Reverse and Forward Translational Neuropharmacology in Psychiatric Drug Discovery

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In drug discovery and early clinical development, translational pharmacology occurs when the same drug‐dependent effect is observed preclinically and clinically at a targeted drug exposure. Such translatability encompasses biomarker and efficacy measures as well as safety/tolerability, particularly for mechanism‐mediated adverse events (AEs). Importantly, however, are the numerous variables underlying “translational pharmacology” that must be carefully assessed to determine if it is indeed achieved, such as: interspecies differences in target expression and/or drug potency; concordance between animal model(s) and the tested clinical population; an identical or essentially equivalent biomarker and/or behavior; and the temporal exposure–response relationship in the preclinical model vs. that tested in humans (e.g., acute vs. chronic dosing, direct vs. indirect pharmacokinetic‐pharmacodynamic relationship), which ultimately dictates the optimal dosing regimen(s) for translational pharmacology studies. These analyses require the systematic integration of highly interdisciplinary data with seamless nonclinical and clinical interactions, especially for therapeutic indications lacking a clinical gold standard to enable high‐confidence reverse translation.
In addition to these considerations, translational neuropharmacology is uniquely challenged by the requirement of a systemically dosed therapeutic to cross the blood–brain barrier satisfactorily, which is sometimes very different across species. It may be argued that many “negative” neuroscience clinical trials were unsuccessful due more to inadequate central drug exposure for full neuropharmacological evaluation than to a conceptually flawed mechanistic rationale or truly absent translational pharmacology. Fortunately, significant advances in more fully understanding and manipulating test‐molecule neuropharmacokinetics to optimize central target engagement, and an adaptation to diligently establishing quantitative exposure–target engagement–biomarker effect relationships before initiating larger proof‐of‐concept trials, should allow confidently vetting future neuropharmacological mechanisms.
Successful reverse translation is so critical not only to allow preclinical studies to better understand the underlying neuropharmacology, but to enable the testing of other mechanisms that may undergo forward translation for their own clinical evaluation; together, such directional translations comprise an iterative approach. An example of an ideal psychiatry‐centric reverse translational pharmacology correlation is with selective serotonin reuptake inhibitors, where 80% serotonin transporter occupancy affords antidepressant efficacy.1 This clinically established target occupancy‐based outcome biomarker has been backtranslated to preclinical models for further research. Another seemingly effective neuropharmacological reverse translation is for L‐DOPA‐induced dyskinesia in Parkinson's disease (PD‐LID) via the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐rendered Parkinsonian nonhuman primate model (MPTP‐NHP), in which PD‐LID‐tested metabotropic glutamate receptor 5 negative allosteric modulators suggest a receptor occupancy of ≥80% is required for efficacy in both MPTP‐NHP and PD‐LID. As these examples accentuate, such associations require not only extensive clinical datasets, but a clinically validated imaging agent to quantitatively link drug concentration to target engagement and it to clinical outcome. Therefore, the confident assessment of the translation of neuropharmacological mechanisms requires the careful, and often iterative, approach of matching across species the precise temporal exposure–response relationship, which is ideally linked quantitatively to drug–target engagement (i.e., occupancy). Unfortunately, one often lacks the ability to directly establish such target‐occupancy relationships, which makes assured reverse translation more difficult, particularly for molecules with polypharmacology.
A recent highly encouraging example of reverse translation in psychiatry is with ketamine, an anesthetic discovered in the 1960s. As summarized herein, the bridging of ketamine's clinically observed cognitive impairment (an AE) and antidepressant efficacy at consistent interspecies exposures has facilitated mechanistic studies and new drug evaluation for both cognitive impairment associated with schizophrenia (CIAS) and major depressive disorder (MDD). Furthermore, application of a backtranslated ketamine‐induced cognitive impairment NHP model to clinically translate a novel mechanism proposed for CIAS is illustrated to highlight opportunities to enhance psychiatric translational neuropharmacology.
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