`Negative' Clinical Trial Is Complex Creature

On the surface this trial appeared to be just one more negative, or failed, drug trial funded by industry. However, it found itself published in a prestigious journal, illustrating the adage, “the devil is in the details.”

Those details, however, are anything but common, according to Steven Roose, M.D., a professor of clinical psychiatry at Columbia University College of Physicians and Surgeons and a psychopharmacology researcher at the New York State Psychiatric Institute.

The trial did not just show that the highly selective serotonin reuptake inhibitor citalopram (Celexa) did not beat placebo in treating depression in those over age 75; the trial raised several questions, partially answered others, and above all, clearly showed that the beast known as a clinical drug trial is a complex being—one that science is far from clearly defining or understanding.

Roose was first author on the multisite, randomized, controlled study, on behalf of the Old-Old Depression Study Group, which includes researchers at Duke University, the University of Pittsburgh, Cornell Institute of Geriatric Psychiatry at Weill Medical College, UCLA-Neuropsychiatric Institute, the University of Pennsylvania, and the Mental Illness Research Education and Clinical Center at the Forest Research Institute in Philadelphia. The research, funded by Forest Laboratories, maker of Celexa, appears in the November American Journal of Psychiatry.

“First of all, to set the stage,” Roose told Psychiatric News, “older people are the most rapidly growing segment of the population. Second, depression is a very prevalent illness and a very important illness in this population because it significantly impairs quality of life, it leads to suicide, and when depression is comorbid with other medical illnesses common to this population—like cardiovascular disease—the other illness is often made significantly worse by the depression. So, we really wanted and need to find safe and effective treatments for depression in the old-old.”

Citalopram seemed a logical choice. It is highly selective for the brain serotonin reuptake transporter and therefore was thought to be associated with fewer adverse effects than more general serotonin reuptake inhibitors. It was also thought to have a lower likelihood of drug-to-drug interactions. Thus the drug should be relatively safe in the geriatric population.

Forest agreed to the researchers' demand that all control over study design and methodology would rest with the researchers. In addition, all data had to be in the researchers' possession, and all analyses had to be completed by the group.

“That was something that was rather unprecedented,” Roose noted, “and it was an important precedent.”

Digging Beneath the Surface

“A lot of people are going to say, `Oh look, this study shows that if somebody comes in with depression, it doesn't make a bit of difference whether you give them a drug or don't do anything,'” Roose said. “But we are saying, `Wait a minute. This is far from doing nothing.'”

The study involved 174 patients at 15 clinical sites. The patients, on average, were just under 80 years old and had a mean baseline Hamilton Depression Rating Scale (HamD) score of 24.3. Fifty-eight percent of the subjects were women.

Patients were randomly assigned to either citalopram (10 mg to 40 mg a day) or placebo over the course of eight weeks. The primary outcome variable was improvement over the eight weeks in HamD scores, and remission was defined as an endpoint HamD score of less than 10.

For those treated with citalopram, 35 percent met remission criteria at week eight, compared with 33 percent for those on placebo.

“These patients all came in and saw the doctor, and they all had a medical workup, MRI scan, neuropsychiatric testing, et cetera,” said Roose. “What it all amounts to is that degree of attention apparently has a therapeutic effect itself.” But Roose cautioned, “Even the attention doesn't work for everybody. If you look at the people with severe depression, those people didn't do as well on placebo as they did on the drug.”

In fact, in the subgroup of patients with severe depression, those on citalopram averaged a remission rate of 35 percent, compared with 19 percent for those taking placebo. But that doesn't mean that the drug was more effective for severe depression than for less-debilitating depression.“ What this tells you is that placebo was less effective [for those with severe depression],” Roose concluded. “That is a very interesting finding.”

All Things Not Being Equal

There are many other factors that affect results in clinical drug trials, factors Roose characterized as “psychological factors or nonphysiologic factors.” They influence the results, often in ways impossible to imagine or believe, he noted.

“If you use a drug like citalopram in a trial where you are comparing it with placebo, the response rate in your study is likely to be about 40 percent,” Roose said. “In active comparator trials—where everybody gets some kind of active drug, even though you don't know which drug—the response rates average 60 percent to 65 percent,” he added. The same drug, given different methodologies, but given to similar populations, may have a very different rate of response or remission.

Placebo Effect Can Be Puzzling

But the clinical-trial field has long struggled with significant placebo effects in depression treatment trials. Roose questioned just how informative high placebo response rates are.

“In the clinical setting, we don't give placebos,” Roose observed. “Everybody knows they are getting active drug, so what response rate should you expect in the clinical setting? It's probably closer to the response rates in active-comparator trials than those in placebo-controlled trials.” But that does not discount the placebo response.

Interestingly, Roose noted, the researchers saw a significant effect of site on remission rates in their study.

“Even though we have very good investigators, and they are all [at] academic medical center sites, and we demonstrated high interrater reliability on the Hamilton, where you got treated [in our study] made more difference than what you got treated with. Site variability is very common, and we just don't have [a good] understanding of this.”

Finding Meaning in Failure

“There are a lot of things that impact a clinical trial that we don't know about or necessarily understand,” Roose suggested.

“If we really want to do meaningful clinical trials, we should really do the gold-standard, placebo-controlled, randomized trials, but in a way that sort of mimics the clinical experience.” In the clinical setting, the patient is seen, prescribed a drug, and not followed up for weeks. A clinical trial should be done where the “attention” factor of the placebo-effect is mitigated, he said.

“So, [our study was] a negative study then, meaning that the drug wasn't different from placebo,” Roose said. “And it was really a study that says, `Look, clinical trials are complicated, and there are many variables that influence outcomes of studies that we don't understand.'”

However, “it would be wrong to conclude from this study that it doesn't matter if you give a patient a drug or do nothing,” Roose emphasized. “Frankly, we'd like to believe we understand what influences our clinical trials, but we really don't. And we have to be humble about that.”

The article, “Antidepressant Pharmacotherapy in the Treatment of Depression in the Very Old: A Randomized, Placebo-Controlled Trial,” is posted online at<http://ajp.psychiatryonline.org/cgi/content/full/161/11/2050?>.▪

Am J Psychiatry 2004 161 2050