Revolution Stalled

Hyman, Steven E.

doi:10.1126/scitranslmed.3003142

Cited by 235 publications

(189 citation statements)

References 29 publications

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“…1 This idea remains well within the current bench to bedside paradigm. Insel takes a different tack 2 by optimistically emphasizing that many unexplored targets remain: ''…one conspicuous observation from the genetics of mental disorders is that none of the scores of candidates from genome-wide association studies (GWAS) involve the usual psychopharmacologic suspects, monoamine transporters or receptors… interesting candidates emerge.…”

Section: The Bench To Bedside Modelmentioning

confidence: 89%

“…1 Molecular ''targets'' such as the serotonin and norepinephrine receptors are affected within minutes by psychotropic agents, whereas clinical benefit takes several weeks. Such ''targets'' are only the first domino.…”

Section: The Bench To Bedside Modelmentioning

confidence: 99%

“…Two recent commentaries from National Institute of Mental Health (NIMH) directors agree that the situation is catastrophic. 1,2 In announcing the move to investors and analysts, GlaxoSmithKline Chief Executive Andrew Witty explained that pain, depression, and anxiety were areas where ''the probability of success is relatively low… the cost of attaining success is disproportionately high.'' 3 CNS drugs cost more and take longer to bring to market than other types of drugs.…”

Section: Introductionmentioning

confidence: 99%

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Industry withdrawal from psychiatric medication development

Klein

Glick

2014

Rev. Bras. Psiquiatr.

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Between 1950 and 1969, on a serendipitous basis, psychiatric drug development flourished. However, there has been a steep decline in the development of new medication classes. Instead of new molecular entities, slight molecular modifications producing ''me-too'' drugs attempted to garner market share. With failing profitability, industry is now withdrawing from psychiatric medication development. Managed care drastically shortened contact between patients and clinicians, so the possible observation of unexpected benefits has been nullified. The randomized, parallel-groups design met FDA requirements for specific pharmacological efficacy. However, it does not determine whether a patient who improved while drug-treated required the drug or would have gotten better on his own. Further, pathophysiology benefit remains obscure. The major psychotropic drugs have no benefits for normal subjects. Their remarkable benefits must stem from a necessary interaction with a pathophysiological state. Therefore, understanding therapeutic benefit by treating normal subjects becomes unlikely. The claim that therapeutic knowledge in psychiatry proceeds from bench to bedside has proven vacuous, primarily because of our limited understanding of brain pathophysiology. The utility of the alternative intensive design for understanding diagnosis, therapeutic benefit, and pathophysiology is emphasized.

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Section: The Bench To Bedside Modelmentioning

confidence: 89%

Section: The Bench To Bedside Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Industry withdrawal from psychiatric medication development

Klein

Glick

2014

Rev. Bras. Psiquiatr.

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“…2014.11a2 reporting the O'Brien study referenced here.). As Steven Hyman puts it -in a paper entitled 'revolution stalled' -this is largely because of an inability to demonstrate efficacy (Hyman, 2012). Hence the paradox -more and more people are taking the drugs, especially for relatively minor problems of mental health -while the hypothesis on which they are based is no longer viable.…”

Section: Crisis Of Treatmentmentioning

confidence: 99%

Neuroscience and the future for mental health?

Rose

2015

Epidemiol Psychiatr Sci

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Psychiatry is in one of its regular crises. It is a crisis of its diagnostic systems despite -perhaps because -of the recurrent claims about the extent of diagnosable 'brain disorders'. It is a crisis of its explanatory systems despite -perhaps because -of its current wager on the brain as the ultimate locus for explanations of mental disorders. It is a crisis of its therapeutic capacities despite -perhaps because -more and more people are making use of its primary mode of intervention focussed on the brain -psychiatric drugs. In this editorial, I will suggest that this triple crisis of diagnosis, explanation and therapeutics arises from the dominant reductionist approaches to the role of neurobiology in psychiatry that priorities the analysis of brain mechanisms, at the expense of an understanding of the whole living organism in its milieu, and the processes which social experience shapes neurobiology from the moment of conception if not before. I shall suggest a different approach that starts from the experience of persons coping with adversity in their forms of life. This approach does not require giving up on our search for plausible explanations of mental health problems that engage neurobiological mechanisms, but it begins from a commitment to understanding, and hence intervening in, the ways in which social adversity shapes and blights the lives of so many of our fellow citizens.

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“…In another example, genome-wide association studies in large population samples have revealed genetic loci linked to psychiatric disorders such as schizophrenia [7]. Perhaps the functional effects of these genetic changes will reveal a phenotype (e.g., decreased synaptic function in neuronal subtypes) against which new compounds can be screened [8]. This "phenotypic screening" method for drug discovery, which focuses on correcting a biological signature associated with the disease process rather than targeting a specific protein, has been widely used in other fields [9].…”

Section: Outcome-oriented Approachmentioning

confidence: 99%

The Fox and the Hedgehog: A Vision of Neuroscience Research in Psychiatry

Hsin

2015

Acad Psychiatry

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In his essay on the writings of Leo Tolstoy, philosopher Isaiah Berlin [1] proposed two types of historical thinkers: those seeking to explain the world through unified principles (hedgehogs) and those seeking to approximate it through various, sometimes disparate, paths of understanding (foxes). As a metaphor for two different approaches to prediction, Berlin's idea raises an intriguing tension between explanation and approximation of natural phenomena. With a new decade of the brain dawning in psychiatry, a similar tension appears to underlie two different ways that neuroscientific thinking encroaches upon clinical understanding and practice: for simplicity, one can be termed a mechanismoriented approach and the other, an outcome-oriented approach. These approaches differ in terms of modeling principles, research methods, implications for drug discovery, and skill set needs (Table 1). The contrast between these two approaches raises interesting considerations for the field of psychiatry on scientific and clinical levels. Mechanism-Oriented ApproachMechanisms in traditional biology are deterministic in nature: part A causes, permits, or inhibits part B in a biological process, and perturbations in a part will result in predictable changes to the biological state. These parts could be proteins in an intracellular signaling cascade, for example, or cortical nuclei in a neural circuit. Predictions are based on hypothesis testingexperiments where the mechanistic model is interrogated by functional changes to specific parts, as in a genetic mutation or drug inhibiting a protein's function, or the surgical ablation of a neuronal population. These experiments generate a unifying model of the biological process in question. The hope here is that therapies can be developed to target a specific biological component ("target-based" drug discovery) for a beneficial clinical effect. In certain subfields of oncology, a cancerous mutation is identified and a pharmacological agent is found that targets this oncogenic component in patients-as in the successful drug imatinib, which inhibits an overactive enzyme found in patients with chronic myelogenous leukemia [2].This hope is also reflected in recent priorities of the National Institute of Mental Health (NIMH) [3]. Neurobiological models of disease, validated by biological experiments to have high explanatory power, should guide the discovery of targeted therapeutic interventions for various psychiatric disorders. A clinical trial demonstrating the effectiveness of these interventions should, in principle, also show the expected mechanistic effects on neurobiological targets [3]. Pharmaceutical companies have extended this idea to "proof of concept" clinical trials, where new drugs developed through targetbased discovery are tested on small homogeneous populations of target-defined patients [4]. For example, a compound that targets a protein regulated by the Fragile X gene product can be tested in a subpopulation of patients carrying the same genetic and epigenetic characteri...

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Revolution Stalled

Cited by 235 publications

References 29 publications

Industry withdrawal from psychiatric medication development

Industry withdrawal from psychiatric medication development

Neuroscience and the future for mental health?

The Fox and the Hedgehog: A Vision of Neuroscience Research in Psychiatry

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