New Study Finds Higher Risk of Psychosis with Amphetamine Treatment for ADHD

Attention deficit hyperactivity disorder (ADHD) is a common disorder that typically develops in childhood and is characterized by hyperactivity, inattention and impulsive behavior.[1] The proportion of children and adolescents diagnosed with ADHD has increased significantly over the years. It was estimated that 10% of children and adolescents aged four to 17 years in the U.S. were diagnosed with ADHD in 2015 to 2016.[2] ADHD is less common in adults but can persist into adulthood in about 30% of children with the disorder.[3]

The cause of ADHD is unknown, and there is no specific diagnostic test for the disorder. The criteria for diagnosing ADHD are based on the age of symptom onset, severity and duration of inattention, and hyperactivity and impulsivity that interfere with proper function or development.[4],[5] Diagnosing ADHD correctly requires special psychological, educational and social evaluations. Other mental disorders also must be ruled out as a cause of the symptoms. Importantly, many children diagnosed with ADHD have problems that are primarily caused or worsened by inadequate teachers, unsuitable educational settings or problems with their parents.

There are several approaches for treating ADHD. Behavioral therapy, which aims to reinforce positive behavior and eliminate negative and disruptive behavior, is recommended as an important first step in ADHD management, particularly in children younger than six years.[6],[7] Medications also can be used for children six years and older if behavioral therapy alone is insufficient.[8] The stimulant methylphenidate (ADHANSIA XR, APTENSIO XR, CONCERTA, COTEMPLA XR-ODT, DAYTRANA, JORNAY PM, METADATE, METHYLIN, QUILLICHEW ER, QUILLIVANT XR, RITALIN) is the first-choice ADHD drug. Various amphetamine drugs — including amphetamine (ADZENYS, DYANAVEL XR, EVEKEO), dextroamphetamine (DEXEDRINE) and combination amphetamine-dextroamphetamine (ADDERALL XR, MYDAYIS) — are second-choice ADHD drugs.[9],[10] Approximately 70-80% of children who take these medications respond to them.[11]

Despite their effectiveness, serious adverse effects, including hallucinations and other psychotic symptoms, can occur with stimulant treatment of ADHD.[12] A study published in the New England Journal of Medicine (NEJM) on March 21, 2019, examined the risk of psychosis with methylphenidate and amphetamine use in adolescents and young adults with ADHD.[13] It found that approximately 1 out of 660 such patients treated with methylphenidate or amphetamine developed new-onset psychotic symptoms. Moreover, patients taking an amphetamine were twice as likely to develop psychosis as those taking methylphenidate.

The NEJM study design

Using data from two large U.S. national health insurance claims databases, researchers identified all patients aged 13 to 25 years with a confirmed diagnosis of ADHD who started taking amphetamine or methylphenidate from January 2004 to September 2015. They included only patients who had no prescription of an ADHD stimulant in the 12 months prior to study entry. The study excluded patients with previous psychosis, hallucinations, bipolar disorder and other psychiatric disorders, as well as diseases affecting the brain and spinal cord. The researchers also excluded patients on mood-stabilizing drugs, antipsychotic medications or stimulants typically used to treat conditions other than ADHD during the 12 months prior to entry into the study, as well as patients using oral corticosteroids, which are associated with psychosis, during the 60 days prior to study entry.

Starting seven days after the initial prescription for the amphetamine or methylphenidate was filled, the researchers followed the patients included in the study to see whether they were diagnosed with psychosis and prescribed an antipsychotic medication within 60 days after the psychosis diagnosis was made.

Study findings

The researchers identified nearly 338,000 adolescents and young adults with ADHD who met the study inclusion criteria. From these patients, they selected a group of approximately 110,000 patients prescribed an amphetamine and matched it to a second group of 110,000 patients prescribed methylphenidate that had similar demographic and medical characteristics.

Importantly, the researchers found that amphetamine prescriptions for ADHD increased by nearly fourfold from 2005 to 2014. Methylphenidate prescriptions, on the other hand, increased by only 1.6-fold over the same time period.

Approximately three-quarters of the patients treated by family medicine or internal medicine physicians and two-thirds of those treated by psychiatrists were prescribed amphetamines, whereas only one-half of patients treated by pediatricians were given amphetamines.

In total, there were 343 reported episodes of psychosis among the 222,000 subjects prescribed stimulants: 237 in the amphetamine group and 106 in the methylphenidate group. Although new psychotic episodes were infrequent overall, with approximately one case occurring out of every 660 subjects, patients who were prescribed an amphetamine were twice as likely to experience a psychotic episode as patients taking methylphenidate. The median time from the initial dispensing of a stimulant prescription to a psychotic episode was approximately four months.

On further analysis, the investigators found that the risk of a psychotic episode was greater in subjects aged 13 to 17 years than in those aged 18 to 25 years.

Several potential limitations may have influenced the results of this study. First, the researchers were unable to account for underreported substance use disorders in patients. Second, there also was a lack of information regarding whether the patients took their stimulants as prescribed — this is particularly important because patients commonly give their prescribed stimulants to others. Third, there was no information on the race, ethnicity or socioeconomic status of the subjects. Finally, the study did not include patients without health insurance and, as such, these findings cannot be generalized to these individuals.

In conclusion, the use of amphetamines for treatment of ADHD in adolescents and young adults appears to be associated with a greater risk of psychosis than the use of methylphenidate. Although the risk of psychosis overall was small, the findings of the NEJM study are worrisome given the rapidly expanding use of amphetamine in recent years.

What You Can Do

If you or your child has been diagnosed with ADHD, make sure the diagnosis was accurate before starting any treatment. Then, work with your doctor to develop a treatment plan, preferably starting with behavioral therapy. If this is not successful and you or your child is prescribed a stimulant to treat ADHD symptoms, you should monitor for any changes in mood or unusual behavior and contact your doctor immediately if such changes occur.
 

References

[1] Krull KR. Attention deficit hyperactivity disorder in children and adolescents: overview of treatment and prognosis. Up to Date. May 22, 2019.

[2] Xu G, Strathearn L, Liu B, et al. Twenty-year trends in diagnosed attention-deficit/hyperactivity disorder among US children and adolescents, 1997-2016. JAMA Netw Open. 2018;1(4):e181471.

[3] Barbaresi WJ, Colligan RC, Weaver AL, et al. Mortality, ADHD, and psychosocial adversity in adults with childhood ADHD: A prospective study. Pediatrics. 2013;131(4):637-44.

[4] Steinau S. Diagnostic criteria in attention deficit hyperactivity disorder –changes in DSM 5. Front Psychiatry. 2013;4(49):1-2.

[5] Centers for Disease Control and Prevention. Symptoms and diagnosis of ADHD. August 26, 2019. https://www.cdc.gov/ncbddd/adhd/diagnosis.html. Accessed October 2, 2019.

[6] Centers for Disease Control and Prevention. Treatment of ADHD. August 26, 2019. https://www.cdc.gov/ncbddd/adhd/treatment.html. Accessed October 3, 2019.

[7] Krull KR. Attention deficit hyperactivity disorder in children and adolescents: overview of treatment and prognosis. Up to Date. May 22, 2019.

[8] Ibid.

[9] National Institute for Health and Care Excellence (NICE). Medication for ADHD. March 2018. https://pathways.nice.org.uk/pathways/attention-deficit-hyperactivity-disorder#path=view%3A/pathways/attention-deficit-hyperactivity-disorder/medication-for-adhd.xml&content=view-node%3Anodes-medication-choice-children-5-years-and-over-and-young-people. Accessed October 3, 2019.

[10] Subcommittee on Attention-Deficit/Hyperactivity Disorder; Steering Committee on Quality Improvement and Management, Wolraich M. 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.

[11] Centers for Disease Control and Prevention. Treatment of ADHD. August 26, 2019. https://www.cdc.gov/ncbddd/adhd/treatment.html. Accessed October 3, 2019.

[12] Mosholder AD, Gelperin K, Hammad TA, et al. Hallucinations and other psychotic symptoms associated with the use of attention-deficit/hyperactivity disorder drugs in children. Pediatrics. 2009;123(2):611-616.

[13] Moran LV, Ongur D, Hsu J, et al. Psychosis with methylphenidate or amphetamine in patients with ADHD. N Engl J Med. 2019;380(12):1128-1138.