- Email: [email protected]
Improving Research Standards to Restore Trust in Intranasal Oxytocin
Correspondence Improving Research Standards to Restore Trust in Intranasal Oxytocin To the Editor: Leng and Ludwig (1) provide the much needed first step toward an open discussion regarding the quality of intranasal oxytocin research in humans. They further highlight a clear knowledge gap in the pharmacology of intranasal drug delivery. We provide pragmatic solutions for improving research standards in this field and outline extensive evidence supporting intranasal delivery of large molecules to the brain. In the mid-1990s, the World Health Organization and International Conference on Harmonisation published detailed Good Clinical Practice (GCP) guidelines (2,3). These guidelines ensure that drug treatment trials in humans maintain the highest ethical and scientific standards. Given the extraordinary financial stakes in commercial drug development, industry sponsors typically maintain great rigor in their implementation of GCP. Before they consider granting marketing approval, regulatory bodies thoroughly scrutinize industry-sponsored research to ensure the studies are adequately powered, define eligibility criteria and outcome measures a priori, and use rigorous statistical analysis plans. Investigator-initiated clinical trials are typically more exploratory in nature and often do not fully adhere to GCP guidelines. The ethics committees and regulatory bodies that approve these protocols are mostly concerned with the safety of experimental drugs and generally do not provide detailed guidance on study design and governance. To date, there have been no sponsor-initiated clinical trials investigating the neurocognitive effects of intranasal oxytocin in humans. This is largely because oxytocin is a generic molecule; without strong “method of use” or “composition of matter” patent protection, there is little incentive for commercial organizations to conduct research in this space. It is the responsibility of funding bodies and academic scientists to ensure investigator-initiated clinical trials of intranasal oxytocin are adequately powered and strictly conform to GCP. Scientific and medical journals should also ensure that this research strictly conforms to Consolidated Standards of Reporting Trials (4) and International Committee of Medical Journal Editors (5) guidelines so that all aspects of trial methodology are clearly outlined before manuscripts are published. Despite the aforementioned criticisms, investigator-initiated clinical research generally maintains a much higher standard than preclinical animal research. Preclinical scientists never pre-register studies, rarely conduct formal power analyses, typically do not outline eligibility criteria or outcome measures a priori, use inadequate or no blinding techniques, frequently use incorrect statistical analyses, and are notoriously protective of their data sets. The impact of these low research standards is catastrophic, with recent estimates of irreproducible preclinical research costing an astronomical 28,000,000,000 USD per year in the United States alone (6). Additionally, .90% of preclinical behavioral neuroscience research fails to translate to humans, largely because of poor
Biological Psychiatry
research standards (7). In order to improve these dire statistics, the US National Institutes of Health recently published a list of Principles and Guidelines for Reporting Preclinical Research (8). However, to date, conformance to these principles and guidelines from preclinical scientists and the journals that publish their research has been abysmal (6). Despite these concerning issues, many of the complex neurocognitive effects of centrally administered oxytocin in animal models have been successfully replicated in animals and translated to humans with intranasal oxytocin. For example, Calcagnoli et al. (9) recently demonstrated potent anti-aggressive and prosocial effects in rats after central administration of oxytocin, and these effects were replicated with intranasal delivery. Recent human research also provides strong support for the effects of intranasal oxytocin on the brain and behavior. For example, in a with-in group functional neuroimaging study of autism (n 5 40), intranasal oxytocin robustly restored medial prefrontal activity (Cohen’s d 5 1.1), and prosocial behavioral outcomes maintained medium to large effects (Cohen’s d . .5) (10). With functional studies, any observed effects are uniquely confined to the neural network engaged in a given task. More recent resting-state studies circumvent this issue by showing that intranasal oxytocin also has a significant modulatory effect on resting-state brain activity in healthy participants (11) and subjects with social anxiety disorder (12). However, functional and structural neuroimaging techniques are a poor proxy for direct neurochemical activity. Due to human safety concerns with current radiochemistry techniques, we must rely on preclinical pharmacology to understand the neuropharmacokinetics of intranasal oxytocin. Following the seminal work of Frey and Thorne in the mid1990s, many groups now outline strong evidence that intranasal delivery of large molecules rapidly results in 1) olfactory bulb and rostral brain region penetration via the peripheral olfactory system and 2) brainstem and spinal cord penetration via the peripheral trigeminal system (13). Leng and Ludwig (1) dismiss the ability of intranasal oxytocin to reach the brain, outlining evidence that only .005% of intranasal oxytocin reaches the cerebrospinal fluid (CSF) within 1 hour. However, although CSF drug concentration generally correlates with brain tissue drug concentration after systemic administration, such a correlation does not apply to the intranasal route. In contrast to systemic delivery that follows the slow diffusion pathway from blood vessels into brain tissue, intranasal delivery of large molecules permeates the nasal epithelium and rapidly ( 10 min) enters the olfactory and trigeminal systems, where it reaches widespread brain areas via convective bulk transport within the perivascular space of the cerebrovasculature (13). Intranasal delivery of large-molecularweight biologics (e.g., proteins, gene vectors, stem cells) results in substantial and widespread distribution in brain tissue but with minimal accumulation in CSF or blood. Furthermore, intranasal delivery allows for not only faster transport kinetics but also greater transport quantity to brain tissue than systemic delivery. Thorne et al. (14) showed that intranasal, but not intravenous, delivery of iodinated insulin-like
SEE COMMENTARY ON PAGE
http://dx.doi.org/10.1016/j.biopsych.2015.08.031 ISSN: 0006-3223
e1 & 2015 Society of Biological Psychiatry Biological Psychiatry ]]], 2015; ]:]]]–]]] www.sobp.org/journal
Biological Psychiatry
growth factor-I ( 7.65 kDa) results in significant and rapid (,30 min) brain penetration via olfactory and trigeminal extracellular pathways. Dhuria et al. (15) showed that intranasal hypocretin (3.5 kDa) results in 10-fold lower blood concentrations compared with intravenous administration and leads to significantly greater tissue-to-blood concentrations in all brain regions measured over 2 hours. They additionally showed that the concentration of hypocretin in trigeminal nerves and olfactory bulbs was much higher than the hypocretin concentration in cisternal CSF 30 min after intranasal delivery. Direct evidence outlining the whole-body pharmacokinetics of intranasal radiolabeled oxytocin in animals and humans is urgently needed. Dean S. Carson Hsiangkuo Yuan Izelle Labuschagne
3.
4. 5.
6. 7.
8.
9.
Acknowledgments and Disclosures DSC is an employee of Trigemina, Inc. The opinions expressed here do not necessarily reflect the views or positions of Trigemina, Inc. HY and IL report no biomedical financial interests or potential conflicts of interest.
Article Information From the Department of Psychiatry and Behavioral Sciences (DSC), Stanford University School of Medicine, Palo Alto, California; Department of Neurology (HY), Thomas Jefferson University, Philadelphia, Pennsylvania; and School of Psychology (IL), Australian Catholic University, Melbourne, Australia. Address correspondence to Dean S. Carson, Ph.D., Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Palo Alto, CA 94305; E-mail: [email protected]. See also associated correspondence, http://dx.doi.org/10.1016/j.biop sych.2015.08.030.
10.
11.
12.
13. 14.
References 1. 2.
e2
Leng G, Ludwig M (2015): Intranasal oxytocin: myths and delusions. Biol Psychiatry. International Conference on Harmonisation: Good clinical practice. Consolidated guideline 1996. Available at: http://www.ich.org/.
Biological Psychiatry ]]], 2015; ]:]]]–]]] www.sobp.org/journal
15.
World Health Organization (1995): Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. Annex 3 of The Use of Essential Drugs Sixth Report of the WHO Expert Committee. Geneva: Available at: http://www.who.int/medicines/en/. Rennie D (2001): CONSORT revised—improving the reporting of randomized trials. JAMA 273:408–412. The International Committee of Medical Journal Editors (2013): Recommendations for the conduct, reporting, editing and publication of scholarly work in medical journals. Available at: http://www.icmje. org. Freedman LP, Cockburn IM, Simcoe TS (2015): The economics of reproducibility in preclinical research. PloS Biol 13:e1002165. Garner JP (2014): The significance of meaning: Why do over 90% of behavioral neuroscience results fail to translate to humans, and what can we do to fix it? Ilar J 55:438–456. National Institutes of Health (2014): Proposed principles and guidelines for reporting preclinical research. Available at: http://www.nih. gov/about/reporting-preclinical-research.htm. Calcagnoli F, Kreutzmann JC, de Boer SF, Althaus M, Koolhaas JM (2015): Acute and repeated intranasal oxytocin administration exerts anti-aggressive and pro-affiliative effects in male rats. Psychoneuroendocrinology 51:112–121. Watanabe T, Abe O, Kuwabara H, Yahata N, Takano Y, Iwashiro N, et al. (2014): Mitigation of sociocommunicational deficits of autism through oxytocin-induced recovery of medial prefrontal activity: A randomized trial. JAMA Psychiatry 71:166–175. Sripada CS, Phan KL, Labuschagne I, Welsh R, Nathan PJ, Wood AG (2013): Oxytocin enhances resting-state connectivity between amygdala and medial frontal cortex. Int J Neuropsychopharmacol 16: 255–260. Dodhia S, Hosanagar A, Fitzgerald DA, Labuschagne I, Wood AG, Nathan PJ, et al. (2014): Modulation of resting-state amygdala-frontal functional connectivity by oxytocin in generalized social anxiety disorder. Neuropsychopharmacology 39:2061–2069. Lochhead JJ, Thorne RG (2012): Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 64:614–628. Thorne RG, Pronk GJ, Padmanabhan V, Frey WH (2004): Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 127:481–496. Dhuria SV, Hanson LR, Frey WH II (2009): Novel vasoconstrictor formulation to enhance intranasal targeting of neuropeptide therapeutics to the central nervous system. J Pharmacol Exp Ther 328: 312–320.
Biological Psychiatry
research standards (7). In order to improve these dire statistics, the US National Institutes of Health recently published a list of Principles and Guidelines for Reporting Preclinical Research (8). However, to date, conformance to these principles and guidelines from preclinical scientists and the journals that publish their research has been abysmal (6). Despite these concerning issues, many of the complex neurocognitive effects of centrally administered oxytocin in animal models have been successfully replicated in animals and translated to humans with intranasal oxytocin. For example, Calcagnoli et al. (9) recently demonstrated potent anti-aggressive and prosocial effects in rats after central administration of oxytocin, and these effects were replicated with intranasal delivery. Recent human research also provides strong support for the effects of intranasal oxytocin on the brain and behavior. For example, in a with-in group functional neuroimaging study of autism (n 5 40), intranasal oxytocin robustly restored medial prefrontal activity (Cohen’s d 5 1.1), and prosocial behavioral outcomes maintained medium to large effects (Cohen’s d . .5) (10). With functional studies, any observed effects are uniquely confined to the neural network engaged in a given task. More recent resting-state studies circumvent this issue by showing that intranasal oxytocin also has a significant modulatory effect on resting-state brain activity in healthy participants (11) and subjects with social anxiety disorder (12). However, functional and structural neuroimaging techniques are a poor proxy for direct neurochemical activity. Due to human safety concerns with current radiochemistry techniques, we must rely on preclinical pharmacology to understand the neuropharmacokinetics of intranasal oxytocin. Following the seminal work of Frey and Thorne in the mid1990s, many groups now outline strong evidence that intranasal delivery of large molecules rapidly results in 1) olfactory bulb and rostral brain region penetration via the peripheral olfactory system and 2) brainstem and spinal cord penetration via the peripheral trigeminal system (13). Leng and Ludwig (1) dismiss the ability of intranasal oxytocin to reach the brain, outlining evidence that only .005% of intranasal oxytocin reaches the cerebrospinal fluid (CSF) within 1 hour. However, although CSF drug concentration generally correlates with brain tissue drug concentration after systemic administration, such a correlation does not apply to the intranasal route. In contrast to systemic delivery that follows the slow diffusion pathway from blood vessels into brain tissue, intranasal delivery of large molecules permeates the nasal epithelium and rapidly ( 10 min) enters the olfactory and trigeminal systems, where it reaches widespread brain areas via convective bulk transport within the perivascular space of the cerebrovasculature (13). Intranasal delivery of large-molecularweight biologics (e.g., proteins, gene vectors, stem cells) results in substantial and widespread distribution in brain tissue but with minimal accumulation in CSF or blood. Furthermore, intranasal delivery allows for not only faster transport kinetics but also greater transport quantity to brain tissue than systemic delivery. Thorne et al. (14) showed that intranasal, but not intravenous, delivery of iodinated insulin-like
SEE COMMENTARY ON PAGE
http://dx.doi.org/10.1016/j.biopsych.2015.08.031 ISSN: 0006-3223
e1 & 2015 Society of Biological Psychiatry Biological Psychiatry ]]], 2015; ]:]]]–]]] www.sobp.org/journal
Biological Psychiatry
growth factor-I ( 7.65 kDa) results in significant and rapid (,30 min) brain penetration via olfactory and trigeminal extracellular pathways. Dhuria et al. (15) showed that intranasal hypocretin (3.5 kDa) results in 10-fold lower blood concentrations compared with intravenous administration and leads to significantly greater tissue-to-blood concentrations in all brain regions measured over 2 hours. They additionally showed that the concentration of hypocretin in trigeminal nerves and olfactory bulbs was much higher than the hypocretin concentration in cisternal CSF 30 min after intranasal delivery. Direct evidence outlining the whole-body pharmacokinetics of intranasal radiolabeled oxytocin in animals and humans is urgently needed. Dean S. Carson Hsiangkuo Yuan Izelle Labuschagne
3.
4. 5.
6. 7.
8.
9.
Acknowledgments and Disclosures DSC is an employee of Trigemina, Inc. The opinions expressed here do not necessarily reflect the views or positions of Trigemina, Inc. HY and IL report no biomedical financial interests or potential conflicts of interest.
Article Information From the Department of Psychiatry and Behavioral Sciences (DSC), Stanford University School of Medicine, Palo Alto, California; Department of Neurology (HY), Thomas Jefferson University, Philadelphia, Pennsylvania; and School of Psychology (IL), Australian Catholic University, Melbourne, Australia. Address correspondence to Dean S. Carson, Ph.D., Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Palo Alto, CA 94305; E-mail: [email protected]. See also associated correspondence, http://dx.doi.org/10.1016/j.biop sych.2015.08.030.
10.
11.
12.
13. 14.
References 1. 2.
e2
Leng G, Ludwig M (2015): Intranasal oxytocin: myths and delusions. Biol Psychiatry. International Conference on Harmonisation: Good clinical practice. Consolidated guideline 1996. Available at: http://www.ich.org/.
Biological Psychiatry ]]], 2015; ]:]]]–]]] www.sobp.org/journal
15.
World Health Organization (1995): Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. Annex 3 of The Use of Essential Drugs Sixth Report of the WHO Expert Committee. Geneva: Available at: http://www.who.int/medicines/en/. Rennie D (2001): CONSORT revised—improving the reporting of randomized trials. JAMA 273:408–412. The International Committee of Medical Journal Editors (2013): Recommendations for the conduct, reporting, editing and publication of scholarly work in medical journals. Available at: http://www.icmje. org. Freedman LP, Cockburn IM, Simcoe TS (2015): The economics of reproducibility in preclinical research. PloS Biol 13:e1002165. Garner JP (2014): The significance of meaning: Why do over 90% of behavioral neuroscience results fail to translate to humans, and what can we do to fix it? Ilar J 55:438–456. National Institutes of Health (2014): Proposed principles and guidelines for reporting preclinical research. Available at: http://www.nih. gov/about/reporting-preclinical-research.htm. Calcagnoli F, Kreutzmann JC, de Boer SF, Althaus M, Koolhaas JM (2015): Acute and repeated intranasal oxytocin administration exerts anti-aggressive and pro-affiliative effects in male rats. Psychoneuroendocrinology 51:112–121. Watanabe T, Abe O, Kuwabara H, Yahata N, Takano Y, Iwashiro N, et al. (2014): Mitigation of sociocommunicational deficits of autism through oxytocin-induced recovery of medial prefrontal activity: A randomized trial. JAMA Psychiatry 71:166–175. Sripada CS, Phan KL, Labuschagne I, Welsh R, Nathan PJ, Wood AG (2013): Oxytocin enhances resting-state connectivity between amygdala and medial frontal cortex. Int J Neuropsychopharmacol 16: 255–260. Dodhia S, Hosanagar A, Fitzgerald DA, Labuschagne I, Wood AG, Nathan PJ, et al. (2014): Modulation of resting-state amygdala-frontal functional connectivity by oxytocin in generalized social anxiety disorder. Neuropsychopharmacology 39:2061–2069. Lochhead JJ, Thorne RG (2012): Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 64:614–628. Thorne RG, Pronk GJ, Padmanabhan V, Frey WH (2004): Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 127:481–496. Dhuria SV, Hanson LR, Frey WH II (2009): Novel vasoconstrictor formulation to enhance intranasal targeting of neuropeptide therapeutics to the central nervous system. J Pharmacol Exp Ther 328: 312–320.