Drug firms with a major stake in neurologic and psychiatric drug development are closely monitoring the psychiatric profession as it goes through its once-a-generation revamp of the Diagnostic and Statistical Manual of Mental Disorders.

The first draft of the fifth edition of the manual, dubbed DSM-V and released in early February, proposed a mixed bag of changes for a number of high-profile conditions. Some of the proposed changes should open up new opportunities for the drug industry, such as minor neurocognitive disorder and psychosis risk syndrome.

But others could reduce diagnoses for conditions that already have drugs under development, such as the downgrading of hypoactive sexual desire disorder, which affects mostly women.

Either way, the changes won't affect new psychiatric drug applications and expanded use applications sent to the Food and Drug Administration until 2013 at the earliest. "I don't expect it to have any immediate impact on drug development," said Thomas Laughren, director of the division of psychiatric products at the Center for Drug Evaluation and Research.

The DSM disorder definitions are used routinely by drug companies as inclusion and exclusion criteria in clinical trials submitted to the agency.

However, drug company officials recognize that the changes could trigger major shifts in the field down the road. "This is the bible and the dictionary for mental disorders and we're very much impacted by it," said David Bredt, vice president of neuroscience discovery and clinical research at Eli Lilly & Co., which among major drug firms has the largest stake in the neuroscience arena. Just under $9 billion of its $21.8 billion in sales in 2009 came from neurologic drugs, with atypical antipsychotics Zyprexa ($4.9 billion) and Cymbalta ($3.1 billion) leading the pack.

However, the company is taking a hands-off approach to influencing the outcome of deliberations by the task force and working groups of the American Psychiatric Association, which publishes the DSM.

"We're monitoring it but will not seek to influence the criteria," Bredt said. "It's very helpful for us in thinking about new medicines. It helps us see where the psychiatry profession is going."

Will The Changes Cause Proliferation Or Realism?

Critics of the DSM-V process are sharply divided on how the proposed changes might influence drug development and pharmaceutical sales. "It's going to have a huge impact because most of the new diagnoses are at the boundary of normality and mental disorder," said Allen Frances, professor emeritus of psychiatry at Duke University and chairman of the APA task force that developed DSM-IV, published in 1994.

Pointing to the unintended consequences from some of the diagnoses contained for the first time in DSM-IV, he fears there could be a repeat of the experience with childhood attention deficit hyperactivity disorder, which he said has become increasingly prevalent because of diagnostic creep and not a change in the underlying behavior of kids.

"What worries me are the proliferation of new diagnoses and reduced thresholds for existing diagnoses that in aggregate could result in the misdiagnosis of tens of millions of false positive patients resulting in costly, stigmatizing and potentially quite harmful treatments," he said.

Daniel Carlat, a psychiatrist and publisher of the Carlat Psychiatry Report, which eschews industry support in delivering continuing medical education credits to its readers, is more sanguine. "This is a realistic document; there's no paradigm shift here," he said. "We know very little about the brain and the neurobiology of disease. All we have is a constellation of symptoms that we match people up for drugs, which in many cases, makes them better. That's a good thing."

Hypoactive Sexual Desire Disorder May Vanish

One area where the proposed changes could prove influential involves an ongoing drug development program for hypoactive sexual desire disorder, which affects mostly women. Boehringer Ingelheim, seeking what the press has dubbed a female version of Viagra , is developing flibanserin to treat the condition.

A company-funded clinical trial involving 2,000 women in North America and Europe, released last November, showed a high dose of the drug increased the frequency of female sexual satisfaction by nearly one event per month compared to placebo. Another company-funded study released in February at the International Society for the Study of Women's Sexual Health in St. Petersburg showed HSDD, whose definition was drawn from DSM-IV, affects about one woman in 10.

But the DSM-V working group on sexual and gender identity disorders no longer thinks HSDD should get a stand-alone diagnosis. It has recommended folding the classification into a broader "sexual interest/arousal disorder in women." The broader designation would give greater credence to the emotional circumstances in which arousal disorders occur.

The APA declined to make members of the working group available for an interview. However, University of British Columbia psychologist Lori Brotto recently wrote in the Archives of Sexual Behavior that occasional sexual dysfunction might be a "normal reaction to a problematic context and therefore should not be pathologized," according to an article that appeared last week in the British Medical Journal.

The working group's proposal drew a strong rebuke from Sheryl Kingsberg, president of the ISSWSH and a professor of reproductive biology at Case Western Reserve University in Cleveland. She consults and conducts clinical trials for Boehringer-Ingelheim. "I do think there's tremendous overlap in almost all female sexual disorders, but it doesn't mean they are the same disorders," she said. "Desire is a distinct entity."

Kingsberg said there was an unmet need for drugs to treat HSDD. European regulators have approved P&G's Intrinsa , a testosterone patch, for the disorder and about 20 percent of testosterone patch prescriptions in the U.S. are for females, even though a 2004 FDA advisory committee rejected it for the HSDD indication. Besides low efficacy, it has a number of unwanted side effects, such as increased facial hair and acne.

Kingsberg said she just completed a Phase III trial for flibanserin that will show "it is effective for pre-menopausal women with HSDD." And she doesn't think the proposed changes in DSM-V will stand in the drug's way. She predicted field trials by clinicians likely will lead to keeping HSDD as a stand-alone disorder.

She also said it wouldn't change the presentation of her clinical trial data when it is eventually presented to FDA (the company has not yet filed a new drug application). "I wouldn't worry about changing it because we don't know where the DSM-V will end up," Kingsberg said.

Is Binge Eating Disorder Too Broadly Defined?

Other changes were viewed more positively by drug developers. For instance, Lilly is collaborating with at least one clinical trial that uses Cymbalta to combat binge eating disorder, which is proposed as an independent disorder for the first time in DSM-V. The proposed change "certainly fits with some of our work," said Lilly's Bredt. "Not all patients with high body mass index are the same. This should help us define better" who might qualify for the medication if this trial or subsequent trials prove successful.

But it is expanded indications like binge eating disorder that worry critics like Frances, who led the DSM-IV effort. He estimated that as much as six percent of the population could be diagnosed as binge eaters under the proposed classification. "What's needed is a careful risk-benefit analysis of each of these suggestions and a critical review of the scientific literature that serves as their rationale," he said.

FDA's Role In The Process

FDA is closely monitoring the DSM process since the new definitions will be crucial to future drug development programs. The agency probably will offer official comments on the proposal, according to CDER's Laughren. The APA will be taking comments and conducting field trials of the proposed diagnoses over the next two years with final publication slated for 2013.

Laughren pointed out that the DSM isn't the only guidepost for developing new drugs for neurologic and psychiatric conditions. FDA has recognized cognitive impairment in schizophrenia as a treatable condition, which wasn't listed in DSM-IV and hasn't been proposed for DSM-V. Since 2002, the National Institutes of Mental Health have funded the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) program at the University of California at Los Angeles to develop criteria for the condition.

"It's quite typical for schizophrenics to have cognitive impairment one to two standard deviations off the norm, which can be more disabling to social functioning in some cases than the more typical symptoms" like hallucinations and delusion, he said. "There are now several companies developing drugs" for cognitive impairment in schizophrenia based on MATRICS criteria.

Laughren cautioned that some expansions in the proposed criteria in DSM-V, which at first blush might look like gifts to the pharmaceutical industry, could wind up actually making it harder for companies to develop new drugs. Take the proposed "minor neurocognitive disorder," which could be interpreted to include millions of aging people showing early symptoms of mental decline. "If you capture a heterogenous group of patients with a single diagnostic label, it lessens your chances of showing a positive drug effect" when conducting clinical trials, he said.

He did offer one piece of good news for drug developers, though. When the changes in diagnostic categories occur, they shouldn't affect existing drug labels that were developed under previous editions of the DSM. "There's unlikely to be any dramatic change," Laughren said. "It doesn't invalidate what was done at a certain point in time."

- Merrill Goozner ( ¹ pinkeditor@elsevier.com )

DSM-V Revisions Could Open - Or Close - Opportunities For Drug Industry

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