ADHD medication treatment and risk of psychosis
Authors: Lily Hechtman
Journal: The Lancet Psychiatry (2019)

Chris Hollis and colleagues' Article1Hollis C Chen Q Chang Z et al.Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study.Lancet Psychiatry. 2019; published online June 17. http://dx.doi.org/10.1016/S2215-0366(19)30189-0Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar in The Lancet Psychiatry has many strengths. It addresses an important clinical question: does methylphenidate treatment for ADHD increase the risk of psychosis in patients with and without previous psychotic symptoms. Hollis and colleagues used Swedish national registers to review a large number (n=23 898) of health records, to examine the incidence of psychotic symptoms 12 weeks before, 12 weeks after, and 1 year after starting medication treatment, with a longitudinal within-subject study design. Their results indicated that methylphenidate treatment for ADHD does not increase psychotic symptoms in the short-term or long-term in patients with and without previous psychosis. There is some suggestion in their study that methylphenidate might, in fact, decrease the risk of a psychotic episode, particularly in patients with a history of psychosis. The findings of their study should therefore be reassuring to clinicians. However, as the authors themselves point out, the study has several limitations that could affect the reassuring message. It is unclear whether patients with a history of psychotic symptoms received antipsychotics at the time of their treatment with methylphenidate for their ADHD. Antipsychotic treatment would likely help to protect them from developing psychotic symptoms secondary to their treatment with methylphenidate. There have been a few small studies2Biederman J Hammerness P Doyle R Risperidone treatment for ADHD in children and adolescents with bipolar disorder.Neuropsychiatr Dis Treat. 2008; 4: 203-207Crossref PubMed Google Scholar and case reports3Hechtman L Russell RC Young LJ Psychosis in a boy with ADHD treated with stimulants and acute lymphocytic leukemia treated with chemotherapy and steroids.Neuropsychiatry. 2013; 3: 17-21Crossref Scopus (4) Google Scholar that have demonstrated the protective value of antipsychotics in preventing psychotic symptoms in patients who developed such symptoms secondary to underlying psychotic conditions or exposure to medication that can provoke psychotic reactions (such as steroids). Whether patients with previous psychotic symptoms were simultaneously taking antipsychotic medication could be important, and the database that Hollis and colleagues were using likely has this information. Long-term prospective follow-up studies4Swanson JM Arnold LE Molina BSG et al.Young adult outcomes in the follow-up of the multimodal treatment study of attention-deficit/hyperactivity disorder: symptom persistence, source discrepancy, and height suppression.J Child Psychol Psychiatry. 2017; 58: 663-678Crossref PubMed Scopus (146) Google Scholar, 5Hechtman L Swanson JM Sibley M et al.Functional adult outcomes 16 years after childhood diagnosis of Attention-Deficit/Hyperactivity Disorder: MTA results.J Am Acad Child Adolesc Psychiatry. 2016; 55: 945-952Summary Full Text Full Text PDF PubMed Scopus (156) Google Scholar have reported that adherence to ADHD treatment with medication substantially decreases in late adolescence and early adulthood, finding that less than 10% of individuals treated in childhood still take stimulant medication during this period. In this age group, adherence is often intermittent, with patients only taking medication before examinations or big projects with approaching deadlines. It is not clear whether the dataset used in the study by Hollis and colleagues can provide information on medication adherence via prescription renewal rates. We know that the high dosages of stimulants observed in substance abuse situations present greater risks for psychosis than smaller therapeutic dosages. However, we have no knowledge of the dosages that were prescribed or used by the patients in their study. Similarly, if prescribed dosages were low, the findings might be a function of these low dosages. The importance of dose was seen in our report6Chammas M Ahronheim GA Hechtman L Reintroduction of stimulant treatment for patients with ADHD, after stimulant-related psychosis.Clinical Practice. 2014; 11: 289-294Crossref Scopus (5) Google Scholar on reintroduction of stimulant treatment in patients with ADHD after stimulant-related psychosis. Patients who were being treated with stimulant medication (such as long-acting methylphenidate and amphetamines) who developed psychotic symptoms were discontinued from these medications. The psychotic symptoms disappeared when the individuals ceased their medication and, after a variable period (1–16 months), patients were restarted on stimulant medication at very low initial dosages and, slowly and carefully, they were monitored during a very gradual increase in dosage. All participants benefited and had few adverse events during this careful, low-dose reintroduction of stimulant medication, and they showed no reoccurrence of the psychotic symptoms. Thus, dosages and adherence are important in the evaluation of stimulant medication on psychotic symptoms. The study by Hollis and colleagues focused on methylphenidate treatment for ADHD, since that is the medication that is used most often in Sweden. However, in other parts of the world, such as Canada and the USA, amphetamines are widely used. A 2019 study7Moran 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: 1128-1138Crossref PubMed Scopus (50) Google Scholar on psychosis with methylphenidate or amphetamines in participants with ADHD clearly showed an increased risk of psychosis with use of amphetamines (0·21%) relative to that with methylphenidate (0·10%) treatment. The study sample was very large, comprising 110 923 patients taking amphetamines and 110 923 patients taking methylphenidate. The age range was 13–25 years, which is similar to that in the study by Hollis and colleagues. However, most of the patients in the older range (18–25 years) were taking amphetamine medication, which might be a factor in the increased incidence of psychosis seen with amphetamines. A previous study8Shyu YC Yuan SS Lee SY Yang CJ Yang KC Lee TL Attention-deficit/ hyperactivity disorder, methylphenidate use and the risk of developing schizophrenia spectrum disorders: a nationwide population-based study in Taiwan.Schizophr Res. 2015; 16: 161-167Crossref Scopus (34) Google Scholar has suggested that ADHD alone is a risk factor for psychotic disorder compared with control individuals. In this study, patients with ADHD who were using methylphenidate had a significantly increased risk of developing psychotic disorder but not schizophrenia. This study had a large sample of 73 049 patients who were newly diagnosed with ADHD and 73 049 controls from Taiwan's National Health Insurance database. In summary, Hollis and colleagues provide some reassurance that the risk of psychotic symptoms is not increased with methylphenidate treatment in young people who are given methylphenidate to treat ADHD, both with and without previous psychotic symptoms. However, limitations of the study make one less certain of the conclusions in this study—eg, were patients medicated for their psychotic symptoms, what dosages of methylphenidate were used, and what was the adherence to the methylphenidate treatment? Patients with a history of psychotic symptoms and current ADHD require careful, slow titration of stimulant medication, preferably with methylphenidate rather than amphetamines and, if necessary, simultaneous treatment with antipsychotic medication. For participants without a history of psychotic symptoms, careful titration with stimulants is still advisable. Informing patients of this possible side-effect and the dangers of suddenly markedly increasing the dose of the stimulant medication could also be useful. I report research support from and have served on advisory boards and been a speaker for Ortho-McNeil-Janssen, Purdue Pharma, Shire, and Ironshore Pharmaceuticals, and I report book royalties from Guilford, APA, Johns Hopkins University Press, and Oxford University Press. Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort studyContrary to clinical concerns, we found no evidence that initiation of methylphenidate treatment increases the risk of psychotic events in adolescents and young adults, including in those individuals with a history of psychosis. Our study should reassure clinicians considering initiating methylphenidate treatment for ADHD in adolescents and young adults, and it challenges the widely held view in clinical practice that methylphenidate should be avoided, or its use restricted, in individuals with a history of psychosis. Full-Text PDF Open Access