See case report by Wink et al

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Does the Clinical Benefit of Ketamine Treatment Offer Any Clues to Autism Spectrum Disorder Etiology?

To the Editor: Wink et al1 reported the first case study demonstrating clinical improvement in mood and eye fixation scores from intranasal ketamine treatment in a “complicated” subject with autism spectrum disorder (ASD). Arnold et al2 recently highlighted perioperative differences among patients with or without ASD, finding that the most salient difference was the use of premedication types. ASD patients were 3 times more likely to use nonstandard premedicants (eg, intramuscular ketamine) versus standard medications (eg, midazolam). These studies suggest that ketamine, regardless of its delivery, may exert positive benefit in stressed ASD subjects, although the mechanism underlying this pharmacologic benefit is less clear, particularly given the oculomotor impairment often observed after ketamine administration, including gaze-evoked nystagmus.3–5

Consistent with other epidemiologic studies6 suggesting an association between air pollution and ASD, I have previously proposed that early gestational exposure to the environmental air pollutant nitrous oxide (N2O) may be the underlying etiology of ASD and similar neurodevelopmental conditions.7 Others have noted that the μ-receptor agonist sufentanil relieved impairments in human lung function attributable to exposure to ozone, suggesting opioidergic activity may modulate the physiological response to similar air pollution exposures.8

Ketamine is similar to N2O in terms of its physiological targets, including acting as both a κ-opioid receptor (KOR) full agonist and an N-methyl-d-aspartate (NMDA) receptor antagonist.9 NMDA receptor antagonism has been shown to mitigate physical opiate dependence10; however, a psychological desire to seek the drug may persist given the drug’s targeting of KORs,11 confirming the involvement of multiple neurochemical substrates in the effects of N2O exposure. KORs may be particularly relevant in ASD given that the receptor functionality remains intact in the μ-receptor knockout mice,12 a genotype that displays autistic-like social deficits.13

Interestingly, Richardson and Shelton14 were unable to demonstrate N2O-like stimulus effects from midazolam administration, further supporting the hypothesis that nonstandard medications, like ketamine, may be preferentially used during stressful experiences in ASD populations due to their outstanding N2O mimicry and satiation of an amplified dynorphin/KOR system developed in utero. Additional research is needed to understand which physiological mechanisms may be able to explain the increased use of nonstandard premedications, like ketamine, in ASD populations, as found by Wink et al1 and Arnold et al.2

References

1. Wink LK, O’Melia AM, Shaffer RC, et al. Intranasal ketamine treatment in an adult with autism spectrum disorder. J Clin Psychiatry. 2014;75(8):835–836. PubMed doi:10.4088/JCP.13cr08917

2. Arnold B, Elliott A, Laohamroonvorapongse D, et al. Autistic children and anesthesia: is their perioperative experience different? Paediatr Anaesth. 2015;25(11):1103–1110. PubMed doi:10.1111/pan.12739

3. Condy C, Wattiez N, Rivaud-Péchoux S, et al. Ketamine-induced distractibility: An oculomotor study in monkeys. Biol Psychiatry. 2005;57(4):366–372. PubMed doi:10.1016/j.biopsych.2004.10.036

4. Godaux E, Cheron G, Mettens P. Ketamine induces failure of the oculomotor neural integrator in the cat. Neurosci Lett. 1990;116(1-2):162–167. PubMed doi:10.1016/0304-3940(90)90403-V

5. Radant AD, Bowdle TA, Cowley DS, et al. Does ketamine-mediated N-methyl-D-aspartate receptor antagonism cause schizophrenia-like oculomotor abnormalities? Neuropsychopharmacology. 1998;19(5):434–444. PubMed doi:10.1016/S0893-133X(98)00030-X

6. Volk HE, Lurmann F, Penfold B, et al. Traffic-related air pollution, particulate matter, and autism. JAMA Psychiatry. 2013;70(1):71–77. PubMed doi:10.1001/jamapsychiatry.2013.266

7. Fluegge K. Prenatal antidepressant use and risk of autism spectrum disorders in children [Comment & Response] [published online May 31, 2016]. JAMA Pediatr. PubMed doi:10.1001/jamapediatrics.2016.0739

8. Passannante AN, Hazucha MJ, Bromberg PA, et al. Nociceptive mechanisms modulate ozone-induced human lung function decrements. J Appl Physiol (1985). 1998;85(5):1863–1870. PubMed

9. Nemeth CL, Paine TA, Rittiner JE, et al. Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats. Psychopharmacology (Berl). 2010;210(2):263–274. PubMed doi:10.1007/s00213-010-1834-7

10. Bisaga A, Comer SD, Ward AS, et al. The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans. Psychopharmacology (Berl). 2001;157(1):1–10. PubMed doi:10.1007/s002130100739

11. Chavkin C, Ehrich JM. How does stress-induced activation of the kappa opioid system increase addiction risk? Biol Psychiatry. 2014;76(10):760–762. PubMed doi:10.1016/j.biopsych.2014.08.015

12. Kitchen I, Slowe SJ, Matthes HW, et al. Quantitative autoradiographic mapping of mu-, delta- and kappa-opioid receptors in knockout mice lacking the mu-opioid receptor gene. Brain Res. 1997;778(1):73–88. PubMed doi:10.1016/S0006-8993(97)00988-8

13. Wöhr M, Moles A, Schwarting RK, et al. Lack of social exploratory activation in male μ-opioid receptor KO mice in response to playback of female ultrasonic vocalizations. Soc Neurosci. 2011;6(1):76–87. PubMed doi:10.1080/17470911003765560

14. Richardson KJ, Shelton KL. N-methyl-D-aspartate receptor channel blocker-like discriminative stimulus effects of nitrous oxide gas. J Pharmacol Exp Ther. 2015;352(1):156–165. PubMed doi:10.1124/jpet.114.218057

Keith Fluegge, BAa

keithfluegge@gmail.com

aInstitute of Health and Environmental Research, Cleveland, Ohio

Potential conflicts of interest: None.

Funding/support: None.

J Clin Psychiatry 2016;77(7):e903

dx.doi.org/10.4088/JCP.16lr10663

© Copyright 2016 Physicians Postgraduate Press, Inc.