BioWorld Perspectives Contributing Writer

Editor's note: Mike Williams is an adjunct professor in the Feinberg School of Medicine, Northwestern University in Chicago, from where he shares his personal views on today's drug discovery industry.

In the publishing world, few areas can be considered more specialized and mundane than scientific and medical monographs. With arcane subject matter, a very limited audience (usually institutional and departmental libraries) and prices that can run into hundreds of dollars, scientific texts are infrequently heard of outside of their target audience, let alone discussed in the media two years before the release of a new edition.

An exception to this is the American Psychiatric Association's (APA's) Diagnostic and Statistical Manual of Mental Disorders, otherwise known as DSM, the new edition of which, DSM-5, is targeted for publication in May 2013. The popularity of DSM is reflected by sales of approximately half a million for each recent edition and in a lengthy entry on Wikipedia that runs to six printed pages with numerous hyperlinks (1). In comparison, the entry for Harrison's Principles of Internal Medicine, a basic text in medicine in its 17th edition, occupies a mere five lines. DSM has been the subject of two New Yorker articles (1, 2), an ongoing series in Science (3-5), a lively (6, 7) and entertaining debate in Psychiatric Times (8), as well as significant coverage in the popular press (9,10) and on PBS' NewsHour (11). So why such interest in DSM-5?

Limits of DSM and the 'One Gene, One Disorder' Approach
First published in 1952, DSM has been described as "the handbook of psychiatry," "The Dictionary of Disorder," a "cultural phenomenon" (1) and "a poor mirror of nature" (5). Its third edition, 1980's DSM-III (DSM-5 is the first to use Arabic numbering and a non-italicized font) was viewed as potentially revolutionizing the practice of psychiatry, providing Americans (specifically) with the means to "tame the anarchy of their emotional lives" (1). DSM editors sought to standardize the APA's definitions of psychiatric disorders to improve the reliability of diagnosis and treatment. This is integral to DSM, as studies show that only in 20 percent to 40 percent of cases do psychiatrists actually reach the same diagnosis for the same patient. This makes the identification of disease causality a thorny problem, with "garbage in" in the form of faulty diagnoses guaranteeing "garbage out."

Thus, the listing for each disorder in DSM-IV is a cluster of symptoms based on clinical observation rather than any discrete genetic or mechanistic causality confounding robust diagnosis. Genome-wide association studies (GWASs) in psychiatric patient cohorts were thought to provide a solution to this lack of precision, as it was anticipated that each disorder in DSM-5 would have an irrefutable genetic basis to support each distinct phenotype. Unfortunately, the concept of a "one-gene, one disorder" approach to mental dysfunction yielded to the more pragmatic appreciation that each disorder can result from multiple gene interactions on which the environment — epigenetics — has a major and still evolving impact.

Schizophrenia, for example, was once thought to be confined to a mere two to three variations. As a result of GWAS, it has potentially evolved to a spectrum of 30 or more distinct, but related, gene-associated disorders that may eventually coalesce under the controversial rubric "psychosis risk syndrome" (9).

Personality Syndromes in Psychiatrists?
Added to the "symptom versus causes" debate on psychiatric diagnoses are concerns related to the influence of the biopharmaceutical industry on the practice of psychiatry where "patients who seek psychiatric help . . . stand a good chance of being diagnosed with a disease that doesn't exist" (1, 2, 5, 9, 12, 13). This has led to accusations of collusion between the industry and key opinion leaders (KoLs) in the psychiatric field, who are perceived to be turning the specialty into a non-PC "pharmaceutical brothel"(14). This perception certainly has not been helped by recent Senate conflict-of-interest cases involving seven KoLs in psychiatry or by recent comments from the head of the National Institute of Mental Health (NIMH), who noted that "the close connection between leading psychiatrists and the pharmaceutical industry, once a sign of progress . . . is now cited as evidence of a corrupt influence" (13, 15, 16).

A DSM diagnosis has a major financial impact in the provision of mental health care. It is required by insurance companies for reimbursement, for federal grant funding, and also in selecting the targeted disease indications for new chemical entities making their way through the clinic or being "repurposed" (2, 5). Thus, the existence of disorders like restless legs syndrome and fibromyalgia has been questioned on the assumption that these may be psychosomatic and, as such, targets of what is termed "disease mongering" — where biopharma is viewed as creating markets to sell drug products (17, 18).

That psychiatric disorders may be confused with marketing campaigns also has been reflected in the assertion by Menand that "psychiatry is not . . . really a science"(2). Should bereavement, the death of a loved one (once known as sadness), or shyness, be considered disorders in need of psychotherapy? Are addictions to cocaine, alcohol, gambling, shopping, sex, the Internet and eating all part of a similar disorder in anhedonic individuals? What is the role of behavioral therapy and does the use of antidepressants, anxiolytics, hypnotics, sedatives, etc., negate the true value of the life experience (2, 12)? Given the largely phenomenological state of diagnosis already discussed, this debate will be long and contentious with psychiatrists, rather than journalists or drug companies, being held accountable in the task of preventing everyday behaviors like grief and apprehension from being diagnosed as depression and anxiety (9).

As a side note, in response to the various articles on DSM in the popular press, specifically that of Menand (2) and another on the "upside of depression" by Lehrer in The New York Times Magazine (20), the editor of Psychiatric Times in a tongue-in-cheek editorial reported on the organization, PELQPP — Professors of English and Literature Qualified to Pontificate on Psychiatry — and also questioned Lehrer's credentials in writing on depression stating that he lacked "any known medical expertise" (8). The "response" from The New York Times Magazine was: "Look, if it had been an article on oncology, we would have had a cancer specialist write it. If it had been an article on heart disease, we would have had a cardiologist write it. But psychiatry — gimme a break! That's like talking about sports or the weather or maybe the movies! Pretty much everybody is qualified to write about it."

So psychiatrists, like the late comedian, Rodney Dangerfield, appear to have little respect — a situation that does not make the task of the editors of DSM-5 — or psychiatrists — any easier.

Neural Networks as an Alternative to DSM-5?
As the various APA task forces continue to debate and recommend changes in DSM-5, a number of these already have become topics of heated debate and include: psychosis risk syndrome, mixed anxiety depression, temper dysfunctional disorder with dysphoria, binge eating disorder, hypersexuality disorder, the various use disorders, and autism spectrum disorders that now include Asperger's disease. On the other hand, minor neurocognitive disorder that describes the aging process of the brain and includes mild cognitive impairment may be an aid in conducting better and hopefully more successful trials for Alzheimer's disease.

Gene-based diagnoses have proven significantly less useful than anticipated, and attention now has turned to brain imaging and the role of brain networks in defining psychiatric disorder causality (20). As DSM is based on symptoms rather than causes and has as a result been viewed as "hampering research" (5), the NIMH has a new initiative to classify psychiatric disorders based on neural circuitry. Termed Research Domain Criteria (RDoC), it involves five domains: negative emotionality, positive emotionality, cognitive process, social processes and arousal/regulatory symptoms (5). Once better defined, RDoC is anticipated to be the basis of federal grant applications for psychiatric research rather than the evolving DSM criteria.

The stakes remain high in precisely what criteria will be used in the future to develop treatments for bona fide psychiatric disorders. A number of issues tend to undermine public trust in the psychiatric profession: the major schism between KoLs on the value of DSM, the conflicts of interest with big biopharma in terms of the clinical testing and use of new treatments, and federal initiatives like CATIE (Clinical Antipsychotic Trials in Intervention Effectiveness) that have disputed the improved efficacy and safety of second generation, atypical antipsychotics. All of these also may impact the decision of some major biopharma companies to reduce efforts in neuropsychiatric research (13, 21, 22).

Notes:

1. Spiegel A. "The Dictionary of Disorder," The New Yorker, Jan. 3, 2005.
2. Menand L. "Head Case: Can psychiatry be a Science?" The New Yorker, March 1, 2010.
3. Miller G., Holden C. "Proposed revisions to psychiatry's canon unveiled." Science, 2010, 327,770-771.
4. Holden C. "Behavioral addictions debut in proposed DSM-V." Science, 2010, 327, 935.
5. Miller G. "Beyond DSM seeking a brain-based classification of mental illness." Science, 2010, 327, 1437.
6. Frances A. "Alert to the research community — be prepared to weigh in on DSM-V." Psychiatric Times, Jan. 7, 2010.
7. Frances A. "Opening Pandora's Box: The 19 Worst Suggestions For DSM5." Psychiatric Times, Feb. 11, 2010.
8. Pies RW. "American Psychiatric Headquarters Seized by Giant English Teachers!" Psychiatric Times, March 3, 2010.
9. Shorter E. "Why Psychiatry Needs Therapy." The Wall Street Journal, Feb. 27, 2010.
10. Carey B. "Revising Book On Disorders Of The Mind." The New York Times. Feb. 10, 2010.
11. PBS NewsHour. "Mental Illness, Treatment Guidelines Under Review," (video), Feb. 10, 2010.
12. Moncrieff J. "Is Psychiatry for Sale?: an examination of the influence of the pharmaceutical industry on academic and practical psychiatry." Maudsley Discussion Paper 13, 2003.
13. Insel TH. "Psychiatrists' relationships with pharmaceutical companies." JAMA, 2010, 303, 1192-1193.
14. Torrey F. Forward to "Is Psychiatry for Sale?: an examination of the influence of the pharmaceutical industry on academic and practical psychiatry." Maudsley Discussion Paper 13, 2003.
15. Harris, G. "Top Psychiatrist Didn't Report Drug Makers' Pay." The New York Times, Oct. 3, 2008.
16. Warner J. "Diagnosis: Greed." The New York Times Opinionator, Oct. 9, 2008.
17. Woloshin S, Schwartz L. "Giving Legs to Restless Legs: A Case Study of How the Media Helps Make People Sick." PLoS Med 2006, 3, e170.
18. Berenson A. "Drug Approved. Is Disease Real?" The New York Times, Jan. 14, 2008.
19. Lehrer J. "Depression's Upside." The New York Times Magazine, Feb. 25, 2010.
20. Akil H. et al. "The Future of Psychiatric Research: Genomes and Neural Circuits." Science, 2010, 327, 1580-1581.
21. Carroll J. "AstraZeneca outlines deep cuts in global R&D ops." FiercePharma, March 3, 2010.