1 Boring Old Man

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…

^{… [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…}

^{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.}

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.

^{… 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.}