ADHD Drug May Improve PTSD, TBI Symptoms

Liam Davenport

November 13, 2015

Individuals with posttraumatic stress disorder (PTSD) and/or traumatic brain injury (TBI) may benefit from treatment with a drug normally prescribed for treatment of attention-deficit hyperactivity disorder (ADHD), results of a multicenter US study have revealed.

The researchers found that methylphenidate (multiple brands) not only improved PTSD symptoms but also depressive and postconcussive symptoms in individuals with PTSD, TBI, or both. The drug also improved cognition.

In contrast, galantamine (Razadyne, Janssen Pharmaceuticals, Inc), which is commonly used to treat patients with Alzheimer's disease, only improved episodic memory and had no effect on trauma-related symptoms.

"These findings are of particular interest given anecdotal reports of widespread prescribing of methylphenidate by clinicians working with veterans and military personnel with PTSD, and highlight the pressing need for additional research to determine the utility and safety of this drug (or other drugs with potentially overlapping mechanisms of action, such as atomoxetine) in this patient population," the investigators, led by Thomas W. McAllister, MD, chair of the Department of Psychiatry, Indiana University School of Medicine, in Indianapolis, write.

The research was published online October 28 in Neuropsychopharmacology.

Cognitive Complaints Common

Speaking to Medscape Medical News, Dr McAllister set out the reasoning behind the study.

"In folks with mild brain injury, whether it's a military cohort or civilian cohort, cognitive complaints are very prominent," he said. "People will report that they have trouble with reading, attention, concentration, and the like, and, in fact, you can usually measure small deficits in these domains," Dr McAllister told Medscape Medical News.

"What's less widely appreciated is that people with posttraumatic stress have similar complaints, so they'll report difficulties in attention and concentration. They may also report problems with memory. They have too much memory for traumatic events and not enough memory for common, day-to-day events, so they feel somewhat impaired by their cognitive complaints as well.

"So we thought that maybe this would be a good place to start, and the idea was that if we could help people with their cognitive complaints, and even maybe cognitive performance, then that might have some positive downstream effects in terms of mood and psychological health in general."

The investigators conducted a 12-week, randomized, double-blinded, placebo-controlled study in which 32 individuals with a history of PTSD, TBI, or both conditions were assigned to receive galantamine or methylphenidate at doses used in previously published trials or placebo.

Of the participants, 15 were civilians without a history of military service; the remainder were veterans or active duty military personnel. The distribution of PTSD, TBI, or both was roughly equal, and the distribution of military and nonmilitary participants did not differ across treatment groups.

As expected, the investigators found methylphenidate to be associated with significant improvements relative to placebo in terms of cognitive complaints (effect size = 0.337) and in the Digit Symbol measure of attention (P = .011).

Galantamine was associated with significant improvements in episodic memory relative to placebo, as measured on the long-delay recall of the Rey Auditory-Verbal Learning Test (P = .011).

Significant Improvement

Strikingly, methylphenidate was also associated with significant reductions in postconcussive symptoms relative to placebo at weeks 4, 8, and 12 (effect size at week 12, 0.886). In addition, the drug was associated with significant improvements in depressive symptoms at all three time points (effect size at week 12, 0.497).

The researchers also found that PTSD symptoms, as reflected on scores on the Posttraumatic Stress Disorder Checklist, were significantly improved with methylphenidate over placebo at all time points, at an effect size of 0.881 at 12 weeks. This equated to a mean drop of 13 points by week 12.

In contrast, galantamine was not associated with significant changes vs placebo in either postconcussive symptoms or PTSD symptoms and with only mild improvements in depressive symptoms (effect size at 12 weeks, 0.157).

Discussing the findings, Dr McAllister pointed out that the study is "very small, so all the usual caveats apply."

Nevertheless, he said that although both galantamine and methylphenidate achieved the expected improvements in cognitive performance in their respective domains of influence, the results in terms of posttraumatic stress and depressive and postconcussive symptoms with methylphenidate were surprising.

Dr McAllister noted that this is particularly interesting, given the comments that came up on several occasions when the researchers were seeking approval from the institutional review boards at each of the study sites.

"What Are You Thinking?"

He explained: "[They] said: 'We're a little worried about this, because you're talking about taking people with posttraumatic stress, who are hypervigilant and quite anxious and not sleeping well and have an exaggerated startle response....'

"'What are you thinking? You're going to give them a stimulant, and that's going to make everything worse, and they're going to sleep less, they're going to be more agitated, etc, etc.' "

Dr McAllister continued: "We said: 'Well, maybe, but there's also the fact that when you talk to clinicians in this area, and they've been using methylphenidate, they've been reporting anecdotally that people are actually getting better.' "

He said that the next stage for the research is to replicate the findings in a larger sample. "Let's assume for a moment that it is replicated, and that's a big 'if'.... Then I think really the issue that needs to be addressed is, Why is it working? What is the mechanism?"

Dr McAllister noted that methylphenidate augments both dopamine and norepinephrine, which play important roles in memory and attention, which is why the drug is given to individuals with ADHD.

He explained: "So might it be the case that if you are improving some of the tension, they're actually able to attend to other things, normal things, in their environment.

"If they say, 'This is something I want to pay attention to,' and they can't, then the default is to start thinking of the traumatic memories and the troubles that they're having, and so forth.

"I'm really speculating here, [but] if you're actually able to dial up their attentional capabilities, perhaps they're able to pay more attention to things in the moment, and therefore are less likely to default to the pathological memories and their troubles," he said.

Another mechanism that might be in play, Dr McAllister suggested, is that the drug is somehow facilitating the "forgetting" of traumatic memories, although more work would be needed to determine how that would occur.

This study was funded by the United States Department of Defense. Several coauthors have disclosed relevant financial relationships, which are listed in the original article.

Neuropsychopharmacology. Published online October 28, 2015. Abstract


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