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Psychotic Symptoms in Children on Stimulants. What are the Implications for the Clinician? :

January 7, 2016

Stimulant medications have been previously reported as the cause of adverse psychiatric symptoms in children, including mania and psychosis.1 New work by MacKenzie and colleagues in this month’s Pediatrics...

Stimulant medications have been previously reported as the cause of adverse psychiatric symptoms in children, including mania and psychosis.1 New work by MacKenzie et al. in this month’s Pediatrics (10.1542/peds.2015-2486) provides new insight into a subpopulation apparently at very high risk for this concerning side effect. Children diagnosed with ADHD and treated with stimulants, whose parent or parents have major depressive disorder, bipolar disorder or schizophrenia, have a significantly greater risk of psychotic symptoms than their peers.

Previous work has examined post-market surveillance data and pooled randomized clinical trials data for drugs used to treat ADHD,  provided by pharmaceutical manufacturers to the Federal Drug Administration: among those exposed to stimulant, the rate of adverse events related to mania or psychosis was 1.48 per 100 person years of treatment.2  The public health impact of this seemingly uncommon group of adverse events is magnified by the high population prevalence of children being treated with stimulants for diagnosis of ADHD, reported as 6.1% of all children ages 4-17 years in 2011.3  The work by MacKenzie and colleagues puts a microscope on the subpopulation of children with ADHD diagnosis, whose risk of psychotic symptoms with stimulant treatment is substantially higher, and whose main risk factor for this adverse event is not always readily identified by the primary provider. Parents with major mental illness may not be eager or willing to share their mental health diagnosis with the primary or prescribing provider, due to fear of stigmatization, lack of insight regarding its significance for their child’s care, or due simply to not being asked.

MacKenzie and colleagues took a highly rigorous approach to their investigation.  They were able to utilize a study population, as oppose to simply collecting cases. In studies like Families Overcoming Risks and Building Opportunities for Wellbeing, “…a study of developmental psychopathology in offspring of parents with severe mental illness…” both parent and child diagnoses and symptoms were well established and validated with the use of questionnaires, interview and clinician assessment. They were further able to compare children diagnosed with ADHD, who were treated, versus those who were not treated with stimulants to buttress their hypothesis that the symptomatology was due to the medication.  The authors lead us through their thinking using a clear and logical approach so that no specialized knowledge about psychiatry is needed to appreciate the study.

A little background digging revealed to me that this study is the tip of a new iceberg relative to ADHD diagnosis, stimulant treatment, and risk in adulthood of psychotic mental health disorders or episodes.  Work by Moran and colleagues shows that individuals with psychotic disorders who were exposed to stimulants in their youth appear to have a significantly earlier age of onset of psychosis than those who are unexposed, even after correcting for intelligence, marijuana use, educational attainment and family history.4 The authors postulate, as do MacKenzie and colleagues, that long term increases in dopamine release are a biologically plausible mechanism explaining this concerning finding.   An additional body of growing evidence suggests that ADHD diagnosis in childhood is associated with an increased risk for adult diagnosis of psychotic disorders including schizophrenia, even without potentiation by stimulant medications. 5,6

What can and should clinicians do in response to this study? First, become aware of the association between increased risk of psychotic events among children with ADHD diagnosis treated with stimulants and severe parental mental illness, assuming (as I do) that MacKenzie and colleagues have uncovered an important and clinically meaningful association.  Second, thinking about all of the children in our practice, we can directly impact their health care via a tactful and thorough family history that includes enquiry about mental health diagnoses as a routine question, and uses an empathic nonjudgmental approach to eliciting this critically important health information. Primary providers have the relationship and opportunity to make this needed information a part of every child’s health record.

1. MacKenzie et al Stimulant medication and psychotic symptoms in offspring of parents with mental illness. Pediatr  [blog article]

2. Mosholder  AD, Gelperin K, Hammad TA, Phelan  K, Johann-Liang  R. Hallucinations and other psychotic symptoms associated with the use of attention-deficit/hyperactivity disorder drugs in children. Pediatr. 2009;123:611-6.

3. Centers for Disease Control and Prevention. Attention Deficit/Hyperactivity Disorder ADHD Home page. <>, accessed 11-24-2015.

4. Moran  LV, Masters  GA, Pingali S, Cohen  BM, Liebson E, Rajarethinam  RP, Ongur D Prescription stimulant use is associated with earlier onset of psychosis. J  Psychiatr Res. 2015;71:41-7.

5. Rho  A, Traicu A, Lepage M, Iyer SN, Malla  A, Joober R. Clinical and functional implications of a history of childhood ADHD in first-episode psychosis. Schizophr  Res. 2015;165:128-33.

6. Dalsgaard  S, Mortensen  PB, Frydenberg M, Maibing CM, Nordentoft  M, Thomsen  PH. Association between Attention-Deficit Hyperactivity Disorder in childhood and schizophrenia later in adulthood. Eur Psychiatry. 2014; 29:259-63.

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