The market for psychiatric drugs is, of course, booming. In 2011, spending on psychiatric medications can expect to top $40 billion. Yet, in spite of this soaring market, a number of pharmaceutical companies are now dramatically scaling back  their efforts to develop new psychiatric drugs. It is easy to identify three reasons that the pharmaceutical industry has turned bearish on psychopharmacology's future, and they reveal that the Prozac era, launched with such fanfare in 1988, is coming to an end not with a bang, but with a whimper.

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1. The Brain Remains a Black Box

During the past 25 years, the National Institute of Mental Health (NIMH) and academic psychiatrists have regularly informed the public that mental disorders are "brain diseases," just like diabetes and other physical illnesses. But if that were so, the industry's development of new psychiatric drugs would be flourishing, as companies would be finding novel ways to ameliorate the disease process. Unfortunately, as the drug companies well know, the biological causes of major mental disorders remain unknown. While researchers may report that PET scans show differences in blood flow with different patient groups, or announce that they have identified small differences in brain function for some patients in various diagnostic categories, they haven't been able to elucidate a disease pathway for any mental disorder. As a result, drug firms lack molecular targets for new drug development.

In a recent report published in European Neuropsychopharmacology, British neuroscientists David Nutt and Guy Goodwin explained it this way: "Predictive and prognostic biomarkers for psychiatric disorders are largely non-existent." As such, they wrote, there are "deficiencies in the science that underpins drug discovery."

Undoubtedly, we will continue to hear from the NIMH and from academic psychiatry that researchers are making great progress in untangling the biology of mental disorders. We have been hearing this same story for decades now, and we will be told that such discoveries will one day bring new and better drug therapies. But the drug companies, with their retreat from this field, are revealing a different reality: the biology of mental disorders remains a mystery, and this is not a mystery they expect to be solved any time soon.

2. The NIMH-Funded Studies of Prozac-Era Drugs Told of a Failed Form of Care

When the SSRI antidepressants and atypical antipsychotics came to market, the public was told that these new drugs were much better than the old ones. The pharmaceutical industry, it seemed, had developed new "wonder" drugs. But then the NIMH funded a number of longer-term studies of psychiatric drugs, and time and again those studies failed to shows that these medications regularly helped a majority of people get well and stay well, or that the new drugs were any better than the old ones.

To wit:

• In the CATIE study of antipsychotics for schizophrenia, 74% of the 1,432 patients stopped taking the assigned medication within 18 months, mostly because of "intolerable side effects" or the drug's "inefficacy." The atypical antipsychotics did not produce better results than the standard antipsychotic.

• In the STAR*D study of antidepressants, fewer than half of the 4,041 depressed patients ever remitted, even for a brief period, and at the end of 12 months, there were only 108 patients-3% of the original cohort -who had remitted, stayed in the trial, and not relapsed.

• In the STEP-BD study of 4,360 patients, antidepressants were not found to be beneficial for bipolar patients. Furthermore, in the one-year naturalistic follow-up study involving 1,742 patients, only 409 patients (23%) remained well and in the trial throughout the 12 months. The remaining patients either dropped out (32%), or suffered one or more new mood episodes (45%).

• In the MTA study of children with ADHD, by the end of three years, "medication use was a significant marker not of beneficial outcome, but of deterioration." At the end of six years, continued medication use was "associated with worse hyperactivity-impulsivity and oppositional defiant disorders symptoms," and with greater "overall functional impairment." As one of the principal investigators confessed, "there were no beneficial effects (with medication), none."

• In the TEOSS study of antipsychotics for teenagers with early onset schizophrenia spectrum disorder, only 12% of the initial cohort responded to an antipsychotic and then successfully stayed on the medication for a year.

These results did not tell of a paradigm of care that "worked" for most people. In a 2009 paper, NIMH director Thomas Insel summed up the results for the antipsychotics and antidepressants in this way: "For too many people, antipsychotics and antidepressants are not effective, and even when they are helpful, they reduce symptoms without eliciting recovery."

For pharmaceutical companies, these poor results-and the fact that the second-generation drugs weren't more effective than the first-generation agents-provide a second reason for exiting this field of research. Drug companies want to invest their research dollars in a venture that is likely to produce a true advance in treatment (and thus will be quite profitable.) They like to build on past progress in a disease area, as this gives the companies confidence that their investment in R&D will pay off. But in psychiatry, drug companies have spent billions of dollars researching mental disorders during the past 40 years, yet that research has failed to produce any real therapeutic progress. The second-generation drugs are no more effective than the first-generation agents. And thus drug companies are left with this sobering fact: in the absence of any new insight into the biology of mental disorders, why should the future be any different? If they spend billions more on research and development, how likely is it that this investment will pay-off?

3. Having Spent Their Goodwill on Prozac-Era Drugs, Drug Companies Can't Expect to Use Their Marketing Prowess to Tell the Public a Story of a New Generation of "Wonder" Drugs.

Pharmaceutical companies did hit the financial jackpot with their second-generation psychiatric drugs. But that success was built from marketing, rather than true therapeutic progress, and the drug companies know that this marketing door -- in terms of their ability to convince the public that new wonder psych drugs have arrived -- is partially closed to them now.

Up until the Prozac era, the American public generally viewed the pharmaceutical industry in a favorable light. The industry did have a good track record of bringing helpful drugs to market for infectious diseases, for treating cancers, and for any number of other physical ailments, and that medical progress generated public goodwill. The industry capitalized on that goodwill-and our society's faith in medical progress and academic medicine-to create a booming market for the SSRIs, the atypical antipsychotics, and other psychiatric drugs. But now that goodwill has been spent.

The public is coming to understand that the market for the Prozac-era drugs was built on dishonest science and through a story-telling partnership-between industry and psychiatrists at academic medical centers-that can't be trusted. The industry-funded trials of many of the Prozac-era drugs were biased by design; the published results were spun to make the drugs look better; negative studies went unpublished; and harmful side-effects were downplayed or hidden. Investigations by Senator Charles Grassley and others revealed that the drug companies paid academic psychiatrists handsome sums of money to promote the drugs; i.e., that they were acting as shills for the drugs. Finally, both the federal government and states have sued a number of drug companies for their illegal off-label marketing of psychiatric drugs, with many companies having paid large fines to settle the complaints.

As a result, the public is now quite wary of the pharmaceutical industry, at least when it comes to its promotion of psychiatric drugs. The industry can't ramp up the same marketing machinery it used to sell its Prozac-era drugs in order to sell a new generation of "wonder" drugs. This time around, the drug companies will have to develop drugs that truly are superior to the existing ones, and they don't have any scientific vision for doing that.

The Pipeline Has Dried Up . . . Which Provides an Opportunity for Society to Rethink Psychiatric Care

In a recent editorial titled "Vanishing clinical psychopharmacology," the British Journal of Clinical Pharmacology detailed the dire state of affairs in this field. In 2010, the journal noted, the FDA only approved two drugs with a broadly defined "psychiatric or neurological indication," and the two were actually older drugs that had been on the market for other uses. No novel drugs have come to market in a long time, and the journal concluded that there wasn't anything "promising in the pipeline" either. At the 2011 meeting of the American Society for Clinical Psychopharmacology, only 13 of the abstracts were on psychopharmacology, and there were no abstracts that told of novel drugs.

While this is disheartening-it would be a very good thing if the drug industry could develop new agents that were more effective and caused many fewer side effects-there is a silver lining to be found in this story of "vanishing clinical psychopharmacology." As the existing Prozac-era drugs continue to go off patent, with more and more generics in use, the manufacturers of the brand-name drugs will likely reduce their advertising budgets for these products. If so, it is possible that the drug tsunami that has swept over our society will begin to ebb, and this will provide our society an opportunity to rethink its psychiatric care.

With our current medical model, drug treatments focus on reducing the symptoms of a "disease." In the future, perhaps our society will embrace a "wellness" model, and thus focus on treatments-whether drug therapies or psychosocial care-that promote physical, emotional, and social well-being. Peer groups are already advocating for this change in focus. Furthermore, the scientific literature provides evidence of non-drug therapies that are effective in this manner, and thus if our society does decide to rethink psychiatric care, there is an "evidence base" that it can rely upon for guidance.

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