The NIMH experimental medicine initiative
Open accessAbstract
Much has been written about the dire state of treatment development for mental disorders 1. While there has been progress in the development of devices and psychosocial treatments, psychopharmacology over the past decade appears to have stalled after four decades of exuberant growth 2. There are several reasons for the lack of progress in medication development: preclinical studies appear neither predictive or reproducible, there are few novel targets for Phase I and Phase II studies, and several expensive recent Phase III studies have failed. Psychiatric drug development is now seen as high risk. Indeed, large pharmaceutical companies have reduced investment in central nervous system disorders from 267 projects in 2009 to 129 projects last year, with many of these projects focusing on neurological and not psychiatric disorders 3. It is important to note that four decades of drug development resulting in over 20 antipsychotics and over 30 antidepressants have not demonstrably reduced the morbidity or mortality of mental disorders. While there may be many explanations for the unabated public health needs associated with mental illness, there can be little doubt that we need additional research and development to provide the preventive interventions and cures that will reduce morbidity and mortality. Current medications have an important role in the toolbox of interventions but, either alone or in combination with other treatments, they have not proven sufficient. The question is how to develop the next generation of interventions. The National Institute of Mental Health (NIMH) has tried to answer this question by focusing on each of the issues noted above: problematic preclinical studies, lack of novel targets, and failure of Phase III trials. Others have argued for the need to move rapidly into human trials due to the difficulty extrapolating from preclinical results 4, 5. Here we describe changes in the clinical trials portfolio to search for novel targets and increase the likelihood of Phase III success. The approach has been called the shift to experimental medicine at NIMH. Although this term has been used to describe broadly the clinical study of mechanisms of disease, for NIMH, experimental medicine refers to an approach to clinical trials. The first step before changing the clinical trials approach was a review of the portfolio in 2012. In the previous year, NIMH supported over 250 clinical trials at a cost of roughly $150M per year. More than half of these trials were for psychosocial interventions. Our initial review demonstrated a large number of under-powered trials that were slow to recruit and even slower to publish. Indeed, a 2012 review of trials across the National Institutes of Health (NIH) reported that fewer than half published results within 30 months of completion 6. Most trials were looking for an efficacy signal, but were designed not to rigorously test a hypothesis about how or for whom the intervention should work. Few trials included any test of mechanism of action. Trials rarely included measures of dose-response or tests of duration that could inform their adoption and reimbursement in the real world. Given the range of issues, NIMH announced in 2014 that it would no longer accept proposals for clinical trials unless they were responsive to a Request for Applications (RFA). In 2014, NIMH released three RFAs to solicit proposals for clinical trials (see http://grants.nih.gov/grants/guide/rfa-files/). In line with an experimental medicine approach, each of these RFAs refocused trials from simple tests of efficacy to studies of disease mechanism 7. The new approach required a measure of target engagement, where the target ideally was linked to some mechanism of disease but could also be a mechanism of action of the intervention. The prototype of a target might be a measure of receptor occupancy. A clinical trial of a drug thought to work as a dopamine receptor antagonist would need to demonstrate a dose for engagement or occupancy of the dopamine receptor and then test for efficacy at that dose. This simple requirement has two important implications. First, it allows negative efficacy data to be informative. Second, it allows a test of the importance of the target. In five decades of treatment development, there have been essentially no mechanisms falsified in neuropharmacology, in part because target mechanisms are rarely tested in clinical trials. Of course, receptor occupancy is a high bar for target engagement, unlikely to be feasible in most studies. For psychosocial studies, the target could be a shift in attentional bias or social cognition or family dynamics, as assessed by changes in objective measures included in the trial. For device studies, the target might be a change in EEG or evoked potentials or the blood-oxygen-level dependent (BOLD) signal. The choice of target is critical because the choice of intervention is almost always iterative. Each new intervention is a st
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The study was grounded within the NIMH experimental therapeutics pipeline, in which engagement of an identified treatment target must first be established before pursuing tests of clinical efficacy.
“This study was grounded within the National Institute of Mental Health experimental therapeutics pipeline(46) in which engagement of an identified treatment target (i.e., hypothesized mechanism underlying a clinical or functional outcome of interest) must first be established before pursuing tests of clinical efficacy.”
The experimental therapeutics framework necessitates focus on a central treatment target to inform next step decisions about treatment evaluation.
“the experimental therapeutics framework necessitates focus on a central treatment target to inform next step decisions about treatment evaluation,(46)”
Psychosocial treatment development rarely evaluates the requisite dose or duration of treatment needed to exert its effects.
“Psychosocial treatment development rarely evaluates the requisite dose or duration of treatment needed to exert its effects;(46)”
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Medial prefrontal transcranial alternating current stimulation for apathy in Huntington's disease
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Adjunctive cognitive training with exposure enhances fear and neural outcomes in social anxiety
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The Potential Impact of Selected Bacterial Strains on the Stress Response
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The use of probiotics in depression
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Are omega-3 fatty acids efficacious in the treatment of depression? A review
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EPA’s proposed transparency rule: Factors to consider, many; planets to live on, one
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Randomized controlled trial of computerized working memory training for Veterans with PTSD
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Cognitive Enhancement in Schizophrenia and Related Disorders
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Whose Signals Are Being Amplified? Towards a More Equitable Clinical PsychophysiologyPreprint
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Do You Believe the Field of Psychological Science Is Headed in the Right Direction?
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- Authors
- Insel, T. R.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Insel, Thomas R.
- ORCID
- Insel, Thomas R.
- Venue
- World Psychiatry
- Publisher
- Wiley
- Published
- 2015-06
- Volume
- 14
- Issue
- 2
- Pages
- 151-153
- ISSN
- 1723-8617 (ISSN-L)
- PMC
- PMC4471962
- OpenAlex
- W1563383822
- Cited by
- 165
- References
- 9
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 14 · 2023: 15 · 2022: 22 · 2021: 21 · 2020: 8 · 2019: 36 · 2018: 13 · 2017: 14 · 2016: 6 · 2015: 1
- FWCI
- 12.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- World Psychiatry (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Health and Medical Research Impacts
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- experimental medicine, psychiatric drug development, mental illness, trial recruitment, trial publication, novel therapeutic targets, phase III trial failure, psychopharmacology, National Institute of Mental Health, research funding priorities
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