The Comparison of Methylphenidate and Psychotherapy in adult ADHD Study (COMPAS) was a prospective, randomized multicenter clinical trial, comparing methylphenidate (MPH) with placebo in combination with cognitive-behavioral group psychotherapy or (GPT) individual clinical management (CM), the latter two being active controls. This was a year-long trial.
The German study team randomly assigned 433 participants with adult ADHD to each of the four study groups. As this was a 2 x 2 matrix trial, each study group included both one pharmacological intervention (MPH or placebo) and one psychological intervention (GPT or CM).
GPT included mindfulness training, skills for stress management, emotion regulation, and time management as well as behavioral analyses. CM sessions focused on participants' current concerns and medication.
As is usual in such trials, the number of participants decreased throughout the study as some individuals dropped out. At 13 weeks, 337 participants were still taking their study medication.
Both MPH and placebo were started at 10 mg doses, then up-titrated depending on clinical response. After 13 weeks, the mean MPH dose had risen to 50 mg, and the mean dose of placebo to 58 mg.
Safety
Among those taking MPH, 96 percent of participants reported at least one adverse event. Among those on placebo, the equivalent figure was 88 percent.
The principal adverse events occurring significantly more frequently in the MPH group were decreased appetite (22 vs. 3.8 %), dry mouth (15 vs. 4.8 %), palpitations (13 vs. 3.3 %), gastrointestinal infection (11 vs. 4.8 %), agitation (11 vs. 3.3 %), restlessness (10 vs. 2.9 %), excessive sweating, rapid heartbeat, and weight decrease (all 6.3 vs. 1.9 %).
The only adverse event that occurred significantly more frequently in the placebo group was a temporary loss of consciousness caused by a fall in blood pressure (2.4 vs. 0%).
Serious adverse events were infrequent in both groups, affecting 7.3 percent of those in the MPH group and 4.3 percent of those in the placebo group. The difference between groups was not statistically significant. There were no deaths.
While patients on MPH lost an average of 1.2 Kg during the year, those on placebo remained constant (gained 0.3 Kg). Changes in blood pressure were negligible in both groups. Average heart rate rose by 3 beats per minute in the MPH group, versus a 1 beat per minute decline in the placebo group. There were no significant differences in clinically relevant electrocardiogram abnormalities between the two treatment groups.
Turning to psychological interventions, 90 percent of participants in the GPT group and 94 percent in the CM group experienced at least one adverse event. Differences between the two groups were not statistically significant. Serious adverse events occurred in 3.9% of the GPT participants and 7.7 percent of the CN participants, but again the difference between groups was not statistically significant. There were no clinically relevant changes in weight, blood pressure, or heart rates in these groups throughout the study.
The study team found no modulating effects of either form of psychological treatment on the distribution of adverse events under MPH and placebo treatment.
The authors concluded, "adverse events were found more frequently in patients receiving MPH compared to placebo and were mostly attributable to the centrally stimulating and sympathomimetic action of MPH, including agitation, restlessness, dry mouth, decreased appetite, palpitations, tachycardia [rapid heartbeat], and hyperhidrosis [excessive sweating]. About these adverse events, a causal relationship with MPH seems likely, supported by both the pharmacological effects of MPH as well as previous safety data. ... It is important to note that patients receiving MPH in COMPAS significantly profited from the medication about the reduction of ADHD symptom load, thus the risks of adverse events have to be weighed against the clear benefits. ... Premature termination of MPH due to an adverse event as major reason occurred in less than 10 % of patients and was not statistically significantly different from placebo."
Bernhard Kis, Caroline Lücke, Mona Abdel-Hamid, Philipp Heßmann, Erika Graf, Mathias Berger, Swantje Matthies, Patricia Borel, Esther Sobanski, Barbara Alm, Michael Rösler, Wolfgang Retz, Christian Jacob, Michael Colla, Michael Huss, Thomas Jans, Ludger Tebartz van Elst, Helge H. O. Müller, Alexandra Philipsen, "Safety Profile of Methylphenidate Under Long-Term Treatment in Adult ADHD Patients - Results of the COMPAS Study," Pharmacopsychiatry (2020), https://doi.org/10.1055/a-1207-9851.
_logo%201.svg)
