In August the FDA called for new warnings on stimulants used for attention-deficit/hyperactivity disorder (ADHD). Amphetamines now carry black box warnings that say, “Misuse of amphetamines may cause sudden death and serious cardiovascular adverse events.” Amphetamines and methylphenidates used for ADHD include expanded information about cardiovascular risks at usual dosages for patients with heart conditions.
To examine the clinical implications of these warnings, Current Psychiatry hosted a conversation between ADHD experts Anthony Rostain, MD, MA, and Lenard Adler, MD.
Dr. Rostain: Changes to warnings on ADHD medications have many psychiatrists looking for guidance on using stimulants. Can you give us some background and discuss the labeling changes?
Dr. Adler: Stimulants have been used for more than 40 years as ADHD treatments, and they’ve been shown to be highly effective. The FDA, which monitors issues of cardiovascular safety and stimulants in an ongoing way, examined specific isolated cases and changed some of the warnings as a result.
Dr. Rostain: What should practicing psychiatrists be concerned about if they’re thinking of prescribing stimulants for an ADHD patient?
Dr. Adler: The take-home point is that stimulants—because of the way they work—have been known to have minor effects of increasing blood pressure and pulse (Box 1).1-3 Clinicians have known about issues regarding stimulant use by patients with pre-existing cardiovascular conditions, but now the warnings are more formal for the methylphenidate and amphetamine products.
Dr. Rostain: An FDA committee recommended black box warnings on all stimulants used for ADHD, but the FDA decided instead to clarify warnings in prescription information for some medications. What was the FDA process?
Dr. Adler: The discussion was internal at the FDA, so I can’t say what their thinking was. The black box warning on amphetamines notes two issues. One is the potential for abuse and diversion, and the other warns of potential for sudden death and serious cardiovascular effects if the drug is misused. A warning has also been placed on all methylphenidate products regarding cardiovascular risk for patients with pre-existing cardiovascular conditions, but it is not a black box warning.
Cardiovascular effects of ADHD medications
in healthy children and adults
in healthy children and adults
Researchers at Massachusetts General Hospital have examined the effects of ADHD medications on blood pressure and heart rate in children and adults.
Children and adolescents. The first study1 was a 1-year extension of an open-label trial of once-daily, osmotic-release methylphenidate (MPH) in 432 children (age 6 to 13) with ADHD. Their blood pressure and heart rate were recorded at baseline and monthly.
At 12 months, MPH use at 18 to 54 mg/d was associated with minor but statistically significant mean increases in:
- systolic blood pressure (3.3 mm Hg [P<0.001])
- diastolic blood pressure (1.5 mm Hg [P<0.001])
- heart rate (3.9 bpm [P<0.0001]).
Adults. In a 24-month study,2 223 healthy adults with ADHD (age≥18) received mixed amphetamine salts extended-release (MAS XR) in an open-label extension of a 4-week, double-blind, placebo-controlled trial. MAS XR was started at 20 mg/d for 1 week, then increased up to 60 mg/d based on therapeutic effect, as measured by the ADHD Rating Scale IV.
Blood pressure and pulse were measured at baseline, weekly, then monthly, and 12-lead ECGs were obtained at baseline, weekly, then at 3- and 6-month intervals. Changes after 2 years were small and not statistically significant:
- systolic blood pressure (2.3±12.5 mm Hg)
- diastolic blood pressure (1.3±9.2 mm Hg)
- pulse (2.1±13.4 bpm).
A clinically insignificant increase was observed in the mean QTcB interval (7.2 msec; P<0.001), although no patient’s QTcB interval exceeded 480 msec. Seven patients dropped out because of cardiovascular side effects (5 with hypertension, and 2 with palpitation/tachycardia), which were not reported as being serious.
Stimulants and nonstimulants. In another study,3 the same researchers analyzed the cardiovascular effects of three stimulants (methylphenidate, amphetamine compounds, and pemoline) and two nonstimulants (bupropion and desipramine) used to treat ADHD in adults. Data on a total of 125 patients (mean age 39±9 years) from three previous placebo-controlled studies were re-examined for the medications’ effects on blood pressure and heart rate.
Minor but statistically significant changes in blood pressure and heart rate were found to be associated with both stimulant and nonstimulant medications:
- systolic blood pressure (bupropion, +5.9 mm Hg [P<0.05]; amphetamine, +5.4 mm Hg [P<0.05])
- diastolic blood pressure (desipramine, +7.1 mm Hg [P<0.05])
- heart rate (bupropion, +6.9 bpm [P<0.05]; amphetamine, +7.3 bpm [P<0.05]; methylphenidate, +4.5 bpm [P<0.05]).
In the last two studies, the authors concluded that although the cardiovascular effects of ADHD medications in healthy adults were minimal, clinicians should monitor vital signs at baseline and periodically during treatment.
Dr. Rostain: How were the warnings clarified?
Dr. Adler: The FDA has changed the language. Now physicians are warned that sudden death can occur at usual doses in patients with a pre-existing structural cardiac abnormality or other serious heart problem. So, stimulants generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug.