Possible Tie to First-Line ADHD Drug and Hallucinations, Other Psychotic Symptoms

Damian McNamara

August 30, 2018

Hallucinations and other psychotic symptoms may arise in children and adolescents treated with methylphenidate (multiple brands) for attention-deficit/hyperactivity disorder (ADHD), new research suggests.

The meta-analysis, which included 10 randomized controlled trials, 17 nonrandomized studies, and 18 patient reports, showed that 1% to 2.5% of participants experienced such troublesome symptoms. However, investigators emphasize that the quality of the data in the included studies is subpar and that there is a possibility of bias.

Therefore, the results do not provide definitive proof of an association between methylphenidate and increased risk for psychotic symptoms, they write.

Nonetheless, until more definitive findings become available, "physicians, patients, and their caregivers should be aware of this possible adverse event," lead author Erica Ramstad, MD, a physician and researcher in the Department of Children and Youth Psychiatry, Psychiatric Research Unit, Region Zeland, Denmark, told Medscape Medical News.

"However, concerns about this rare possible adverse event should of course be balanced against the potential beneficial effects of methylphenidate on ADHD symptoms, general behavior, and quality of life," Ramstad added.

The study was published online July 10 in the Scandinavian Journal of Child and Adolescent Psychiatry and Psychology.

First-Line Therapy

Methylphenidate and other psychostimulants are the recommended first-line therapy for ADHD in multiple guidelines.

Previous studies have reported psychotic symptoms in children and adolescents treated with this agent for ADHD. However, Ramstad and colleagues note that to the best of their knowledge, no previous systematic review of the literature has examined psychotic symptoms in this patient population.

"Because so many children and adolescents are prescribed methylphenidate, it is important that the risk of adverse events is better understood," they write.

The investigators examined two previous Cochrane systematic reviews that assessed the safety and efficacy of methylphenidate in children and adolescents with ADHD.

One review assessed randomized clinical trials; the other, which is currently in press, included observational studies, randomized trials without a placebo or comparator group, and patient reports.

The researchers updated these systematic reviews with additional randomized clinical trials published through March 2017.

The study included 1103 participants from randomized clinical trials, another 76,237 participants from nonrandomized studies, and 12 reports or small series describing 18 additional patients.

In the randomized trials, the median age of the patients was 9.5 years. The ways in which researchers recorded psychotic symptoms varied across these studies. Six randomized trials used rating scales with a psychotic symptom item; two studies reported adverse events; and another two assessed spontaneous reports.

Although the authors contacted relevant pharmaceutical companies for unpublished data, they were unsuccessful.

Sparse Adverse Event Data

Only one psychotic episode was reported in a placebo cohort in the meta-analysis. The event occurred in a crossover trial without any washout period, which led the researchers to call the report "dubious."

This trial of 508 placebo-receiving patients with psychotic symptoms translated to a pooled prevalence of 1.7% (95% confidence interval [CI], 0.7 - 4.0). In contrast, the meta-analysis yielded 10 of 654 methylphenidate patients (pooled prevalence, 2.5%; 95% CI, 1.4 - 4.3).

In the nonrandomized studies, which included 55,603 total participants, the researchers found 873 instances of psychotic symptoms that occurred during methylphenidate treatment. These included symptoms of psychotic disorder; symptoms of psychosis/mania; hallucinations; and delusions. The pooled prevalence was 1.2% (95% CI, 0.7 - 2.4).

The grand total pooled prevalence was 1.8% (95% CI, 1.2 - 2.8) after the researchers combined those randomized controlled trials that employed placebo as a comparator and nonrandomized studies.

Dose, methylphenidate formulation, and patient age had no significant impact on the subanalysis findings. Likewise, another subanalysis found no significant difference between data from parallel group trials and data from crossover trials.

The investigators also performed a trial sequential analysis, which is a statistical method that helps researchers understand whether sparseness of data causes an apparent lack of effect. The approach confirmed that the meta-analysis was underpowered; the meta-analysis included only 649 of the 4639 participants (14%) necessary to meet the diversity-adjusted number.

"Considering methylphenidate has been prescribed for over 50 years, it is surprising that the data on adverse events, including psychotic symptoms, are too sparse to draw solid conclusions and that the quality of evidence is so low," Ramstad said.

The relevance of patients' comorbidities or sex remains unknown because the researchers had insufficient data to perform these subanalyses. The investigators were likewise unable to rule out development of a comorbid psychotic disorder over time that was unrelated to methylphenidate treatment.

In addition, bias may have led to underreporting of psychotic symptoms in some studies.

"Our results are primarily based on trials at high risk of bias [9 of 10 randomized controlled trials] and accordingly low quality evidence. In fact, the high risk of bias, including vested interest, may be a reason for under-reporting of psychotic symptoms," the researchers write.

"Thorough, Systematic" Research

Although the current study was performed in accordance with rigorous Cochrane guidelines and the literature search was "thorough and systematic," methodologic problems precluded definitive conclusions as to the occurrence of psychotic symptoms in association with the use of methylphenidate.

"We believe that our approach has led to the best possible gathering of relevant literature on the subject," the investigators write.

Future adverse rating scales for methylphenidate should include specific assessment of psychotic symptoms, the investigators note. Asking a patient, "Do you ever hear voices or sounds that no one else can hear?," is one such example.

In addition, a clinical interview, although time consuming, remains the best approach to assess whether reported psychotic symptoms are independent of a psychotic disorder.

Additional trials with large sample sizes that include standardized screening tools or clinical interviews to assess these symptoms are warranted, Ramstad said.

"Of course, high-quality, long-term, randomized placebo-controlled trials are on the top of the wish list, but long-term placebo administration is ethically questionable, and therefore also nonrandomized studies may be of great importance," she said.

She added that "fortunately," principal investigator Ole Jakob Storebø, PhD, and the Psychiatric Research Unit in Region Zealand have recently established a Center for Evidence-based Psychiatry — the first of its kind in the Nordic countries.

"The center will continue to focus on research in ADHD but also on research in the effect of the available treatment of other psychiatric diseases, such as personality disorders and schizophrenia. The center will also focus on improving methods to perform meta-analyses and systematic reviews," Ramstad said.

Effective Treatment

Commenting on the findings for Medscape Medical News, Michele Nelson, MD, child psychiatrist and assistant clinical professor, University of California, Riverside, said that stimulants have been "used for years" and are very effective for treating ADHD.

The current investigators raised "a good point about what physicians need to look for and monitor," she said. They also revealed rates of hallucinations and other psychotic symptoms that were "higher than what was previously thought.

"Methylphenidate is the first-line treatment, the first stimulant we tend to use with a child or adolescent," Nelson said. She added that methylphenidate increases the amount of dopamine and norepinephrine by essentially blocking the dopamine and norepinephrine reuptake transporter.

"That is important to distinguish from, say, Adderall," she said. Adderall is a combination medication that contains amphetamine and dextroamphetamine; it has a dual mechanism action that prevents the reuptake of dopamine and norepinephrine and promotes additional release of these two factors.

"So, just based on the mechanism, it is theoretically much more likely with Adderall, the amphetamine, to potentially cause psychosis," she said.

Nelson emphasized the importance of asking children about any psychosis at the time of ADHD diagnosis, prior to medication prescription, and on an ongoing basis. Many times they will not talk about psychotic symptoms "unless you specifically ask," she said.

"Use With Caution"

Also commenting on the study, Michael D. McGee, MD, chief medical officer for the Haven at Pismo, an addiction treatment center in San Luis Obispo, California, told Medscape Medical News that methylphenidate "and other amphetamines, for that matter" carry a risk of causing hallucinations and other psychotic symptoms.

"Fortunately, the risk is fairly low in people who do not carry an underlying vulnerability to psychosis, such as schizophrenia or bipolar disorder. Methylphenidate and other amphetamines need to be used with caution in these populations," McGee said.

"If a person truly has ADHD, as corroborated by competent collaterals, and thus has significant impairments in functioning, methylphenidate and other amphetamines can be transformative, enabling people to function at levels never before possible," he added. "While there are risks with all medications, the benefits generally far outweigh the risks."

"The vast majority of children treated with stimulant medications experience no such reactions and thus may be safely treated with these medications," agreed Russell A. Barkley, PhD, Virginia Treatment Center for Children and clinical professor of psychiatry at Virginia Commonwealth University School of Medicine in Richmond, when asked to comment.

"Clinical researchers studying stimulants in children with ADHD have known since the 1970s that both this drug and amphetamines may result in an average of 3% of children developing hallucinations, often tactile, and thus could not tolerate the medication," he added.

This meta-analysis confirms such earlier observations that a very small percentage of children may experience psychoticlike symptoms as an adverse event while taking stimulant medication, Barkley said.

"The reaction is temporary, lasting only during the time course of the last dose, and no cases are known to have been permanently so affected," he said. "When such adverse reactions occur, treatment with antipsychotic drugs such as haloperidol may be useful to hasten the recovery from the adverse event."

The study was funded by the Region Zealand Research Foundation, the Psychiatric Research Unit of Region Zealand, and the Copenhagen Trial Unit at the Center for Clinical Intervention Research. Erica Ramstad, Dr Nelson, Dr McGee, and Dr Barkley have disclosed no relevant financial relationships.

Scand J Child Adolesc Psychiatr Psychol. Published online July 10, 2018. Full text

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