A drug long used to treat post-traumatic stress disorder (PTSD) appears to have done patients no good and may even have done some harm. In the first-ever randomized, placebo-controlled trial of guanfacine (Tenex) for the alleviation of PTSD, "we found that it really offered patients no benefits of any symptoms, and we looked at a lot of symptoms," said lead researcher Dr. Thomas Neylan, medical director of the PTSD treatment program at the San Francisco VA Medical Center.

"We looked at whether people were feeling less anxious, whether they were sleeping better, whether they startled less, whether they were having fewer intrusive memories," said Neylan, who is also an associate professor of psychiatry at the University of California, San Francisco. "But in anything that we looked at, we found there was no benefit for the drug over placebo."

The study results may come as a surprise to psychiatrists and patients, since guanfacine and a related drug, clonidine (Catapres), have been used for years to treat PTSD.

"They are commonly used, but what we hope now is that people shy away from using clonidine and guanfacine," Neylan said.

One expert said he was taken aback by the findings.

"I was so shocked that I had to think about it for two days. I was trying to find a hole in the science and I can't this is a state-of-the-art clinical trial," said Dr. Randall Marshall, director of Trauma Studies and Services at New York State Psychiatric Institute. "There's no hint of a benefit."

Guanfacine's rise and apparent fall as a PTSD treatment may be an object lesson in why randomized, controlled trials-such as the one Neylan's group conducted-are so important to assessing a drug's worth, he said.


But no one had ever put this idea to the test in a randomized, controlled trial.

The Study

In its eight-week study, Neylan's group compared the effects of guanfacine and an identical-looking placebo pill in 63 male and female veterans diagnosed with PTSD. Twenty-nine participants were randomly picked to take guanfacine while the other 34 took the dummy pill.

By the end of the study, the researchers found no net difference between the two groups in terms of changes in symptoms.

"But the one thing that did clearly come out was that there were more side effects with guanfacine," Neylan said. "There was more sedation, feeling fatigued, dry mouth."

Possible Explanation

Why did a pill that should have worked so well in theory fall flat in practice? Neylan offered one possible answer."[Too much) norepinephrine can be a bad thing," he noted, "but you also need it for your brain to work well. So, lowering the whole pool of norepinephrine did not seem to be an effective strategy."

He said the relatively small sample size in the study means he can't be absolutely certain that alpha-2 agonists have no benefit, "but we did get a zero effect size. That means that even if we had five or six times this sample, the probability of showing a meaningful difference is really, really low."


Marshall agreed that the methodology is sound, and the findings conclusive. "I think this pretty much answers the question of whether, in this population, guanfacine should be considered as either a primary or an adjunctive treatment. The answer is no-it's a big surprise," he said.

The finding will change the way he and psychiatrists everywhere treat PTSD patients, said Marshall, who is also associate director of the Anxiety Disorders Clinic and an associate professor of clinical psychiatry at the Columbia University College of Physicians and Surgeons.

Alternative Treatments

Neylan said a newer drug that works on norepinephrine receptors, but in a different way, might still succeed where guanfacine has failed.

That drug, called prazosin (Minipress), blocks one receptor, the alpha-l receptor, but does not lower norepinephrine release in the brain. "There have been a few trials to show that prazosin does have some promise, and I know the VA is gearing up to do a large multi-site study. It is becoming more popular."

In the meantime, he said, it's important to remember that the first-line therapy for most people with PTSD is antidepressants and/or psychotherapy, especially "exposure therapy," where patients are gently confronted with reminders of the traumatic event itself.

"Most people feel that PTSD benefits most from a combination of pharmacologic treatment and psychotherapy," Neylan said.

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