whither the crisis…

Posted on Friday 5 April 2013

Dr. Steven Hyman was Director of the NIMH from 1996-2001 then returned to Harvard as a Provost from 2001-2011. He is currently the "Director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard… He has worked, more recently to open psychiatric classifications, including the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases, Mental and Behavioral Disorders to fundamental rethinking including the incorporation of neuroscience and genetics the recognition that many mental disorders are quantitative deviations from health rather than categorically different."
Psychiatric Drug Development: Diagnosing a Crisis
The Dana Foundation: Cerebrum
By Steven E. Hyman
April 02, 2013

… In 1949, John Cade, who was interested in the properties of uric acid, recognized that it was the lithium moiety of his lithium urate salts that was sedating his guinea pigs. This led him with breathtaking rapidity to test lithium on patients with mania. In 1950, the French surgeon Henri Laborit tested the new drug chlorpromazine, originally developed as an antihistamine, as a medication to be used before general anesthesia. Based on chlorpromazine’s sedating properties, he recommended that his psychiatric colleagues, Jean Delay and Pierre Deniker, test it on agitated psychotic patients. Remarkably, the sedation turned out to be a side effect; the true benefit of chlorpromazine [later branded as Thorazine] was its ability to diminish the hallucinations and delusions of patients with schizophrenia and related disorders.
As chemists attempted to improve upon the three-ring structure of chlorpromazine, one of the compounds that emerged, imipramine, failed to treat psychosis but markedly elevated mood. Imipramine was then developed as the first of the tricyclic antidepressants, and it became the prototype antidepressant that increases the concentration of the monoamine neurotransmitters [serotonin or norepinephrine] in synapses. It works by blocking the reuptake “pump” that normally removes these neurotransmitters from synapses after they have delivered their signal. The other major antidepressant mechanism, monoamine oxidase inhibition, was based on yet another serendipitously identified drug, iproniazid. It was synthesized in attempts to produce chemical alternatives to isoniazid, a drug used to treat tuberculosis. Iproniazid failed to treat tuberculosis but markedly improved the depressed mood of the chronically ill patients in its clinical trial…

This paper by Dr. Hyman is meant to be a diagnostic look at the crisis in psychiatric drug development occasioned by the pharmaceutical companies shutting down their CNS drug development programs over the last several years. The paragraphs above are Hyman describes the birth of psychopharmacology. They sound the same as they did when I arrived in psychiatry forty years ago except for leaving out the benzodiazepines. "The first benzodiazepine, chlordiazepoxide [Librium], was discovered accidentally by Leo Sternbach in 1955, and made available in 1960…" The irony, of course, is that except for the so-called me-too SSRI antidepressants and the atypical antipsychotics, that’s essentially where the story still stands today, in spite of the intervening years of psychiatry’s domination by biological research and treatments.

I’m going to talk about some other things from this piece by Hyman, but I actually think it’s worth a read through whether you’re friend or foe. It’s a line of thinking that’s foreign to me, now or at any other time in my life – but he states it clearly. Dr. Hyman is a neuroscience type who talks about Translational Medicine as if it’s his native tongue. It was his baby when he was at the NIMH, along with the mega-trials [STAR*D, CATIE, etc], many reported after he left. He now sees his Translational Medicine as stalled, something he says from the point of view of the pharmaceutical companies:
… [the]pharmaceutical companies do not see a feasible path to the discovery and development of novel and effective treatments . Given the steady stream of drugs that have gained approval during recent years for treating depression, anxiety, schizophrenia, and bipolar disorder, this scientific stall may have seemed to come out of the blue. However, payers [both insurance companies and governments] and regulatory agencies have given up their willingness to accept even more expensive new drugs that, despite marketing efforts, have turned out to be no more than variations on very old themes…
One reason that I suggest you read the whole article is that in his thinking, the perspectives of the pharmaceutical industry, psychiatry, and the NIMH are discussed as if they are the same thing. For example, he discusses academic research and pharmaceutical research as if they are in synergy with different strengths and weaknesses, an unbroken chain:
Industry plays a critical role in producing new treatments. There is overlap between research in industry and in academia — each realm has different core strengths. Academics are able to tackle projects that are too risky and long-term for companies focused on increasing stock prices or returning dividends to shareholders. The equation also includes the funders of academic science—largely governments and foundations, which also have a far longer time horizon than do investors in private companies. Funded by tax and philanthropic dollars, academics can accept greater risk and can recognize that the significant leaps into the unknown by which science progresses may have no obvious practical implications in the short run, and that creative explorations commonly produce failure more often than they produce success.

Academia is therefore in a better position than industry to investigate basic mechanisms of disease, as well as other matters that may ultimately be relevant to therapeutics but are still distant from the design of products. Such research can reveal genes, proteins, or other molecules that, if activated, blocked, or otherwise modified, might exert therapeutic benefits and be labeled drug targets. If the research convincingly demonstrates a potential role in the disease processes, the research may earn a “validated drug targets” label. At this point, pharmaceutical companies generally need to take the next step, which is to search for chemical compounds that bind to and modify the target in desired ways.

It is the role of medicinal chemists, most often company based, to painstakingly synthesize and study variations on promising chemical compounds in the search for a good drug  — a chemical compound that has the desired effect on the target, that is not too toxic, that can be absorbed into the body, and, in the case of psychiatric medicines, that can enter the brain. Once identified, the promising drug must be tested in humans and shown to have the desired therapeutic effects without disproportionate side effects. The clinical trials that take a chemical compound from the stage of discovery to approval by regulators such as the Food and Drug Administration are extensive and costly. Large companies have the necessary resources and experience to orchestrate such trials, which are critical steps in producing new medicines for psychiatric disorders.
We’ve read this kind of notion of a symbiosis between academia and industry before. Dr. Insel talks about it all the time on his blog. There was a paper with a similar take by Dr. Christian Fibiger [Psychiatry, The Pharmaceutical Industry, and The Road to Better Therapeutics] I reported on last year [psychopharmacological evangelism: “serendipitous clinical observation”…]. Here’s the thing about that argument – I can’t think of any examples. The drugs that have characterized the post-DSM-III era are all me-too drugs developed by pharma. What the academics have done is sign on to the industry’s papers as KOLs, involve themselves as sites for drug trials, and traveled around on speaker’s bureaus. If the academics are doing what he described, I missed it. Dr. Hyman, Fibiger, and Insel should be in a better position than I am to know about such things – but I think that this scheme, at least over the last quarter century, is more their shared delusion fantasy than some hard reality.

So while it seems a cynical thing to say, I can’t think of any accomplishments by the Translational Medicine era to mention other than to produce a lot of articles and a few new journals. So how could it be stalled? It never took flight in the first place except as a monotonous rhetorical device and a name for a bunch of centers that haven’t produced very much. The Translational Medicine rallying cry "from bench to bedside" has lacked in productivity from the bench side of the equation.

In my cynical take on Hyman’s story, the pharmaceutical industry has carried the ball and academic psychiatry has involved itself mainly by riding the waves as marketers and guest authors, but not a the primary scientific arm of some team. So the crisis that Dr. Hyman is talking about is in academia – without the pharmaceutical industry, the current brand of academic is hanging in the breeze, trying to figure out how to get them to come back.
… Whether or not engineered neurons or human neural circuits on a chip prove to be good systems for studying gene function, researchers will make substantial efforts to turn genetic clues into ideas for therapeutics. Many researchers hope that such efforts will help attract the pharmaceutical industry back to psychiatry by demonstrating new paths to treatment development. The emerging genetic results may be the best clues we have ever had to the etiology of psychiatric disorders. If other areas of medicine can guide us, there is enormous promise in deprioritizing existing drugs and old-fashioned animal-based assays as investigative tools and instead focusing on actual disease mechanisms identified by genetics. Technology has only recently begun to make this possible.
I might add that the graphic I started with [the brain + a dollar sign] is a recolored version of the image that was actually attached to this article. More to come…
    April 5, 2013 | 9:29 PM

    I was working out in the gym along side of a well-respected psychiatrist colleague of mine at our well respected and major medical/academic department of psychiatry. I asked him: “What have we reaped in terms of treatment efficacy with the biological psychiatry revolution? How have we helped our patients?” He smiled and said: “We have given them nothing in efficacy but we have given them a greater array of side effects to choose from.” I laughed. But then I cringed. I think he is right.

    April 5, 2013 | 9:47 PM

    The “division of labor” between academia and industry proposed by Steven Hyman is enough to give anyone hives if they stop to think about it. Academics can study basic physiological processes, identify possible components and catalysts of our most important life functions … so that corporations can then step in to convert this fundamental knowledge into profitable pills. Ummm… what if the best way to engage with and possibly enhance or modify a newly-identified brain region or neurochemical process is NOT A PILL? What if, in fact, designing a drug to turn off or amp up a biological function proves to be the perfect way to screw it up royally in the long term? (I am thinking here of SSRI’s, benzos and other psych drugs, but I could just as easily be thinking of the damned proton pump inhibitors for your stomach acid, or the marvelous asthma drugs that have “fatal asthma attacks” listed among their possible side effects.)

    It’s like telling chemists to get busy discovering the most advanced and amazing polymers, so that some bored thirteen-year-old kids can huff them and figure out which ones get you high. Or psychologists to dig deep into the complicated root structure of human sexual attraction … so that GM can use it to sell cars. And what if the most important application of your research is not to produce a new product, but to get us to STOP using a product … like, say, DDT, cigarettes or partially hydrogenated cottonseed oil? Oh well, I guess that’s not “translational.” Hugely important and potentially life-saving, but no corporation will license it to make themselves rich. Better toss that research. I swear, capitalism is going to kill science altogether, and then where will capitalism be?

    berit bj
    April 6, 2013 | 4:00 AM

    The corrupted field of psychiatry need other voices than current and former directors of NIMH – if the profession aims to be more beneficial than damaging to vulnerable persons, patients, families, environments and society. Professionals blind to dominating, contaminating, rampaging, industrial elephants, are not trustworthy.

    We need the independent voices of those who dare to see and think and speak honestly. 1BOM is an excellent example in a (rapidly?) growing, fertile, crosspollinating field, like another Socrates, of whom I was just reading a stimulating article in the ISPS’ journal Psychosis.

    berit bj
    April 6, 2013 | 4:24 AM

    Breaking news: Building collapse in Mumbai kills dozens.

    Free associations: Illegally built structure – pharmaceutical rats seen leaving the sinkhole before crash – number of global victims unknown …

    April 6, 2013 | 9:19 AM

    Johanna, I think this every time the media hyperventilates over influenza. Air out your home. Get sunshine and fresh air. Exercise your lungs. Wash your hands with regular soap— NOT antibacterial soap. Get plenty of sleep.

    Worried about the “stomach flu”? Heat and cool foods to appropriate temperatures. Use a food thermometer. Handle raw chicken and egg very carefully. Wash hands with mild, emollient soap and water. Get plenty of sleep.

    If it were profitable we would be bombarded with the message that getting adequate sleep is the best thing we can do for our immune system (and our mood and cognition), and would have had it drilled into us that getting sick from a virus or bacteria isn’t about “getting a germ” but about getting a sufficient number of germs to overwhelm our immune system. Most people wouldn’t make the mistake of thinking that they “don’t have any germs” because they don’t have any symptoms if these simple truths were repeated by the medical establishment, the press, and our schools.

    The simplest tenets of self-care are drowned out by the barkers of drug peddling. “Mental illness” is infinitely more mysterious and so is more easily exploited and propagandized.

    April 6, 2013 | 2:09 PM

    The “division of labor” in translational medicine is created by pharma shifting its money to lobbying governments to take on the expense and risk of psychiatric drug research. That money goes to research projects; if any pan out, pharma will swoop in, make a sweet deal for the intellectual property, and reap the profits.

    Having the public subsidize research for pharmaceutical companies is a brilliant business strategy. Ya gotta hand it to pharma, their ingenuity has turned up excellent transfer of wealth strategies (also true of the finance and energy industries).

Sorry, the comment form is closed at this time.