Risk of psychosis with stimulants used for ADHD

Samuele Cortese, MD, PhD

Lauren V Moran, MD

Correct diagnosis of ADHD

Michael S Jellinek, MD

The ability of physicians to talk to patients about their health concerns and how to manage them is fundamental to good clinical care. One important area of this conversation is the ability to help patients weigh the benefits and risks of medications based on the best evidence available.

This can be tricky. Patients need to know about common potential adverse effects, but how do physicians talk about the rare potential adverse effect? The inquisitive patient who reads the packing label on the medication may ask, as may the patient watching the evening news after hearing about new research on a rare risk linked to the medicine they are taking.

Pediatricians who prescribe stimulants for children and adolescents with attention-deficit/hyperactivity disorder (ADHD) may be asking themselves how best to talk with patients and their families about a rare potential adverse effect associated with stimulants-psychosis-given the recent media attention to a new study published in late March in the New England of Medicine that compared the incidence of psychosis between 2 major classes of stimulants used to treat ADHD.¹

Specifically, the study compared the incidence of psychosis in children and adolescents with ADHD treated with either methylphenidate or amphetamines. Although the study found a low incidence of psychosis with any stimulant, it reinforces the need for pediatricians to talk to patients and parents about the real risk of such a rare adverse effect by placing it in context with what the evidence actually shows as well as what it doesn’t show.

“[The study] provides relevant data on the prevalence of psychotic events during treatment with ADHD medications that clinicians should discuss with patients when they consider starting a pharmacologic treatment for ADHD, when both possible benefits and possible harms of the medication need to be taken into account,” says Samuele Cortese, MD, PhD, Centre for Innovation in Mental Health, faculty of Environmental and Life Science School of Psychology, and Clinical and Experimental Sciences, faculty of Medicine, University of Southampton, Southampton, United Kingdom.

Cortese emphasizes, however, that the study could not show that the psychotic events were caused by the stimulants. “It is important to highlight that the design of the study is not suitable to assess the causal link between stimulants and occurrence of psychotic events,” he says.

So, what does the study show and what is important for the community pediatrician to know when seeing a child in the clinic with ADHD?

Psychosis is a low risk

One key takeaway from the study is the low incidence of psychosis in patients with ADHD on stimulants.

“Psychotic events are rare with prescribed stimulants,” says the lead author of the study, Lauren V. Moran, MD, assistant professor of Psychiatry, McLean Hospital, Belmont, Massachusetts.

In the study, Moran and colleagues retrospectively assessed the incidence of new-onset psychosis in 337,919 adolescents and young adults (aged 13 to 25 years) with ADHD after initiating treatment with either methylphenidate (n=110,923) or amphetamines (110,923) between January 2004 and September 2015. Data were obtained from 2 commercial insurance claims databases.

New-onset psychosis in the study was defined as a diagnosis of psychosis for which an antipsychotic medication was prescribed during the first 60 days after the onset of psychosis. Diagnoses included unspecified psychosis, hallucinations, delusional disorder, schizophrenia spectrum disorders, major depressive or bipolar disorder with psychotic features, and other stimulant use disorders with psychosis.¹

The study found a total of 343 psychotic episodes in the full cohort, with 106 episodes (0.10%) in the patients taking methylphenidate and 237 episodes (0.21%) in the patients taking amphetamines.

“The rate of psychosis after starting stimulant medication for ADHD is low-1 in 660 in adolescents and young adults,” says Michael S. Jellinek, MD, professor emeritus of Psychiatry and Pediatrics, Harvard Medical School, Boston, Massachusetts. “The rate is twice as high, but still low, when using amphetamines compared to methylphenidate.”

This last point underscores another key takeaway from the study-the higher incidence, yet still low occurrence, of psychosis in patients on amphetamines versus methylphenidate.

Methylphenidates as first-line treatment

“We’ve known for a long time that stimulants can lead to psychosis, but there hasn’t been any comparison between these two types of stimulants and this is the first study comparing the two,” says Moran.

For Moran, the finding of an increased incidence of psychosis in patients taking amphetamines compared with methylphenidate suggests that methylphenidates should be considered as first-line treatment for ADHD, particularly in children and young adolescents.

When looking at the prescribing practices by physician type, she says that family practitioners and psychiatrists were more likely to prescribe an amphetamine (ie, Adderall) and pediatricians more likely to be split, prescribing an amphetamine half the time and methylphenidate half the time.

Although current guidelines by the American Academy of Pediatrics (AAP) indicate equal efficacy between the 2 stimulant classes,² Moran points out that many physicians perceive amphetamines as more potent.

Evidence from a recently published meta-analysis by Cortese and colleagues supports this.³ Pooled data from 133 double-blind, randomized controlled trials were assessed to compare the efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults. The study underscored the efficacy of ADHD medications for all patients, showing that all the medications (except for modafinil in adults) were more efficacious for the short-term treatment (12 weeks) of ADHD for all age groups. When looking at head-to-head comparisons of the different medications, amphetamines were the most efficacious in all age groups.

However, the study highlighted the need to factor in the tolerability of these medications for prescribing practices. When looking at the tolerability, the investigators found that amphetamines were less well tolerated in children.

Importantly, methylphenidate was the only medication with better acceptability compared with placebo for children and adolescents. As such, Cortese and colleagues say this most recent evidence supports methylphenidate as the first-choice medication for children and adolescents with ADHD for short-term treatment, whereas amphetamines could be considered the first choice for adults.³

Weighing in with a clinician’s perspective in managing ADHD in children and adolescents for many years, Harlan R. Gephart, MD, clinical professor of Pediatrics emeritus, University of Washington School of Medicine, Seattle, Washington, called methylphenidate more “gentle” than amphetamines and the preferred first choice for many children with ADHD because it lessens the most common adverse effects of stimulant medications-disturbances in sleep and appetite-and you can “fine-tune it.”

“Methylphenidate is somewhat less likely to affect sleep and appetite than the amphetamines, particularly in the younger population,” Gephart says. However, he underscores that only about 70% of children will respond to methylphenidate, as is true of amphetamines. “Together if we try one stimulant and then another, we can usually get 90% or better response,” he says.

Gephart points out, however, that his choice of stimulant is not based on the potential risk of psychosis given its rarity as well as the lack of evidence showing a causal relationship between stimulants and psychosis.

“I don’t want people to think that the medications are the cause of psychosis because there are so many confounding factors,” he says, adding that the medications may act as a trigger to children who are vulnerable to experiencing a psychotic episode.

The lack of proven causality between stimulants and psychosis and the need to tease out confounding factors when assessing the risk of psychosis with stimulant use are important issues for pediatricians both in their assessment of patients and their vulnerability to psychosis as well as when talking to patients and families about the risk of psychosis when taking a stimulant.

Predicting psychosis

In a commentary accompanying the study by Moran, Cortese highlighted the limitations of retrospective studies such as the study by Moran and colleagues that permit observations about common adverse events in clinical practice but cannot control for confounding factors to establish causality.⁴

For example, Moran and investigators cite a number of potential confounding factors that may influence the incidence of psychosis observed in their patient population. These factors also may be considered risk factors for the development of psychosis, including ongoing substance abuse or using cannabis, or family history of psychosis.

“Because [psychosis] is such a rare side effect, you should consider other risk factors for psychosis if you’re going to start someone on a stimulant, particularly an amphetamine,” Cortese says, adding that if a patient presents with a risk factor for psychosis, “you may want to shy away from an amphetamine or try methylphenidate first.”

Jellinek also stresses the importance of comprehensive care when assessing a child/adolescent with ADHD, which, he says, includes taking a family history of mental illness that covers ADHD, substance use, depression, and psychosis.

“I would look for any signs of prodrome for psychosis, such as social isolation, mania that looks like ADHD, or severe depression,” Jellinek says. “If I was concerned about any aspects of the history, I would proceed with caution, closer monitoring, and likely a psychiatric consultation.”

Cortese, however, stresses the impossibility of predicting which patients may develop a psychosis while on a stimulant. Citing data suggesting that persons may have a low or high vulnerability risk to developing psychosis while on stimulants, Cortese wrote in his commentary that “whether psychosis is due to stimulant use, to inherent vulnerability to psychosis, or to the interaction of these 2 factors remains unclear.”⁴

Jellinek echoes these concerns. “We do not know family histories of these patients that may have added to their vulnerability and we do not know the role of any substance abuse. Maybe college-aged patients were less adherent in taking their medication or diverted it to peers,” he says. “So, despite the high quality of this study, we cannot predict which patients taking stimulants will develop psychosis.”

Benefits vs risks of stimulants

What is important for pediatricians to glean from this study and how to talk to patients about the risk of psychosis?

The study raises again the importance for pediatricians to educate their patients about ADHD; the overall treatment approach that includes school accommodations; behavioral therapy; as well as stimulants and how to weigh the benefits and risks of stimulants. Gephart underscores that stimulant medication with careful monitoring of adverse effects and regular follow-up is the standard of care for most adolescents correctly diagnosed with ADHD (see “Correct diagnosis of ADHD”), and that discussion of developing a very rare adverse effect like psychosis is not a major factor in the decision to treat or not. He also emphasizes the need to talk about the risks of not treating ADHD, particularly in adolescents, given the clear evidence in untreated adolescents on the increased incidence of driving accidents/fatalities, school drop-outs, and substance abuse. “Basically, all the risk factors of adolescence are 2 to 3 times greater in the nonmedicated ADHD adolescent compared to the medicated ADHD adolescent,” he says.

When talking about the adverse effects of stimulants, Gephart focuses first on the common adverse effects such as appetite suppression and sleep disturbances and how to work around these. For example, because stimulants suppress the appetite, he recommends that children/adolescents eat a good breakfast because they may not be hungry at noon when they take their medication. He next talks about potential significant adverse effects, such as aggressiveness and acting like a “zombie,” that are intolerable and unacceptable and that usually indicate the need to adjust dose, and then explains the very rare potential adverse effects of delusions or hallucinations.

To help parents and patients understand better how stimulants work and the potential adverse effects, Gephart talks about their mechanisms of action on enhancing dopamine in the frontal lobes where behaviors including attention, distractibility, and organizational skills are moderated.

“I think it is important to mention that all medications that work on the nervous system, including allergy medications, cardiac and blood pressure medications, antidepressants, and anxiety medications, have the capability of causing strange but intolerable effects on the personality, such as causing aggressive behavior and hallucinations,” he says. “Fortunately, with ADHD medications, these adverse effects are very rare, occur only 1 per several hundreds of patients, and remit when the medication is discontinued.”

Finally, Gephart emphasizes the importance of frequent monitoring of patients, both during the first 4 to 6 weeks of treatment initiation (weekly calls) to establish the appropriate therapeutic dose and look for adverse effects as well as throughout treatment (3 to 4 appointments each year) to ensure lack of significant adverse effects, medication compliance, adequate growth, appropriate academic progress, and no new mental health issues.

References:

1. Moran LV, Ongur D, Hsu J, Castro VM, Perlis RH, Schneeweiss S. Psychosis with methylphenidate or amphetamine in patients with ADHD. N Engl J Med. 2019;380(12):1128-1138.

2. Subcommittee on Attention-Deficit/Hyperactivity Disorder; Steering Committee on Quality Improvement and Management: Wolraich M, Brown L, Brown RT, et al. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128(5):1007-1022. Available at: https://pediatrics.aappublications.org/content/pediatrics/128/5/1007.full.pdf. Accessed April 11, 2019.

3. Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit/hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018;5(9):727-738.

4. Cortese S. Psychosis during attention-deficit/hyperactivity disorder treatment with stimulants. N Engl J Med. 2019;380(12):1178-1180.