A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience
Issue link: http://innovationscns.epubxp.com/i/499434
[ V O L U M E 1 2 , N U M B E R 3 – 4 , S U P P L E M E N T A , M A R C H – A P R I L 2 0 1 5 ] Innovations in CLINICAL NEUROSCIENCE 23S weight reduction outcomes (Figures 4–6). Lesson 1. Human pharmacology. For selective drugs, p harmacodynamics using active concentrations in healthy subjects are often closely related to therapeutic levels. Pharmacokinetic- pharmacodynamic relationships are an important aspect of proof of concept drug development. Lesson 2. Objective biomarkers. Drugs can potentially play a role in the RDoC frameworks. Pharmacology guided dose escalation allows maximization of therapeutic window. This may avoid adverse events associated with unnecessarily high doses. Increased confidence in dose optimization is the result. DISCUSSION In all of the presented cases, a tremendous emphasis was placed on choosing the correct population to enroll into the treatment trial. In Case 1 with pomaglumated, enrolling subjects with treatment-resistant schizophrenia appeared to not be the most optimal cohort as post-hoc analyses indicated that early onset and atypical antipsychotic naïve subjects with schizophrenia may have been the most appropriate cohort to test with this compound. In Case 2, using genetic data to stratify subjects based on risk of MCI due to AD is essential for enrollment in clinical epidemiologic type trial designs. In Case 3, the ability to evaluate neurobiologic changes to drug effect in individuals with symptom of anhedonia, which can cut across numerous psychiatric illness, will be important in assessing if the drug can treat individuals with this presentation. In Case 4, it may have been that testing compounds in healthy volunteers with objective biomarker endpoints would have dictated a more favorable pharmacologic dose portfolio and drug information when it came to testing in certain clinical populations. For these case presentations, choosing the appropriate patient population, as well as having objective biomarkers that direct therapeutic evaluations is FIGURE 6. Doses causing 40% reduction of peripheral activity FIGURE 4. CB1-inhibition of clinically active rimonabant dose: central (60%) > peripheral (40%) suppression rates FIGURE 5. Peripherally restrictive CB1-antagonists: improved therapeutic window?