[Summary] Translating Oxytocin Neuroscience to the Clinic: A National Institute of Mental Health Perspective (Insel 2016)
TLDR; Although early human oxytocin studies are promising, we have to learn more about what oxytocin specifically targets in humans, and what doses are effective
https://dacemirror.sci-hub.do/journal-article/3321fe1aae981a9ee5e34a0454db1621/insel2016.pdf
TLDR; Although we’ve learned a lot from animal studies, and early human oxytocin studies are promising, we have to learn more about what oxytocin specifically targets in humans, and what doses are effective. NIMH now requires demonstrating “target engagement” in studies in order to create more informative studies and results.
Concepts to guide translation from bench to bedside
Translating oxytocin research to clinical trials is exciting and popular, but three concepts can help us manage expectations: sex, species, and chemistry.
“At the end of 2014, a search of “oxytocin and intranasal” revealed 99 trials listed in ClinicalTrials.gov with 253 citations in PubMed since 2009”
“Beyond the specifics of this exciting and growing literature, these studies suggest three general concepts that can guide us as we consider translation from bench to bedside. Given the enthusiasm for clinical trials with intranasal oxytocin, these concepts may be helpful in managing expectations”
(1) Sex matters: oxytocin functions are often female-specific.
“First, sex matters. The canonical functions of oxytocin for parturition and lactation are female-specific and steroid-dependent”
(2) Species matters: oxytocin injections affect different vole species differently (via oxytocin receptor levels).
“Second, species matters. Oxytocin is necessary and sufficient for attachment behavior in prairie voles but has no such effects in meadow voles.”
“Species with high levels of oxytocin receptors in brain regions associated with reward tend to show high levels of affiliative behavior.”
(3) Chemistry matters: intravenous or intranasal oxytocin does not reach the brain well.
“Third, chemistry matters. Neuropeptides are not good drugs. They have limited bioavailability by oral administration, are metabolized quickly in the circulation, and achieve limited access to brain receptors. Intravenous oxytocin with a plasma half-life of about 3 minutes is effective for inducing uterine contraction but not as a central agent. Intranasal administration improves central bioavailability, but dose is difficult to regulate or replicate via this route (7). With opiates, access to a nonpeptide agonist-like morphine has allowed rigorous investigation in humans and experimental animals. However, with oxytocin, developing a nonpeptide agonist has proven challenging, with compounds that are selective for the oxytocin receptor in one species appearing selective for the V1a receptor in another. WAY- 267464 was developed as a selective, nonpeptide agonist with good brain penetration for oxytocin receptors (8), but more recent data have called its selectivity into question (9), and selectivity in humans has yet to be demonstrated”
New requirements for clinical trials
NIMH now requires demonstrating “target engagement” which means evidence of activation of a proposed mechanism (eg oxytocin activates oxytocin receptors in the brain).
“The NIMH no longer accepts unsolicited trials. To improve the rigor and reproducibility of clinical trials, each study must demonstrate target engagement, which means evidence of activation of a proposed mechanism at a clinically effective dose.”
Target engagement evidence will help failed trials distinguish between insufficient dose or insufficient efficacy, which will make trials more informative.
“Why is the NIMH so demanding about target engagement? Ideally, clinical trials should be equally informative with either positive or negative effects of the intervention. If the compound lacks efficacy, without a measure of target engagement, there is no way to distinguish insufficient dose from insufficient efficacy. As a result, most negative trials fail to falsify a hypothesis, are not informative, and never get published. The implicit bias toward positive results leads to reports of efficacy that frequently are not replicable in phase 3 trials (10). Even with positive outcomes, the effective dose may not be clearly defined. Dose may be especially difficult to control with intranasal administration, so these issues are more germane for oxytocin, where randomized, double-blind trials are giving very mixed results for schizophrenia and autism (see other articles in this issue).”
Early signs of human oxytocin research are promising, so we should continue to investigate the target and dosage to make clinical trials more effective.
“A considerable literature describes effects of intranasal oxytocin on social cognition in humans. Before this literature can be translated into clinical trials for patients with social deficits, we need to know the target of intranasal oxytocin and carefully consider the dosage needed for target engagement. In the absence of dose effects with target engagement, negative results would not be interpretable, and positive results may not be reproducible. A safe, effective prosocial compound could have high value for people with social deficits. Although there has been great hope that intranasal oxytocin could be the answer, a nonpeptide agonist might ultimately offer greater efficacy”