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Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish

Published online by Cambridge University Press:  26 January 2015

Lewis A. Opler ,
Mark G. A. Opler  and
Amy F. T. Arnsten
Lewis A. Opler
Affiliation:
Department of Psychiatry, Columbia University Medical Center, New York, New York, USA
Mark G. A. Opler
Affiliation:
Department of Psychiatry, Columbia University Medical Center, New York, New York, USA Department of Psychiatry, New York University School of Medicine, New York, New York, USA ProPhase LLC, New York, New York, USA
Amy F. T. Arnsten*
Affiliation:
Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA
*
*Address for correspondence: Amy F. T. Arnsten, PhD, Dept. Neurobiology, Yale Medical School, 333 Cedar St., New Haven, CT 06510, USA. (Email: amy.arnsten@yale.edu)
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Abstract

This article reviews the antidepressant actions of ketamine, an N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a potential neural mechanism for intranasal ketamine’s ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5–40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (eg, Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia.

Keywords

Antidepressantarea 25glutamateprefrontal cortexrTMS
Type
Review Article
Information
CNS Spectrums , Volume 21 , Issue 1 , February 2016 , pp. 12 - 22
Copyright
© Cambridge University Press 2015 

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Footnotes

This work is dedicated to the memory of Daniel Friedland, with the hope that we may discover more effective treatments to alleviate suffering. This work was funded in part by NIH Pioneer Award DP1AG047744 to AFTA. The authors would like to thank Drs. G. Aghajanian, R. Duman, J. Krystal, H. Mayberg, J. Murrough, G. Sanacora, and J. Singh for informative and inspiring discussions.

References

1. Reich, DL, Silvay, G. Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth. 1989; 36(2): 186–197.Google Scholar
2. Andolfatto, G, Willman, E, Joo, D, et al. Intranasal ketamine for analgesia in the emergency department: a prospective observational series. Acad Emerg Med. 2013; 20(10): 1050–1054.Google Scholar
3. McCarty, EC, Mencio, GA, Walker, LA, Green, NE. Ketamine sedation for the reduction of children’s fractures in the emergency department. J Bone Joint Surg Am. 2000; 82–A(7): 912–918.Google Scholar
4. Anis, NA, Berry, SC, Burton, NR, Lodge, D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurons by n-methyl-aspartate. Br J Pharmacol. 1983; 79(2): 565–575.Google Scholar
5. Moretti, RJ, Hassan, SZ, Goodman, LI, Meltzer, HY. Comparison of ketamine and thiopental in healthy volunteers: effects on mental status, mood, and personality. Anesth Analg. 1984; 63(12): 1087–1096.CrossRefGoogle ScholarPubMed
6. Skolnick, P, Layer, RT, Popik, P, et al. Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry. 1996; 29(1): 23–26.Google Scholar
7. Fava, M, Rush, AJ, Wisniewski, SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry. 2006; 163(7): 1161–1172.Google Scholar
8. Berman, RM, Cappiello, A, Anand, A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000; 47(4): 351–354.Google Scholar
9. Zarate, CAJ, Singh, JB, Carlson, PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006; 63(8): 856–864.CrossRefGoogle ScholarPubMed
10. DiazGranados, N, Ibrahim, LA, Brutsche, NE, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010; 71(12): 1605–1611.Google Scholar
11. aan het Rot, M, Collins, KA, Murrough, JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010; 67(2): 139–145.Google Scholar
12. Lapidus, KA, Levitch, CF, Perez, AM, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry. In press. DOI: 10.1016/j.biopsych.2014.03.026.Google Scholar
13. Opler, LA, Opler, MG, Arnsten, AFT. Ultrarapid response to intranasal ketamine in outpatients with long-term treatment-refractory depression. Unpublished results.Google Scholar
14. Duman, RS, Aghajanian, GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012; 338(6103): 68–72.Google Scholar
15. Li, N, Lee, BT, Liu, RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010; 329(5994): 959–964.Google Scholar
16. Orser, BA, Pennefather, PS, MacDonald, JF. Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors. Anesthesiology. 1997; 86(4): 903–917.Google Scholar
17. Erreger, K, Dravid, SM, Banke, TG, et al. Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles. J Physiol. 2005; 563(Pt 2): 345–358.Google Scholar
18. Liu, HT, Hollmann, MW, Liu, WH, Hoenemann, CW, Durieux, ME. Modulation of NMDA receptor function by ketamine and magnesium: Part I. Anesth Analg. 2001; 92(5): 1173–1181.Google Scholar
19. Murray, EA, Wise, SP, Drevets, WC. Localization of dysfunction in major depressive disorder: prefrontal cortex and amygdala. Biol Psychiatry. 2011; 69(12): e43–e54.Google Scholar
20. Mayberg, HS, Lozano, AM, Voon, V, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005; 45(5): 651–660.Google Scholar
21. Goldman-Rakic, PS. The prefrontal landscape: implications of functional architecture for understanding human mentation and the central executive. Philos Trans R Soc Lond. 1996; 351(1346): 1445–1453.Google Scholar
22. Goldman-Rakic, PS. Circuitry of the primate prefrontal cortex and the regulation of behavior by representational memory. In: Plum F. ed. Handbook of Physiology, the Nervous System, Higher Functions of the Brain. Bethesda, MD: American Physiological Society; 1987: 373–417.Google Scholar
23. Ongür, D, Price, JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex. 2000; 10(3): 206–219.Google Scholar
24. Ghashghaei, HT, Barbas, H. Pathways for emotion: interactions of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey. Neuroscience. 2002; 115(4): 1261–1279.Google Scholar
25. Barbas, H, Medalla, M, Alade, O, et al. Relationship of prefrontal connections to inhibitory systems in superior temporal areas in the rhesus monkey. Cereb Cortex. 2005; 15(9): 1356–1370.Google Scholar
26. Arnsten, AFT, Wang, M, Paspalas, CD. Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses. Neuron. 2012; 76(1): 223–239.Google Scholar
27. Barbas, H, Saha, S, Rempel-Clower, N, Ghashghaei, T. Serial pathways from primate prefrontal cortex to autonomic areas may influence emotional expression. BMC Neurosci. 2003; 4: 25.Google Scholar
28. Amodio, DM, Frith, CD. Meeting of minds: the medial frontal cortex and social cognition. Nat Rev Neurosci. 2006; 7(4): 268–277.Google Scholar
29. Seo, H, Lee, D. Behavioral and neural changes after gains and losses of conditioned reinforcers. J Neurosci. 2009; 29(11): 3627–3641.CrossRefGoogle ScholarPubMed
30. Funahashi, S, Bruce, CJ, Goldman-Rakic, PS. Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. J Neurophysiol. 1989; 61(2): 331–349.Google Scholar
31. Drevets, WC, Price, JL, Simpson, JRJ, et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997; 386(6627): 824–827.CrossRefGoogle ScholarPubMed
32. Mayberg, HS. Targeted electrode-based modulation of neural circuits for depression. J Clin Invest. 2009; 119(4): 717–725.Google Scholar
33. Dobbs, D. A depression switch? New York Times Magazine. April 2, 2006. http://www.nytimes.com/2006/04/02/magazine/02depression.html?pagewanted=all&_r=0.Google Scholar
34. Vogt, BA, Sikes, RW. The medial pain system, cingulate cortex, and parallel processing of nociceptive information. Prog Brain Res. 2000; 22: 223–235.Google Scholar
35. Bushnell, MC, Ceko, M, Low, LA. Cognitive and emotional control of pain and its disruption in chronic pain. Nat Rev Neurosci. 2013; 14(7): 502–511.Google Scholar
36. Willis, WD, Al-Chaer, ED, Quast, MJ, Westlund, KN. A visceral pain pathway in the dorsal column of the spinal cord. Proc Natl Acad Sci U S A. 1999; 96(14): 7675–7679.Google Scholar
37. Willis, WD, Westlund, KN. Neuroanatomy of the pain system and of the pathways that modulate pain. J Clin Neurophysiol. 1997; 14(1): 2–31.CrossRefGoogle ScholarPubMed
38. Price, DD. Psychological and neural mechanisms of the affective dimension of pain. Science. 2000; 288(5472): 1769–1772.Google Scholar
39. Yan, N, Cao, B, Xu, J, Hao, C, Zhang, X, Li, Y. Glutamatergic activation of anterior cingulate cortex mediates the affective component of visceral pain memory in rats. Neurobiol Learn Mem. 2012; 97(1): 156–164.Google Scholar
40. Monosov, IE, Hikosaka, O. Regionally distinct processing of rewards and punishments by the primate ventromedial prefrontal cortex. J Neurosci. 2012; 32(30): 10318–10330.Google Scholar
41. Ghashghaei, HT, Hilgetag, CC, Barbas, H. Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala. Neuroimage. 2007; 34(3): 905–923.Google Scholar
42. Davis, M. The role of the amygdala in fear and anxiety. Annu Rev Neurosci. 1992; 15: 353–375.Google Scholar
43. LeDoux, J. Fear and the brain: where have we been and where are we going? Biol Psychiatry. 1998; 44(12): 1229–1238.Google Scholar
44. Carmel, PW. Vegetative dysfunctions of the hypothalamus. Acta Neurochir (Wien). 1985; 75(1–4): 113–121.Google Scholar
45. Everitt, BJ, Belin, D, Economidou, D, et al. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction. Philos Trans R Soc Lond B Biol Sci. 2008; 363(1507): 3125–3135.Google Scholar
46. Neafsey, EJ. Prefrontal control of the autonomic nervous system: anatomical and physiological observations. Prog Brain Res. 1990; 85: 147–165.Google Scholar
47. Maeng, S, Zarate, CAJ. The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Curr Psychiatry Rep. 2007; 9(6): 467–474.Google Scholar
48. McCarthy, DJ, Alexander, R, Smith, MA, et al. Glutamate-based depression GBD. Med Hypotheses. 2012; 78(5): 675–681.Google Scholar
49. Salvadore, G, Cornwell, BR, Colon-Rosario, V, et al. Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine. Biol Psychiatry. 2009; 65(4): 289–295.CrossRefGoogle Scholar
50. Nugent, AC, Diazgranados, N, Carlson, PJ, et al. Neural correlates of rapid antidepressant response to ketamine in bipolar disorder. Bipolar Disord. 2014; 16(2): 119–128.CrossRefGoogle ScholarPubMed
51. Deakin, JF, Lees, J, McKie, S, et al. Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study. Arch Gen Psychiatry. 2008; 65(2): 154–164.Google Scholar
52. Carlson, PJ, Diazgranados, N, Nugent, AC, et al. Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: a preliminary positron emission tomography study. Biol Psychiatry. 2013; 73(12): 1213–1221.Google Scholar
53. Hikosaka, O. The habenula: from stress evasion to value-based decision-making. Nat Rev Neurosci. 2010; 11(7): 503–513.Google Scholar
54. Fan, J, Wu, X, Cao, Z, et al. Up-regulation of anterior cingulate cortex NR2B receptors contributes to visceral pain responses in rats. Gastroenterology. 2009; 136(5): 1732–1740.CrossRefGoogle ScholarPubMed
55. Zhou, L, Huang, J, Gao, J, Zhang, G, Jiang, J. NMDA and AMPA receptors in the anterior cingulate cortex mediates visceral pain in visceral hypersensitivity rats. Cell Immunol. 2014; 287(2): 86–90.Google Scholar
56. Wang, M, Yang, Y, Wang, CJ, et al. NMDA receptors subserve working memory persistent neuronal firing In dorsolateral prefrontal cortex. Neuron. 2013; 77(4): 736–749.Google Scholar
57. Goldman-Rakic, PS. Cellular basis of working memory. Neuron. 1995; 14(3): 477–485.Google Scholar
58. Wang, H, Stradtman, GG 3rd, Wang, XJ, Gao, WJ. A specialized NMDA receptor function in layer 5 recurrent microcircuitry of the adult rat prefrontal cortex. Proc Natl Acad Sci U S A. 2008; 105(43): 16791–16796.CrossRefGoogle ScholarPubMed
59. Patel, RB, Patel, MR, Bhatt, KK, Patel, BG, Gaikwad, RV. Evaluation of brain targeting efficiency of intranasal microemulsion containing olanzapine: pharmacodynamic and pharmacokinetic consideration. Drug Deliv. In press. DOI: 10.3109/10717544.2014.912694.Google Scholar
60. Wei, Y, Ying, M, Xu, S, et al. Microdialysis pharmacokinetic study of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration. Drug Deliv. In press. DOI: 10.3109/10717544.2014.910565.Google Scholar
61. Arnsten, AFT. The biology of feeling frazzled. Science. 1998; 280(5370): 1711–1712.CrossRefGoogle Scholar
62. Arnsten, AFT. Stress signaling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci. 2009; 10(6): 410–422.Google Scholar
63. Qin, S, Hermans, EJ, van Marle, HJF, et al. Acute psychological stress reduces working memory-related activity in the dorsolateral prefrontal cortex. Biol Psychiatry. 2009; 66(1): 25–32.Google Scholar
64. Vyas, A, Mitra, R, Shankaranarayana Rao, BS, Chattarji, S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci. 2002; 22(15): 6810–6818.Google Scholar
65. Radley, JJ, Rocher, AB, Miller, M, et al. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex. 2006; 16(3): 313–320.Google Scholar
66. Izquierdo, A, Wellman, CL, Holmes, A. Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice. J Neurosci. 2006; 26(21): 5733–5738.Google Scholar
67. Hains, AB, Vu, MA, Maciejewski, PK, et al. Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress. Proc Natl Acad Sci U S A. 2009; 106(42): 17957–17962.Google Scholar
68. Shansky, RM, Hamo, C, Hof, PR, McEwen, BS, Morrison, JH. Stress-induced dendritic remodeling in the prefrontal cortex is circuit specific. Cereb Cortex. 2009; 19(10): 2479–2484.Google Scholar
69. Liu, RJ, Lee, FS, Li, XY, et al. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry. 2012; 71(11): 996–1005.Google Scholar
70. Liu, RJ, Fuchikami, M, Dwyer, JM, et al. GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology. 2013; 38(11): 2268–2277.Google Scholar
71. Barbas, H, Pandya, DN. Architecture and intrinsic connections of the prefrontal cortex in the rhesus monkey. J Comp Neurol. 1989; 286(3): 353–375.Google Scholar
72. Selemon, LD, Goldman-Rakic, PS. Common cortical and subcortical targets of the dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey: evidence for a distributed neural network subserving spatially guided behavior. J Neurosci. 1988; 8(11): 4049–4068.Google Scholar
73. Riva-Posse, P, Choi, KS, Holtzheimer, PE, et al. Defining critical white matter pathways mediating successful subcallosal cingulate deep brain stimulation for treatment-resistant depression. Biol Psychiatry. In press. DOI: 10.1016/j.biopsych.2014.03.029.Google Scholar
74. Ochsner, KN, Silvers, JA, Buhle, JT. Functional imaging studies of emotion regulation: a synthetic review and evolving model of the cognitive control of emotion. Ann N Y Acad Sci. 2012; 1251: E1–24.Google Scholar
75. Heatherton, TF, Wyland, CL, Macrae, CN, Demos, KE, Denny, BT, Kelley, WM. Medial prefrontal activity differentiates self from close others. Soc Cogn Affect Neurosci. 2006; 1(1): 18–25.Google Scholar
76. Robinson, RG, Lipsey, JR, Bolla-Wilson, K, et al. Mood disorders in left-handed stroke patients. Am J Psychiatry. 1985; 142(12): 1424–1429.Google ScholarPubMed
77. Blumberg, HP, Stern, E, Ricketts, S, et al. Rostral and orbital prefrontal cortex dysfunction in the manic state of bipolar disorder. Am J Psychiatry. 1999; 156(12): 1986–1988.Google Scholar
78. Aron, AR. From reactive to proactive and selective control: developing a richer model for stopping inappropriate responses. Biol Psychiatry. 2011; 69(12): e55–e68.Google Scholar
79. Chen, J, Zhou, C, Wu, B, et al. Left versus right repetitive transcranial magnetic stimulation in treating major depression: a meta-analysis of randomised controlled trials. Psychiatry Res. 2013; 210(3): 1260–1264.Google Scholar
80. Fox, MD, Buckner, RL, White, MP, et al. Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate. Biol Psychiatry. 2012; 72(7): 595–603.Google Scholar
81. Kito, S, Hasegawa, T, Koga, Y. Cerebral blood flow in the ventromedial prefrontal cortex correlates with treatment response to low-frequency right prefrontal repetitive transcranial magnetic stimulation in the treatment of depression. Psychiatry Clin Neurosci. 2012; 66(2): 138–145.Google Scholar
82. Krystal, JH, Sanacora, G, Duman, RS. Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry. 2013; 73(12): 1133–1141.Google Scholar
83. Javitt, DC. Glutamatergic theories of schizophrenia. Isr J Psychiatry Relat Sci. 2010; 47(1): 4–16.Google Scholar
84. Driesen, NR, McCarthy, G, Bhagwagar, Z, et al. The impact of NMDA receptor blockade on human working memory-related prefrontal function and connectivity. Neuropsychopharmacology. 2013; 38(13): 2613–2622.Google Scholar