-term use of MPH. The blockage of the dopamine transporter (DAT) and the norepinephrine transporter (NET) by MPH may help with ADHD symptoms by boosting monoamine levels in the synapse. In the present study, microPET/CT was used to investigate possible neurochemical alterations in the cerebral dopamine system after cessation of long-term MPH administration in nonhuman primates. MicroPET/CT images were collected from adult male rhesus monkeys 6 months after they stopped receiving vehicle or MPH following 12 years of chronic treatment. The neurochemical status of brain dopaminergic systems was evaluated using the vesicular monoamine transporter 2 (VMAT2) ligand [¹⁸F]-AV-133 and a tracer for imaging dopamine subtype 2 (D₂) and serotonin subfamily 2 (5HT₂) receptors, [¹⁸F]-FESP. Each tracer was injected intravenously and ten minutes later microPET/CT images were obtained over 120 min. The binding potential (BP) of each tracer in the striatum was obtained using the Logan reference tissue model with the cerebellar cortex time activity curve (TAC) as an input function. Brain metabolism was also evaluated using microPET/CT images of [¹⁸F]-FDG. [¹⁸F]-FDG was injected intravenously, and ten minutes later, microPET/CT images were obtained over 120 min. Radiolabeled tracer accumulation in regions of interest (ROIs) in the prefrontal cortex, temporal cortex, striatum, and cerebellum were converted into standard uptake values (SUVs). Compared to the vehicle control group, the BPs of [¹⁸F] AV-133 and [¹⁸F]-FESP in the striatum were not significantly altered in MPH treated groups. Additionally, no significant differences were detected in the SUVs of [¹⁸F]-FDG in the MPH treated group compared with control. This study demonstrates that 6 months after cessation of long-term, chronic MPH treatment, there are no significant neurochemical or neural metabolic changes in the central nervous system (CNS) of non-human primates (NHPs) and suggests that microPET imaging is helpful in assessing the status of biomarkers of neurochemical processes linked to chronic CNS drug exposure. (Supported by NCTR).
Long-term methylphenidate exposure and 24-hours blood pressure and left ventricular mass in adolescents and young adults with attention deficit hyperactivity disorder
2022, European Neuropsychopharmacology
Citation Excerpt :
Another study assessed cardiac function by echocardiography and tissue Doppler imaging in 58 stimulant-treated children with ADHD and another 58 treatment naïve children with ADHD and was unable to establish cardiac function impairments (Kara et al., 2018). Children with ADHD are now being treated for longer than was previously the case and are increasingly likely to remain on methylphenidate treatment into adolescence and adulthood. (van de Loo-Neus, Rommelse, and Buitelaar, 2011) Furthermore, an increasing number of individuals are being diagnosed with ADHD in adulthood and methylphenidate is more frequently being started for the first time in adults who are already at greater risk of cardiovascular disorders than children (Elliott et al., 2020).
Young people with attention deficit hyperactivity disorder (ADHD) are now being treated with psychostimulant medication for longer than was previously the case and are increasingly likely to remain on methylphenidate into adolescence and adulthood. This study was designed to determine whether the long-term use of methylphenidate (MPH, immediate release or extended release) increases blood pressure and left ventricular mass (LVM) identified by echocardiography in adolescents and young adults with ADHD aged 12-25 years. In a five-site cross-sectional design two groups were compared for 24- hour blood pressure and heart rate (HR) registrations and LVM: 1) adolescents and young adults with ADHD who had been treated with MPH for > 2 years (N=162, age mean (SD) 15.6 (3.0)), and 2) adolescents and young adults with ADHD who had never been treated with methylphenidate (N=71, age mean 17.4 (4.2)). The analyses were controlled for propensity scores derived from age, sex, height, weight, and 19 relevant background variables.
A blood pressure indicative of hypertension (>95^th percentile) was observed in 12.2% (95% confidence interval 7.3 – 18.9%) of the participants in the MPH treated group and in 9.6% (95%CI 3.2 – 21.0%) of the MPH naïve group, with overlapping intervals. The 24-hour recorded systolic blood pressure (SBP) and HR were significantly higher during daytime in medicated individuals with ADHD than in those with unmedicated ADHD, but were similar in both groups during the night. 24-hour diastolic blood pressure (DBP) did not differ between both groups during either daytime or at night. LVM, corrected for body-surface area (LVMBSA), also did not differ between the two groups (p=0.20, controlling for confounders). Further, MPH daily dose and duration of treatment were unrelated to LVMBSA, SBP, and DBP.
Long-term MPH use in adolescents and young adults with ADHD is associated with small but significant increases of SBP and HR during daytime. Given the current sample size, the proportions of hypertension do not differ significantly between MPH treated and MPH-naïve individuals with ADHD. Future studies with larger samples, longer treatment duration, and/or with within-subject designs are necessary. The results do, however, further support recommendations that highlight the importance of monitoring blood pressure and HR during MPH treatment.
Long term methylphenidate exposure and growth in children and adolescents with ADHD. A systematic review and meta-analysis
2021, Neuroscience and Biobehavioral Reviews
Methylphenidate (MPH) is an efficacious treatment for ADHD but concerns have been raised about potential adverse effects of extended treatment on growth.
To systematically review the literature, up to December 2018, conducting a meta-analysis of association of long-term (> six months) MPH exposure with height, weight and timing of puberty.
Eighteen studies (ADHD n = 4868) were included in the meta-analysis. MPH was associated with consistent statistically significant pre-post difference for both height (SMD = 0.27, 95% CI 0.16-0.38, p < 0.0001) and weight (SMD = 0.33, 95% CI 0.22-0.44, p < 0.0001) Z scores, with prominent impact on weight during the first 12 months and on height within the first 24-30 months. No significant effects of dose, formulation, age and drug-naïve condition as clinical moderators were found. Data on timing of puberty are currently limited.
Long-term treatment with MPH can result in reduction in height and weight. However, effect sizes are small with possible minimal clinical impact. Long-term prospective studies may help to clarify the underlying biological drivers and specific mediators and moderators.
A Randomized Controlled Trial of Interventions for Growth Suppression in Children With Attention-Deficit/Hyperactivity Disorder Treated With Central Nervous System Stimulants
2020, Journal of the American Academy of Child and Adolescent Psychiatry
To examine the impact of central nervous system (CNS) stimulants on the growth of children with attention-deficit/hyperactivity disorder (ADHD), and to assess the efficacy and feasibility of weight recovery interventions on growth.
A total of 230 children aged 5 to 12 years with ADHD with no history of chronic CNS stimulant use were randomly assigned to receive daily CNS stimulants (78%, primarily osmotic release oral system-methylphenidate [OROS-MPH]) or behavioral treatment (22%) for 30 months. After 6 months, children evidencing a decline in body mass index (BMI) of >0.5 z-units were randomized to 1 of 3 weight recovery treatments (WRTs): monthly monitoring of height/weight (MON) plus continued daily medication; drug holidays (DH) with medication limited to school days; or daily caloric supplementation (CS) with a 150-kcal supplement plus daily medication.
Before WRT assignment, medication was associated with significant reductions in standardized weight and height (p values <.01). Adherence to CS and DH during WRT was high, with significant increases in daily caloric intake and decreases in weekly medication exposure (p values <.05). Across all WRT participants (n = 71), weight velocity increased significantly after WRT randomization (β₂ = 0.271, SE = 0.027, p < .001).When analyzed by what parents did (versus what they were assigned to), CS (p < .01) and DH (p < .05) increased weight velocity more than MON. No increase in height velocity was seen after randomization to any WRT. Over the entire study, WRT participants declined in standardized weight (−0.44 z-units) and height (−0.20 z-units).
Drug holidays, caloric supplementation, and increased monitoring all led to increased weight velocity in children taking CNS stimulants, but none led to increased height velocity.
Novel Approach to Stimulant Induced Weight Suppression and Its Impact on Growth; https://clinicaltrials.gov/; NCT01109849.
Long-term effects of theta/beta neurofeedback on EEG power spectra in children with attention deficit hyperactivity disorder
2020, Clinical Neurophysiology
Neurofeedback has been proposed as an effective alternative for pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD), with potentially long-term and delayed benefits. However, the specificity of such long-term behavioral improvements remains inconclusive and therefore additional research into the neurophysiological effects of neurofeedback is needed. We compared long-term effects of theta/beta neurofeedback (NFB) to methylphenidate (MPH) and physical activity (PA, semi-active control intervention) on electroencephalogram (EEG) power spectra. Based on the vigilance stabilization model, we hypothesized further reductions in theta and alpha power in the NFB compared to the control groups.
EEG power spectra (theta, alpha and beta) during resting and task conditions were recorded at pre-, post-intervention and 6-months follow-up in 67 children, aged 7–13 (NFB: n = 24, MPH: n = 23, or PA: n = 20).
Analyses revealed no power spectra differences at follow-up between MPH and NFB (range p = .165–.905) and PA and NFB (range p = .172–.822).
No evidence was found for the specificity of theta/beta NFB at follow-up.
This was the first study into long-term neurophysiological effects of theta/beta NFB. Future studies are encouraged to explore both specific and non-specific mechanisms of NFB.
Clinical trials registration: Train Your Brain? Exercise and neurofeedback intervention for ADHD, https://clinicaltrials.gov/show/NCT01363544, Ref. No. NCT01363544.
Attention Deficit Hyperactivity Disorder
2019, Sleep and ADHD: An Evidence-Based Guide to Assessment and Treatment
Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder. It is a polygenic disorder with multifactorial etiology, including genetic and environmental factors. Onset occurs in childhood, but symptoms usually persist across developmental stages into adult life, at least to some extent. A range of cognitive deficits are seen in ADHD, underpinning the substantial functional difficulties experienced by individuals with the condition. Management includes both pharmacological and nonpharmacological interventions. Comorbidities such as sleep problems are common and contribute to the impairments. These need to be identified and addressed alongside ADHD symptoms. ADHD is associated with an increased risk of negative long-term outcomes however, with support many patients thrive and have successful lives.

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ReviewTo stop or not to stop? How long should medication treatment of attention-deficit hyperactivity disorder be extended?

Abstract

Section snippets

Aims

Methods

Long-term efficacy

Role of comorbid disorders

Long-term safety

Conclusions and recommendations

Role of the funding source

Contributors

Conflict of interest

J. Am. Acad. Child Adolesc. Psychiatry

Child Adolesc. Psychiatr. Clin. N. Am.

J. Am. Acad. Child Adolesc. Psychiatry

Lancet

Biol. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

Biol. Psychiatry

Biol. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

Lancet

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

Behav. Res. Ther.

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD

J. Atten. Disord.

Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders

Neurology

Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text-revision (DSM-IV-TR)

Is adult attention deficit hyperactivity disorder a valid diagnosis in the presence of high IQ?

Psychol. Med.

Efficacy of neurofeedback treatment in ADHD: the effects on inattention, impulsivity and hyperactivity: a meta-analysis

Clin. EEG Neurosci.

Long-acting medications for the hyperkinetic disorders: a systematic review and European treatment guideline

Eur. Child Adolesc. Psychiatry

Long-term stimulant medication treatment of attention-deficit/hyperactivity disorder: results from a population-based study

J. Dev. Behav. Pediatr.

Modifiers of long-term school outcomes for children with attention-deficit/hyperactivity disorder: does treatment with stimulant medication make a difference? Results from a population-based study

J. Dev. Behav. Pediatr.

ADHD in Adults: Diagnosis and Management

Young adult follow-up of hyperactive children: antisocial activities and drug use

J. Child Psychol. Psychiatry

Abuse of amphetamines and structural abnormalities in the brain

Ann. N.Y. Acad. Sci.

Potential adverse effects of amphetamine treatment on brain and behavior: a review

Mol. Psychiatry

Patterns of psychiatric comorbidity, cognition, and psychosocial functioning in adults with Attention Deficit Hyperactivity Disorder

Am. J. Psychiatry

Young adult outcome of attention deficit hyperactivity disorder: a controlled 10-year follow-up study

Psychol. Med.

Do stimulants protect against psychiatric disorders in youth with ADHD? A 10-year follow-up study

Pediatrics

Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder

JAMA

Impact of attention-deficit/hyperactivity disorder on the patient and family: results from a European survey

Child Adolesc. Psychiatry Ment. Health

Review
To stop or not to stop? How long should medication treatment of attention-deficit hyperactivity disorder be extended?