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Greater risk applies only to adolescents, young adults with ADHD treated in primary care
Adolescents and young adults with ADHD who start on amphetamine might have twice the risk of developing new-onset psychosis as do those who start on methylphenidate, a cohort study of more than 220,000 patients suggests.
“The percentage of patients who had a psychotic episode was 0.10% among patients who received methylphenidate and 0.21% among patients who received amphetamine, reported Lauren V. Moran, MD, of the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital in Boston and her colleagues. The study was published by the New England Journal of Medicine.
(aged 13-25 years) with ADHD between January 2004 and September 2015 who were prescribed methylphenidate or amphetamine (both 110,923 patients; 143,286 total person-years of follow-up). They looked for an ICD-9 or ICD-10 code for new-onset psychosis followed by a prescription for an antipsychotic medication the same day or within 60 days of the psychosis diagnosis. Hazard ratios were calculated by matching patients taking methylphenidate with patients taking amphetamine across both databases and calculating the incidence rate of psychosis in each group.
The researchers found 343 new cases of psychosis overall, with an incidence of 2.4 cases per 1,000 person-years. There were 106 episodes of psychosis among patients receiving methylphenidate (0.10%) and 237 new cases among patients receiving amphetamine (0.21%). There was an incidence rate of 1.78 cases per 1,000 person-years for methylphenidate patients and 2.83 cases per 1,000 person-years for amphetamine patients. Across both databases, the pooled hazard ratio for amphetamine use and new-onset psychosis, compared with matched patients, was 1.65 (95% confidence interval, 1.31-2.09).
“The attribution of the higher risk of psychosis to amphetamine use was supported by negative control outcome analyses, which showed that there was no difference in the risk of other psychiatric events between the two stimulant groups,” Dr. Moran and her colleagues reported. “The different biologic mechanisms of methylphenidate and amphetamine activity on neurotransmitters could explain our findings.”
Patients who were prescribed amphetamine by family medicine physicians, internists, and pediatricians were at a higher risk of developing psychosis. That risk, however, did not extend to patients prescribed amphetamine by psychiatrists, the researchers said.
“Psychosis may develop in these patients regardless of stimulant treatment. Alternatively, psychiatrists may prescribe amphetamine more cautiously than other providers and may screen for risk factors for psychosis,” Dr. Moran and her colleagues wrote.
The researchers said the study was limited by unmeasured confounders, such as substance or stimulant misuse; the rate of diversion for amphetamine; and lack of information on race, gender, or socioeconomic status. In addition, they noted, the results could not be generalized to patients with public insurance or no insurance, “which disproportionately applies to patients who are black or Hispanic.”
Dr. Moran reported receiving grants from National Institute of Mental Health (NIMH). The other authors reported grants, personal fees, and other relationships with several entities, including Boehringer Ingelheim, the Food and Drug Administration, the NIMH, and Takeda.
SOURCE: Moran LV et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1813751.
The findings by Moran et al. are consistent with other randomized controlled trials that suggest a better safety profile for methylphenidate over amphetamine. But the data cannot determine causality in this patient population, Samuele Cortese, MD, PhD, wrote in a related editorial.
“The findings of the current study should not be considered definitive. Observational studies such as this one can provide information on uncommon adverse events in real-world clinical practice that are challenging to assess in randomized trials performed over brief periods,” he said. “However, even sophisticated approaches, such as the ones used in this study to address possible biases, do not have the advantages of randomized trials in excluding confounding factors.”
It is still unclear why some patients developed psychosis, such as in cases of patients with stimulant use and had a “low” or “high” vulnerability to developing psychosis after exposure. The lack of association between psychosis and prescribing amphetamines among psychiatrists also might indicate that those clinicians identified risk factors in patients that predicted the development of psychosis and thus avoided prescribing amphetamines to these patients, he said.
“Currently, it is not possible to predict which patients will have psychotic episodes after stimulant treatment,” Dr. Cortese concluded. “Perhaps techniques such as machine learning applied to large data sets from randomized trials, combined with observational data, will provide predictors at the individual patient level.”
Dr. Cortese is affiliated with the Center for Innovation in Mental Health at the University of Southampton (England). These comments summarize his accompanying editorial (N Engl J Med. 2019. doi: 10.1056/NEJMe1900887 ). He reported nonfinancial relationships with the Association for Child and Adolescent Central Health and the Healthcare Convention & Exhibitors Association.
Greater risk applies only to adolescents, young adults with ADHD treated in primary care
Greater risk applies only to adolescents, young adults with ADHD treated in primary care
The findings by Moran et al. are consistent with other randomized controlled trials that suggest a better safety profile for methylphenidate over amphetamine. But the data cannot determine causality in this patient population, Samuele Cortese, MD, PhD, wrote in a related editorial.
“The findings of the current study should not be considered definitive. Observational studies such as this one can provide information on uncommon adverse events in real-world clinical practice that are challenging to assess in randomized trials performed over brief periods,” he said. “However, even sophisticated approaches, such as the ones used in this study to address possible biases, do not have the advantages of randomized trials in excluding confounding factors.”
It is still unclear why some patients developed psychosis, such as in cases of patients with stimulant use and had a “low” or “high” vulnerability to developing psychosis after exposure. The lack of association between psychosis and prescribing amphetamines among psychiatrists also might indicate that those clinicians identified risk factors in patients that predicted the development of psychosis and thus avoided prescribing amphetamines to these patients, he said.
“Currently, it is not possible to predict which patients will have psychotic episodes after stimulant treatment,” Dr. Cortese concluded. “Perhaps techniques such as machine learning applied to large data sets from randomized trials, combined with observational data, will provide predictors at the individual patient level.”
Dr. Cortese is affiliated with the Center for Innovation in Mental Health at the University of Southampton (England). These comments summarize his accompanying editorial (N Engl J Med. 2019. doi: 10.1056/NEJMe1900887 ). He reported nonfinancial relationships with the Association for Child and Adolescent Central Health and the Healthcare Convention & Exhibitors Association.
The findings by Moran et al. are consistent with other randomized controlled trials that suggest a better safety profile for methylphenidate over amphetamine. But the data cannot determine causality in this patient population, Samuele Cortese, MD, PhD, wrote in a related editorial.
“The findings of the current study should not be considered definitive. Observational studies such as this one can provide information on uncommon adverse events in real-world clinical practice that are challenging to assess in randomized trials performed over brief periods,” he said. “However, even sophisticated approaches, such as the ones used in this study to address possible biases, do not have the advantages of randomized trials in excluding confounding factors.”
It is still unclear why some patients developed psychosis, such as in cases of patients with stimulant use and had a “low” or “high” vulnerability to developing psychosis after exposure. The lack of association between psychosis and prescribing amphetamines among psychiatrists also might indicate that those clinicians identified risk factors in patients that predicted the development of psychosis and thus avoided prescribing amphetamines to these patients, he said.
“Currently, it is not possible to predict which patients will have psychotic episodes after stimulant treatment,” Dr. Cortese concluded. “Perhaps techniques such as machine learning applied to large data sets from randomized trials, combined with observational data, will provide predictors at the individual patient level.”
Dr. Cortese is affiliated with the Center for Innovation in Mental Health at the University of Southampton (England). These comments summarize his accompanying editorial (N Engl J Med. 2019. doi: 10.1056/NEJMe1900887 ). He reported nonfinancial relationships with the Association for Child and Adolescent Central Health and the Healthcare Convention & Exhibitors Association.
Adolescents and young adults with ADHD who start on amphetamine might have twice the risk of developing new-onset psychosis as do those who start on methylphenidate, a cohort study of more than 220,000 patients suggests.
“The percentage of patients who had a psychotic episode was 0.10% among patients who received methylphenidate and 0.21% among patients who received amphetamine, reported Lauren V. Moran, MD, of the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital in Boston and her colleagues. The study was published by the New England Journal of Medicine.
(aged 13-25 years) with ADHD between January 2004 and September 2015 who were prescribed methylphenidate or amphetamine (both 110,923 patients; 143,286 total person-years of follow-up). They looked for an ICD-9 or ICD-10 code for new-onset psychosis followed by a prescription for an antipsychotic medication the same day or within 60 days of the psychosis diagnosis. Hazard ratios were calculated by matching patients taking methylphenidate with patients taking amphetamine across both databases and calculating the incidence rate of psychosis in each group.
The researchers found 343 new cases of psychosis overall, with an incidence of 2.4 cases per 1,000 person-years. There were 106 episodes of psychosis among patients receiving methylphenidate (0.10%) and 237 new cases among patients receiving amphetamine (0.21%). There was an incidence rate of 1.78 cases per 1,000 person-years for methylphenidate patients and 2.83 cases per 1,000 person-years for amphetamine patients. Across both databases, the pooled hazard ratio for amphetamine use and new-onset psychosis, compared with matched patients, was 1.65 (95% confidence interval, 1.31-2.09).
“The attribution of the higher risk of psychosis to amphetamine use was supported by negative control outcome analyses, which showed that there was no difference in the risk of other psychiatric events between the two stimulant groups,” Dr. Moran and her colleagues reported. “The different biologic mechanisms of methylphenidate and amphetamine activity on neurotransmitters could explain our findings.”
Patients who were prescribed amphetamine by family medicine physicians, internists, and pediatricians were at a higher risk of developing psychosis. That risk, however, did not extend to patients prescribed amphetamine by psychiatrists, the researchers said.
“Psychosis may develop in these patients regardless of stimulant treatment. Alternatively, psychiatrists may prescribe amphetamine more cautiously than other providers and may screen for risk factors for psychosis,” Dr. Moran and her colleagues wrote.
The researchers said the study was limited by unmeasured confounders, such as substance or stimulant misuse; the rate of diversion for amphetamine; and lack of information on race, gender, or socioeconomic status. In addition, they noted, the results could not be generalized to patients with public insurance or no insurance, “which disproportionately applies to patients who are black or Hispanic.”
Dr. Moran reported receiving grants from National Institute of Mental Health (NIMH). The other authors reported grants, personal fees, and other relationships with several entities, including Boehringer Ingelheim, the Food and Drug Administration, the NIMH, and Takeda.
SOURCE: Moran LV et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1813751.
Adolescents and young adults with ADHD who start on amphetamine might have twice the risk of developing new-onset psychosis as do those who start on methylphenidate, a cohort study of more than 220,000 patients suggests.
“The percentage of patients who had a psychotic episode was 0.10% among patients who received methylphenidate and 0.21% among patients who received amphetamine, reported Lauren V. Moran, MD, of the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital in Boston and her colleagues. The study was published by the New England Journal of Medicine.
(aged 13-25 years) with ADHD between January 2004 and September 2015 who were prescribed methylphenidate or amphetamine (both 110,923 patients; 143,286 total person-years of follow-up). They looked for an ICD-9 or ICD-10 code for new-onset psychosis followed by a prescription for an antipsychotic medication the same day or within 60 days of the psychosis diagnosis. Hazard ratios were calculated by matching patients taking methylphenidate with patients taking amphetamine across both databases and calculating the incidence rate of psychosis in each group.
The researchers found 343 new cases of psychosis overall, with an incidence of 2.4 cases per 1,000 person-years. There were 106 episodes of psychosis among patients receiving methylphenidate (0.10%) and 237 new cases among patients receiving amphetamine (0.21%). There was an incidence rate of 1.78 cases per 1,000 person-years for methylphenidate patients and 2.83 cases per 1,000 person-years for amphetamine patients. Across both databases, the pooled hazard ratio for amphetamine use and new-onset psychosis, compared with matched patients, was 1.65 (95% confidence interval, 1.31-2.09).
“The attribution of the higher risk of psychosis to amphetamine use was supported by negative control outcome analyses, which showed that there was no difference in the risk of other psychiatric events between the two stimulant groups,” Dr. Moran and her colleagues reported. “The different biologic mechanisms of methylphenidate and amphetamine activity on neurotransmitters could explain our findings.”
Patients who were prescribed amphetamine by family medicine physicians, internists, and pediatricians were at a higher risk of developing psychosis. That risk, however, did not extend to patients prescribed amphetamine by psychiatrists, the researchers said.
“Psychosis may develop in these patients regardless of stimulant treatment. Alternatively, psychiatrists may prescribe amphetamine more cautiously than other providers and may screen for risk factors for psychosis,” Dr. Moran and her colleagues wrote.
The researchers said the study was limited by unmeasured confounders, such as substance or stimulant misuse; the rate of diversion for amphetamine; and lack of information on race, gender, or socioeconomic status. In addition, they noted, the results could not be generalized to patients with public insurance or no insurance, “which disproportionately applies to patients who are black or Hispanic.”
Dr. Moran reported receiving grants from National Institute of Mental Health (NIMH). The other authors reported grants, personal fees, and other relationships with several entities, including Boehringer Ingelheim, the Food and Drug Administration, the NIMH, and Takeda.
SOURCE: Moran LV et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1813751.