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Gerald Overman, PharmD, BCPP
Clinical Pharmacy Specialist for the National Institute of Mental Health (NIMH)
National Institutes of Health (NIH) Pharmacy Department

On the final morning of this year’s annual meeting, Drs. Larry Ereshefsky and Brett English provided important insight into new approaches to drug development utilizing neurocircuitry based strategies inspired by the Research Domain Criteria (RDoC). The discussion was meant to challenge the current process of drug development which involves a diagnostic strategy using the Diagnostic and Statistical Manual (DSM), while evaluating future strategies utilizing a neurocircuitry based approach to both assessment of illness and drug response.

Approximately 50% of drugs fail in clinical trials, with new compounds for psychiatry having the lowest success rates when compared to other areas of medicine.1 Some of the possible reasons discussed for these failures included the wrong dose of the compound being studied, the wrong population being studied, high placebo rates, high treatment dropout rates, misdiagnosis of patients and the potential for misinterpretation of pre-clinical data. Additionally, for those patients who get better on medications, approximately 50% need a change in dose or augmentation strategy to stay on it.1 For a higher likelihood for success, Drs. Ereshefsky and English advocated for more work in earlier phase research, potentially incorporating patients into phase I trials in a way to better assess neurocircuitry and to set up for improved success as the process moves to phase II. Issues related to subject selection bias can be addressed utilizing a neurocircuitry based approach via quantitative, objective measures rather than subjective ones currently used (ex. EEG vs. HAM-D). “The goal of phase II should be to get the targets right”, stated Dr. Ereshefsky. The 3 pillars of drug development include; 1) Exposure of drug at the target site, 2) Binding to the pharmacological target and 3) Expression of pharmacological activity.2 Many researchers are using biomarkers, including behavioral assessments, Cerebral Spinal Fluid (CSF) sampling, electroencephalogram (EEG), Event Related Potentials (ERP) and imaging, among others.

RDoC assumes that dysfunction in neural circuits can be measured by electrophysiology, functional imaging, neurocognitive/behavioral assessments and other methods for quantifying connectivity.3,4 Common symptoms, such as anhedonia, that occur in both depression and schizophrenia can be tied together by a neural substrate that is reproducible. RDoC is broken down into domains and constructs. One example of this breakdown is the domain of cognitive systems and the construct of working memory with respect to dopamine signaling during a task. Working memory, as a modifiable construct across various psychiatric disorders can be evaluated via dopamine signaling and drugs can be studied that ‘normalize’ that circuitry of interest. One of the important concepts when evaluating compounds in this way, is the ‘Fast - Fail’ approach. When a compound fails, it is preferred that it fails big and it fails early so that as little time and money as possible is lost prior to moving on to other potential compounds. Various examples of novel technologies were described including PET and MRI imaging and quantitative EEG to finish out the lecture.

New approaches for the development of medications to treat psychiatric disorders are on the horizon. Drs. Ereshefsky and English provided important insight into where the field is headed and provided a framework for future trials that may guide the future of psychiatric pharmacotherapy.

References

  1. Wong EH, Yocca F, Smith MA, et al. Challenges and opportunities for drug discovery in psychiatric disorders: the drug hunters’ perspective. International Journal of Neuropsychopharmacology 2010;13:1269-1284.
  2. Morgan P, Van Der Graaf PH, Arrowsmith J, et al. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving phase II survival. Drug Discov Today 2012, May;17(9-10):419-424.
  3. http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml
  4. Insel T, Cuthbert B, Garvey M, et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry 2010;167(7):748-751.
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