Fast-Fail Trials (FAST)

Why was FAST a priority for NIMH?

Developing medications that effectively treat mental disorders is a priority for NIMH. Although existing medications can be helpful, they often have significant limitations. For example:

• Available antidepressants require weeks to take effect and fail to relieve symptoms in about a third of people who try them.
• Currently approved medications do not target some of the core symptoms of central nervous system disorders, such as cognitive difficulties in schizophrenia or repetitive behaviors, social difficulties, and communication deficits in autism.
• Negative side effects of these medications can be a significant issue for patients. 

A critical first step towards developing more effective medications is identifying new targets in the brain that could correct a dysfunction contributing to illness. Some example targets include molecules or compounds that interact with brain cell receptors or alter brain signaling.

Although targets have been identified, compounds and drugs developed based on those targets often fail to show benefits in the later stages of clinical trials. The reasons for failure are not always clear. Possible reasons drugs do not work are that the dose was too low, the drug did not act as expected in humans, the side effects outweighed the benefits, and so on. The challenge of trying to untangle why a drug failed in clinical trials is one of the main reasons why the pace of developing medications for mental illnesses and autism has been slow.

Under the FAST initiative, NIMH brought together researchers with a broad range of expertise who conducted small, multi-site clinical trials to test candidate compounds. Researchers varied trial designs based on what was known about the molecular targets in humans. Three teams of FAST researchers focused on developing treatments for specific types of mental disorders:

• Autism spectrum disorders (FAST-AS)
• Mood and anxiety spectrum disorders (FAST-MAS)
• Psychotic spectrum disorders (FAST-PS)

FAST aimed to evaluate brain targets of interest and identify compounds that act on those targets. After identifying a promising compound, researchers performed more extensive clinical testing using indicators (or biomarkers) to inform how the compounds act in the brain.

The studies answered the following questions:

• Does the compound engage a target in the brain?
  • For example, does it interact with a specific receptor in brain cells or alter signaling in the brain via a specific neurotransmitter?
• Does the compound measurably change a feature of brain function?
  • For example, does it improve performance on a test of memory, cognition, or attention?

What was the impact of FAST?

Years of experience in drug testing suggested that positive results in preclinical trials and animal studies do not necessarily translate to humans. NIMH designed the FAST approach to overcome this limitation and help researchers determine—quickly and efficiently—whether targeting a specific biological mechanism would have the anticipated effects and provide a promising candidate for further clinical trials.

The outcomes of FAST demonstrated the importance of having rigorously and efficiently designed trials. With this new type of experimental testing, compounds found to engage a target in the brain and alter a biomarker of brain function served as models for testing similar compounds. Even negative results were useful as they helped avoid costly and time-consuming testing and provided new information in designing future trials.

• FAST-AS showed that a resting measure of brain activity could be used to measure medication effects in the brain. The study was the first step in designing future early-stage clinical trials on medications to treat autism spectrum disorders.
• FAST-MAS showed that blocking the kappa opioid receptor in the brain had a significant effect on brain circuits involved in reward and pleasure. The study identified the receptor as a promising target for drug development in future clinical trials of treatments for mood and anxiety disorders.
• FAST-PS showed that a brain imaging-based biomarker could be used to develop glutamate-targeting medications to treat schizophrenia. Glutamate is a neurotransmitter that plays an important role in memory, cognition, and mood. The study identified a measure of the effectiveness of medications that could be used in future clinical trials for psychotic disorders.

Overall, these studies helped identify new and more effective targets in the brain and improved the development and screening of new candidate compounds for treating mental disorders. These measures furthered knowledge about the relationships between specific molecular mechanisms, brain function, and therapeutic effects in people with mental illnesses and autism.

Learn more about FAST

Publications

• The NIMH 'Fast-Fail Trials' (FAST) Initiative: Rationale, Promise, and Progress 
• Derisking Psychiatric Drug Development: The NIMH's Fast Fail Program, A Novel Precompetitive Model 
• The First Implementation of the NIMH FAST-FAIL Approach to Psychiatric Drug Development 
• A Randomized Proof-of-Mechanism Trial Applying the 'Fast-Fail' Approach to Evaluating κ-Opioid Antagonism as a Treatment for Anhedonia 
• Selective Kappa-Opioid Antagonism Ameliorates Anhedonic Behavior: Evidence From the Fast-Fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS) 
• Proof of Mechanism and Target Engagement of Glutamatergic Drugs for the Treatment of Schizophrenia: RCTs of Pomaglumetad and TS-134 on Ketamine-Induced Psychotic Symptoms and PharmacoBOLD in Healthy Volunteers 
• Utility of Imaging-Based Biomarkers for Glutamate-Targeted Drug Development in Psychotic Disorders: A Randomized Clinical Trial 

Science news and research highlights

• Fast-Fail Trial Shows New Approach to Identifying Brain Targets for Clinical Treatments

Last Reviewed: October 2022