R.I.P. RDoC?

Part 1: Is it feasible to develop new psychiatric medications using RDoC guidances?

A few years ago NIMH proposed new guidelines Regarding the Use of Animal Neurobehavioral Approaches in Basic and Pre-clinical Studies. These guidelines were heavily influenced by the Research Domain Criteria (RDoC) which was proposed in 2009:

”RDoC promotes studies that:

• Examine psychological constructs (or concepts) relevant to psychopathology, rather than focusing on mental disorder categories only.

• Study constructs by assessing and integrating a variety of both biological and behavioral measures.

• Analyze constructs dimensionally, along a spectrum of functioning, irrespective of current boundaries of mental disorders.

• Emphasize neurodevelopmental trajectories and environmental influences in studying aspects of functional behavior and pertinent biological systems.”

With respect to basic science, RDoC’s: “intent is to translate rapid progress in basic genetic, neurobiological, and behavioral research to an improved integrative understanding of psychopathology. In so doing, RDoC seeks to facilitate the development of new and/or optimally targeted treatments for mental disorders.”

and:

“NIMH recommends the use of models for addressing neurobiological questions rather than models of specific mental illnesses. Similarly, NIMH strongly discourages description of animal behaviors in terms of emotions and thought processes that are accessible only in humans by self-report (e.g., terms such as depressed, anxious, lonely) or through clinical diagnoses.”

This has led Joshua Gordon MD, PhD then Director of NIMH to state in 2019: "First and foremost, we must realize that there is no such thing as a true animal model of a psychiatric disorder."

Subsequently, studies using conventional models of antidepressant drug action (e.g. forced swim test, tail suspension test) were recommended to no longer be used. I have heard from others that grants to NIMH using these models are typically deprioritized for funding. (I note I was a member of NIMH Council until early this year, but cannot comment on whether or not this is true).

Instead, it was recommended that researchers use more ‘translationally relevant’ animals models (e.g. novelty surpassed feeding; chronic stress paradigms; executive functioning and so on) and a focus on specific domains of the illness (e.g. impaired cognition) was recommended.

Here I will examine the question of whether or not it is feasible to use the RDoC Domain approach to develop new psychiatric medications.

My short answer is NO.

My rationale:

1. As far as I can determine there is no pathway for developing a psychiatric medications that is not focussed on the core symptoms of the disorder (e.g. depressed mood).

   1. Currently, all FDA-approved treatments for psychiatric diseases address the core symptoms of the disease (e.g. depressed mood; hallucinations; delusions; etc).

   2. To my knowledge there are no FDA guidelines for developing a medication which specifically targets a domain of a psychiatric illness (e.g. impaired executive function in schizophrenia; impaired cognition in depression).

   3. There is no evidence that antidepressants, for example, reliably improve cognition (a RDoC domain).

2. There are no medications, to my knowledge, which have been approved for treating major psychiatric diseases using RDoC domains as the primary preclinical screening funnel.

   1. I’m unaware of any that have even shown positive Phase III results…

3. All recently approved drugs for treating major psychiatric illness were developed using conventional animal models of drug action (e.g. forced swim test; tail-suspension test; inhibition amphetamine-induced stereotypy; etc).

My thoughts and impressions:

1. In my visits to most pharmaceutical companies and biotechs involved in CNS drug discovery I have found that no one takes the RDoC approach seriously as a paradigm for discovering new neuropsychiatric medications.

2. I am aware of no pharma/biotechs which have used the ‘recommended’ assays (chronic stress; novelty suppressed feeding; etc) for antidepressant drug action to successfully discover a new medication.

3. I doubt the FDA would ultimately approve a treatment aimed at a subdomain of an psychiatric illness (e.g. impaired executive function in schizophrenia) which didn’t also provide a significant degree of symptom relief (e.g. needs to have antipsychotic activity).

4. I am highly skeptical that insurers would pay for such an (undoubtedly) expensive new pill that modestly (e.g.statistically significantly) improves cognition on miscellaneous measures without providing genuine symptom relief and improved functioning.

Conclusion: it has been more than 15 years since the RDoC recommendations were published. The RDoC recommendations have had no impact on psychiatric drug discovery to date.