'Serendipity' Endangered in Psychiatric Research

Experimenters in every field are fond of quoting Louis Pasteur's dictum that “in the field of observation, chance only favors the prepared mind.”

Generally, this is taken as an admonition for scientists to study well so that when the great moment arrives, they will be ready to recognize its meaning and possibilities. But it might also be considered an argument for rolling the dice more often.

“The emphasis too often falls on the preparation, not on chance,” said Donald Klein, M.D., D.Sc., a professor of psychiatry emeritus, director of research emeritus, and director emeritus of therapeutics at the New York State Psychiatric Institute, in an interview.

That opportunity of chance once led to great strides in the development of psychiatric drugs, wrote Klein in the March 5 Journal of the American Medical Association.

Serendipity—the chance discovery by the prepared mind—has had a long and honorable place in the history of drug development since Pasteur's day. It certainly had a major place in the decades after World War II, when psychopharmacology transformed psychiatry. But Klein asserts that the absence of times and places in which chance or serendipity could do its work has hindered development of psychotropic drugs over the last four decades.

“The four major classes of drugs in psychopharmacology are antipsychotics, antidepressants, anxiolytics, and lithium, [and they] were all discovered out of nowhere from 1955 to 1960, but that's a long time ago,” said Sol Snyder, M.D., a professor of psychiatry at Johns Hopkins.“ We've had some tweaking but no fundamental breakthroughs in 50 years, even though modern tools for drug discovery are incredibly more powerful.”

Long-Term Observation Unlikely

The benefits of these medications were confirmed by psychiatrists watching over the same patients for months in state psychiatric hospitals, said Klein. Such opportunities for long-term observation are rare today, since insurance companies and treatment guidelines militate against extended hospital stays.

Also, changes in how and where medicine is practiced, funding sources, the role of clinical trials, and the government approval process have all contributed to a plateau in drug discovery for psychiatry in recent years, contended Klein.

Randomized, placebo-controlled clinical trials for Food and Drug Administration review emphasize short-term statistical efficacy, but lack the duration to catch changes in response or side effects that show up only later. Klein is also disheartened that the National Institute of Mental Health has shifted its focus to basic neuroscience research, leaving placebo-controlled studies of marketed drugs to industry, which too often fails to carry them out, except to expand indications. Klein would bring serendipity back into research by using “intensive design,” an approach used by some researchers that involves “repeated periods of intervening and not intervening, judging whether benefit synchronizes with intervention.”

These would be small-scale trials that begin with long-term observation of patients taking open-label medications, titrated to give the best response without toxicity. Patients who appear to respond would then be randomized to a double-blinded course of placebo or the drug. Slowly withdrawing the drug and initiating placebo would allow investigators to look for changes in symptoms. Patients who get worse on the placebo are the real responders, not the beneficiaries of a placebo effect in the first round of treatment. They would be put back on the medication. Nonresponders to the placebo who stay well are true placebo responders. Studies like this can help tease out subsyndromes of larger disease categories, said Klein.

Combining Techniques Urged

Intensive design can be coupled with tests like brain imaging for diagnosis as well as response to therapy, he said. “These objective tests can serve as hard diagnostic tests of a subsyndrome and, as response variables, can tell you if the action of the drug is on an appropriate pathway.”

Klein acknowledged that adopting this model would not be easy, given the momentum and investment in current modes of clinical investigation.

One pharmaceutical executive, however, doesn't see that big a gap between Klein's serendipitous ideal and current practice.

“Doctors can often contribute important insight and observation to fold into the drug-development process, especially in the early stages of drug development,” Alan Breier, M.D., chief medical officer at Eli Lilly and Co., told PsychiatricNews. “That kind of observation can lead to proof of concept. I see it as complementary to existing methods, rather than conflicting.”

The phase 1 trial process, looking for the patient who responds to a drug, is not that different from Klein's approach, said Breier. Perhaps it is more systematized and focused and not as unstructured and free, he said.

Breier disagreed with Klein on another point—that the drug companies are not interested in pharmacological dissection, identifying variants of a disorder by seeing which patients with what symptoms respond to a drug.

“The strategic position of Lilly and others is moving toward tailoring, looking for the most homogeneous, responsive subgroups to maximize treatment and minimize side effects,” he said.

The practice is already in use by oncologists, who tailor drugs to subtypes by genes, said Snyder in an interview. “Expanding that approach would be good for drug companies. They might have a smaller market, but they would have more successful drugs.”

Researchers today know about hundreds of pathways and can speculate on which receptors might do what, continued Snyder. Company management may allot money to explore some of these in mouse models for a while, but decisions to go to clinical trials are harder for them to approve.

“What has to change is to lower the hurdle to get [drug testing] into human beings,” he said. “That means doing a necessary minimum of toxicological studies, then getting the drug companies to fund informal studies in academic settings to try compounds in patients of all kinds. Randomized, controlled trials are useful in a later stage.”

Klein brings the weight of 60 years in medicine to his perspective on the plateau in development of new psychotropic drugs. Whether his ideas on serendipity can be returned to practice remains to be seen, but he'll have the ghost of Pasteur at his side, and maybe some others with the same vision, as well.

“Serendipity.. .was the beginning of designed [drug] discovery, but it was not designed discovery because its product was not sought,” wrote Karl Beyer Jr., 30 years ago. Beyer developed a slew of drugs while working in industry and academia. “Serendipity is more advanced than luck as a basis of discovery. It is a more disciplined concept of discovery, without the full randomness that luck implies,” he said.

“The Loss of Serendipity in Psychopharmacology” commentary is posted at<http://jama.ama-assn.org/cgi/content/full/299/9/1063>.▪