Targeting glutamate signalling in depression: Progress and prospects

Nature Reviews Drug Discovery

Volumn 16, Issue 7, 2017, Pages 472-486

  Murrough, James W ^a   Abdallah, Chadi G ^b   Mathew, Sanjay J ^c  

^a MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^b YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c BAYLOR COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 CHLOROKYNURENINE; AMFEBUTAMONE; AMFEBUTAMONE PLUS DEXTROMETHORPHAN; AMPA RECEPTOR; ANTIDEPRESSANT AGENT; APIMOSTINEL; BASIMGLURANT; CYCLOSERINE; DEUDEXTROMETHORPHAN; DEXTROMETHORPHAN; DEXTROMETHORPHAN PLUS BUPROPION; DIAZOXIDE; GLUTAMIC ACID; KETAMINE; METABOTROPIC RECEPTOR; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; RAPASTINEL; RISLENEMDAZ; SARCOSINE; UNCLASSIFIED DRUG; AMINO ACID RECEPTOR BLOCKING AGENT;

CLINICAL RESEARCH; DISEASE MARKER; DOSE RESPONSE; DRUG EFFECT; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; DRUG TARGETING; HUMAN; MAJOR DEPRESSION; NERVE CELL PLASTICITY; NEUROMODULATION; NONHUMAN; PATIENT SELECTION; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIGNAL TRANSDUCTION; TRANSLATIONAL RESEARCH; ANIMAL; ANTAGONISTS AND INHIBITORS; DEPRESSIVE DISORDER, MAJOR; DRUG DESIGN; DRUG EFFECTS; METABOLISM; PATHOPHYSIOLOGY;

ANIMALS; ANTIDEPRESSIVE AGENTS; DEPRESSIVE DISORDER, MAJOR; DRUG DESIGN; EXCITATORY AMINO ACID ANTAGONISTS; GLUTAMIC ACID; HUMANS; KETAMINE; RECEPTORS, N-METHYL-D-ASPARTATE; SIGNAL TRANSDUCTION;

EID: 85015625732     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd.2017.16     Document Type: Review

References (159)

1. Collins, P. Y., et al. Grand challenges in global mental health. Nature 475, 27-30 (2011).
2. Whiteford, H. A., et al. Global burden of disease attributable to mental and substance use disorders: Findings from the Global Burden of Disease Study 2010. Lancet 382, 1575-1586 (2013).
3. Mrazek, D. A., Hornberger, J. C., Altar, C. A., Degtiar, I. A review of the clinical, economic, societal burden of treatment-resistant depression: 1996-2013. Psychiatr. Serv. 65, 977-987 (2014).
4. Rush, A. J., et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR, D report. Am. J. Psychiatry 163, 1905-1917 (2006).
5. Trivedi, M. H., et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR, D: Implications for clinical practice. Am. J. Psychiatry 163, 28-40 (2006).
6. Abdallah, C. G., Sanacora, G., Duman, R. S., Krystal, J. H. Ketamine and rapid-acting antidepressants: A window into a new neurobiology for mood disorder therapeutics. Annu. Rev. Med. 66, 509-523 (2015).
7. Papakostas, G. I., Ionescu, D. F. Towards new mechanisms: An update on therapeutics for treatment-resistant major depressive disorder. Mol. Psychiatry 20, 1142-1150 (2015).
8. Mathew, S. J. Glycine transporter-I inhibitors: A new class of antidepressant Biol. Psychiatry 74, 710-711 (2013).
9. Berman, R. M., et al. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351-354 (2000).
10. Duman, R. S., Aghajanian, G. K. Synaptic dysfunction in depression: Potential therapeutic targets. Science 338, 68-72 (2012).
11. Morris, R. G., Anderson, E., Lynch, G. S., Baudry, M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-d-aspartate receptor antagonist, AP5. Nature 319, 774-776 (1986).
12. Cole, A. J., Saffen, D. W., Baraban, J. M., Worley, P. F. Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature 340, 474-476 (1989).
13. Hardingham, G. E., Fukunaga, Y., Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405-414 (2002).
14. Stanika, R. I., et al. Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicity. Proc. Natl Acad. Sci. USA 106, 9854-9859 (2009).
15. Hardingham, G. E., Bading, H. Synaptic versus extrasynaptic NMDA receptor signalling: Implications for neurodegenerative disorders. Nat. Rev. Neurosci. 11, 682-696 (2010).
16. Papouin, T., Oliet, S. H. Organization, control and function of extrasynaptic NMDA receptors. Phil. Trans. R. Soc. B 369, 20130601 (2014).
17. Duman, R. S., Monteggia, L. M. A neurotrophic model for stress-related mood disorders. Biol. Psychiatry 59, 1116-1127 (2006).
18. Krishnan, V., Nestler, E. J. The molecular neurobiology of depression. Nature 455, 894-902 (2008).
19. Olney, J. W., Labruyere, J., Price, M. T. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244, 1360-1362 (1989).
20. Olney, J. W., et al. NMDA antagonist neurotoxicity: Mechanism and prevention. Science 254, 1515-1518 (1991).
21. Camacho, A., Massieu, L. Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death. Arch. Med. Res. 37, 11-18 (2006).
22. Fan, M. M., Raymond, L. A. N-Methyl-d-aspartate (NMDA) receptor function and excitotoxicity in Huntington's disease. Prog. Neurobiol. 81, 272-293 (2007).
23. Sanacora, G., Zarate, C. A., Krystal, J. H., Manji, H. K. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat. Rev. Drug Discov. 7, 426-437 (2008).
24. Smoller, J. W. The genetics of stress-related disorders: PTSD, depression, anxiety disorders. Neuropsychopharmacology 41, 297-319 (2016).
25. Nowak, G., Ordway, G. A., Paul, I. A. Alterations in the N-methyl-d-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims. Brain Res. 675, 157-164 (1995).
26. Scarr, E., Pavey, G., Sundram, S., MacKinnon, A., Dean, B. Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder. Bipolar Disord. 5, 257-264 (2003).
27. Nudmamud-Thanoi, S., Reynolds, G. P. The NR1 subunit of the glutamate/NMDA receptor in the superior temporal cortex in schizophrenia and affective disorders. Neurosci. Lett. 372, 173-177 (2004).
28. Karolewicz, B., Stockmeier, C. A., Ordway, G. A. Elevated levels of the NR2C subunit of the NMDA receptor in the locus coeruleus in depression. Neuropsychopharmacology 30, 1557-1567 (2005).
29. McCullumsmith, R. E., et al. Decreased NR1, NR2A, SAP102 transcript expression in the hippocampus in bipolar disorder. Brain Res. 1127, 108-118 (2007).
30. Karolewicz, B., et al. Elevated levels of NR2A and PSD-95 in the lateral amygdala in depression. Int. J. Neuropsychopharmacol. 12, 143-153 (2009).
31. Feyissa, A. M., Chandran, A., Stockmeier, C. A., Karolewicz, B. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 70-75 (2009).
32. Chandley, M. J., et al. Elevated gene expression of glutamate receptors in noradrenergic neurons from the locus coeruleus in major depression. Int. J. Neuropsychopharmacol. 17, 1569-1578 (2014).
33. Gray, A. L., Hyde, T. M., Deep-Soboslay, A., Kleinman, J. E., Sodhi, M. S. Sex differences in glutamate receptor gene expression in major depression and suicide. Mol. Psychiatry 20, 1057-1068 (2015).
34. Sanacora, G., Banasr, M. From pathophysiology to novel antidepressant drugs: Glial contributions to the pathology and treatment of mood disorders. Biol. Psychiatry 73, 1172-1179 (2013).
35. Ongur, D., Drevets, W. C., Price, J. L. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc. Natl Acad. Sci. USA 95, 13290-13295 (1998).
36. Banasr, M., et al. Glial pathology in an animal model of depression: Reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol. Psychiatry 15, 501-511 (2010).
37. Duman, R. S., Aghajanian, G. K., Sanacora, G., Krystal, J. H. Synaptic plasticity and depression: New insights from stress and rapid-acting antidepressants. Nat. Med. 22, 238-249 (2016).
38. Popoli, M., Yan, Z., McEwen, B. S., Sanacora, G. The stressed synapse: The impact of stress and glucocorticoids on glutamate transmission. Nat. Rev. Neurosci. 13, 22-37 (2011).
39. Manji, H. K., et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol. Psychiatry 53, 707-742 (2003).
40. Kempton, M. J., et al. Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder. Arch. Gen. Psychiatry 68, 675-690 (2011).
41. Yuksel, C., Ongur, D. Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol. Psychiatry 68, 785-794 (2010).
42. Kaiser, R. H., Andrews-Hanna, J. R., Wager, T. D., Pizzagalli, D. A. Large-scale network dysfunction in major depressive disorder: A meta-analysis of resting-state functional connectivity. JAMA Psychiatry 72, 603-611 (2015).
43. Hasler, G., et al. Reduced prefrontal glutamate/glutamine and-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch. Gen. Psychiatry 64, 193-200 (2007).
44. Sanacora, G., et al. Reduced cortical-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch. Gen. Psychiatry 56, 1043-1047 (1999).
45. Sanacora, G., et al. Subtype-specific alterations of-aminobutyric acid and glutamate in patients with major depression. Arch. Gen. Psychiatry 61, 705-713 (2004).
46. Deschwanden, A., et al. Reduced metabotropic glutamate receptor 5 density in major depression determined by [11C]ABP688 PET and postmortem study. Am. J. Psychiatry 168, 727-734 (2011).
47. Abdallah, C. G., et al. Glutamate metabolism in major depressive disorder. Am. J. Psychiatry 171, 1320-1327 (2014).
48. Hirota, K., Lambert, D. G. Ketamine: Its mechanism(s) of action and unusual clinical uses. Br. J. Anaesth. 77, 441-444 (1996).
49. Zanos, P., et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533, 481-486 (2016).
50. Zhang, J. C., Li, S. X., Hashimoto, K. R, Ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Pharmacol. Biochem. Behav. 116, 137-141 (2014).
51. Yang, C., et al. R-Ketamine: A rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry 5, e632 (2015).
52. Zarate, C. A. Jr, et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63, 856-864 (2006).
53. Murrough, J. W., et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-site randomized controlled trial. Am. J. Psychiatry 170, 1134-1142 (2013).
54. Newport, D. J., et al. Ketamine and other NMDA antagonists: Early clinical trials and possible mechanisms in depression. Am. J. Psychiatry 172, 950-966 (2015).
55. McGirr, A., et al. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol. Med. 45, 693-704 (2015).
56. Caddy, C., et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst. Rev. 9, CD011612 (2015).
57. Aanhet Rot, M., et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol. Psychiatry 67, 139-145 (2010).
58. Murrough, J. W., et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol. Psychiatry 74, 250-256 (2013).
59. Shiroma, P. R., et al. Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression. J. Affect. Disord. 155, 123-129 (2014).
60. Rasmussen, K. G., et al. Serial infusions of low-dose ketamine for major depression. J. Psychopharmacol. 27, 444-450 (2013).
61. Segmiller, F., et al. Repeated S-ketamine infusions in therapy resistant depression: A case series. J. Clin. Pharmacol. 53, 996-998 (2013).
62. Cusin, C., et al. Ketamine augmentation for outpatients with treatment-resistant depression: Preliminary evidence for two-step intravenous dose escalation. Aust. N. Z. J. Psychiatry 51, 55-64 (2017).
63. Singh, J. B., et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am. J. Psychiatry 173, 816-826 (2016).
64. Hu, Y. D., et al. Single i. v. ketamine augmentation of newly initiated escitalopram for major depression: Results from a randomized, placebo-controlled 4-week study. Psychol. Med. 46, 623-635 (2016).
65. Lapidus, K. A., et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol. Psychiatry 76, 970-976 (2014).
66. Loo, C. K., et al. Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression. Acta Psychiatr. Scand. 134, 48-56 (2016).
67. Schoevers, R. A., Chaves, T. V., Balukova, S. M., Rot, M. A., Kortekaas, R. Oral ketamine for the treatment of pain and treatment-resistant depression. Br. J. Psychiatry 208, 108-113 (2016).
68. Lally, N., et al. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry 4, e469 (2014).
69. Lally, N., et al. Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. J. Psychopharmacol. 29, 596-607 (2015).
70. Saligan, L. N., Luckenbaugh, D. A., Slonena, E. E., Machado-Vieira, R., Zarate, C. A. Jr. An assessment of the anti-fatigue effects of ketamine from a double-blind, placebo-controlled, crossover study in bipolar disorder. J. Affect. Disord. 194, 115-119 (2016).
71. Price, R. B., Nock, M. K., Charney, D. S., Mathew, S. J. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol. Psychiatry 66, 522-526 (2009).
72. Price, R. B., et al. Effects of ketamine on explicit and implicit suicidal cognition: A randomized controlled trial in treatment-resistant depression. Depress. Anxiety 31, 335-343 (2014).
73. Ballard, E. D., et al. Improvement in suicidal ideation after ketamine infusion: Relationship to reductions in depression and anxiety. J. Psychiatr. Res. 58, 161-166 (2014).
74. Murrough, J. W., et al. Ketamine for rapid reduction of suicidal ideation: A randomized controlled trial. Psychol. Med. 45, 3571-3580 (2015).
75. Murrough, J. W., et al. Neurocognitive effects of ketamine in treatment-resistant major depression: Association with antidepressant response. Psychopharmacology (Berl. ) 231, 481-488 (2014).
76. Murrough, J. W., et al. Neurocognitive effects of ketamine and association with antidepressant response in individuals with treatment-resistant depression: A randomized controlled trial. Neuropsychopharmacology 40, 1084-1090 (2015).
77. Shiroma, P. R., et al. Neurocognitive performance and serial intravenous subanesthetic ketamine in treatment-resistant depression. Int. J. Neuropsychopharmacol. 17, 1805-1813 (2014).
78. Lee, Y., et al. A new perspective on the anti-suicide effects with ketamine treatment: A procognitive effect. J. Clin. Psychopharmacol. 36, 50-56 (2016).
79. Singh, J. B., et al. Intravenous esketamine in adult treatment-resistant depression: A double-blind, double-randomization, placebo-controlled study. Biol. Psychiatry 80, 424-431 (2015).
80. Maeng, S., et al. Cellular mechanisms underlying the antidepressant effects of ketamine: Role of-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol. Psychiatry 63, 349-352 (2008).
81. Papp, M., Moryl, E. Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. Eur. J. Pharmacol. 263, 1-7 (1994).
82. Li, N., et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959-964 (2010).
83. Autry, A. E., et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91-95 (2011).
84. Donahue, R. J., Muschamp, J. W., Russo, S. J., Nestler, E. J., Carlezon, W. A. Jr. Effects of striatal FosB overexpression and ketamine on social defeat stress-induced anhedonia in mice. Biol. Psychiatry 76, 550-558 (2014).
85. Gideons, E. S., Kavalali, E. T., Monteggia, L. M. Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc. Natl Acad. Sci. USA 111, 8649-8654 (2014).
86. Chowdhury, G. M., et al. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol. Psychiatry 22, 120-126 (2016).
87. Karasawa, J., Shimazaki, T., Kawashima, N., Chaki, S. AMPA receptor stimulation mediates the antidepressant-like effect of a group II metabotropic glutamate receptor antagonist. Brain Res. 1042, 92-98 (2005).
88. Voleti, B., et al. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, antidepressant behavioral responses. Biol. Psychiatry 74, 742-749 (2013).
89. Liu, R. J., et al. GLYX-13 produces rapid antidepressant responses with key synaptic and behavioral effects distinct from ketamine. Neuropsychopharmacology http://dx. doi. org/10. 1038/npp. 2016. 202 (2016).
90. Jimenez-Sanchez, L., et al. Activation of AMPA receptors mediates the antidepressant action of deep brain stimulation of the infralimbic prefrontal cortex. Cereb. Cortex 26, 2778-2789 (2016).
91. Citri, A., Malenka, R. C. Synaptic plasticity: Multiple forms, functions, mechanisms. Neuropsychopharmacology 33, 18-41 (2008).
92. Turrigiano, G. Too many cooks Intrinsic and synaptic homeostatic mechanisms in cortical circuit refinement. Annu. Rev. Neurosci. 34, 89-103 (2011).
93. Popp, S., et al. In search of the mechanisms of ketamine's antidepressant effects: How robust is the evidence behind the mTor activation hypothesis. F1000Res. 5, 634 (2016).
94. Beurel, E., Song, L., Jope, R. S. Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol. Psychiatry 16, 1068-1070 (2011).
95. Liu, R. J., et al. GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology 38, 2268-2277 (2013).
96. Beurel, E., Grieco, S. F., Amadei, C., Downey, K., Jope, R. S. Ketamine-induced inhibition of glycogen synthase kinase-3 contributes to the augmentation of-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor signaling. Bipolar Disord. 18, 473-480 (2016).
97. Yang, J. J., et al. Serum interleukin-6 is a predictive biomarker for ketamine's antidepressant effect in treatment-resistant patients with major depression. Biol. Psychiatry 77, e19-e20 (2015).
98. Wesseling, H., Rahmoune, H., Tricklebank, M., Guest, P. C., Bahn, S. A targeted multiplexed proteomic investigation identifies ketamine-induced changes in immune markers in rat serum and expression changes in protein kinases/phosphatases in rat brain. J. Proteome Res. 14, 411-421 (2015).
99. Park, M., et al. Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression. J. Psychiatr. Res. 84, 113-118 (2016).
100. Milak, M. S., et al. A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder. Mol. Psychiatry 21, 320-327 (2015).
101. Stone, J. M., et al. Ketamine effects on brain GABA and glutamate levels with 1H-MRS: Relationship to ketamine-induced psychopathology. Mol. Psychiatry 17, 664-665 (2012).
102. Luckenbaugh, D. A., et al. Do the dissociative side effects of ketamine mediate its antidepressant effects J. Affect. Disord. 159, 56-61 (2014).
103. Wan, L. L. Ketamine safety and tolerability in clinical trials for treatment-resistant depression. J. Clin. Psychiatry 76, 247-252 (2015).
104. Deakin, J. F., et al. Glutamate and the neural basis of the subjective effects of ketamine: A pharmaco-magnetic resonance imaging study. Arch. Gen. Psychiatry 65, 154-164 (2008).
105. Downey, D., et al. Comparing the actions of lanicemine and ketamine in depression: Key role of the anterior cingulate. Eur. Neuropsychopharmacol. 26, 994-1003 (2016).
106. Li, M., et al. Temporal dynamics of antidepressant ketamine effects on glutamine cycling follow regional fingerprints of AMPA and NMDA receptor densities. Neuropsychopharmacology http://dx. doi. org/10. 1038/npp. 2016. 184 (2016).
107. Murrough, J. W., et al. Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder. Transl Psychiatry 5, e509 (2015).
108. Scheidegger, M., et al. Ketamine administration reduces amygdalo-hippocampal reactivity to emotional stimulation. Hum. Brain Mapp. 37, 1941-1952 (2016).
109. Murrough, J. W., et al. Reduced global functional connectivity of the medial prefrontal cortex in major depressive disorder. Hum. Brain Mapp. 37, 3214-3223 (2016).
110. Abdallah, C. G., et al. Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology http://dx. doi. org/10. 1038/npp. 2016. 186 (2016).
111. Carlson, P. J., et al. Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: A preliminary positron emission tomography study. Biol. Psychiatry 73, 1213-1221 (2013).
112. Nugent, A. C., et al. Neural correlates of rapid antidepressant response to ketamine in bipolar disorder. Bipolar Disord. 16, 119-128 (2014).
113. Machado-Vieira, R., et al. Brain-derived neurotrophic factor and initial antidepressant response to an N-methyl-d-aspartate antagonist. J. Clin. Psychiatry 70, 1662-1666 (2009).
114. Haile, C. N., et al. Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression. Int. J. Neuropsychopharmacol. 17, 331-336 (2013).
115. Esser, S. K., Hill, S. L., Tononi, G. Sleep homeostasis and cortical synchronization: I. modeling the effects of synaptic strength on sleep slow waves. Sleep 30, 1617-1630 (2007).
116. Duncan, W. C., et al. Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder. Int. J. Neuropsychopharmacol. 16, 301-311 (2013).
117. Laje, G., et al. Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biol. Psychiatry 72, e27-28 (2012).
118. Preskorn, S. H., et al. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-d-aspartate antagonist, CP-101, 606, in patients with treatment-refractory major depressive disorder. J. Clin. Psychopharmacol. 28, 631-637 (2008).
119. Sanacora, G., et al. Lanicemine: A low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Mol. Psychiatry 19, 978-985 (2014).
120. Crane, G. E. Cyloserine as an antidepressant agent. Am. J. Psychiatry 115, 1025-1026 (1959).
121. Heresco-Levy, U., et al. A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression. Int. J. Neuropsychopharmacol. 16, 501-506 (2013).
122. Kantrowitz, J. T., Halberstam, B., Gangwisch, J. Single-dose ketamine followed by daily d-cycloserine in treatment-resistant bipolar depression. J. Clin. Psychiatry 76, 737-738 (2015).
123. Zhang, X. L., Sullivan, J. A., Moskal, J. R., Stanton, P. K. A. NMDA receptor glycine site partial agonist, GLYX-13, simultaneously enhances LTP and reduces LTD at Schaffer collateral-CA1 synapses in hippocampus. Neuropharmacology 55, 1238-1250 (2008).
124. Burgdorf, J., et al. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology 38, 729-742 (2013).
125. Preskorn, S., et al. Randomized proof of concept trial of GLYX-13, an N-methyl-d-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. J. Psychiatr. Pract. 21, 140-149 (2015).
126. Ibrahim, L., et al. A randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. J. Clin. Psychopharmacol. 32, 551-557 (2012).
127. Kemp, J. A., et al. 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-d-aspartate receptor complex. Proc. Natl Acad. Sci. USA 85, 6547-6550 (1988).
128. Zanos, P., et al. The prodrug 4-chlorokynurenine causes ketamine-like antidepressant effects, but not side effects, by NMDA/glycineB-site inhibition. J. Pharmacol. Exp. Ther. 355, 76-85 (2015).
129. Mullard, A. Deuterated drugs draw heavier backing. Nat. Rev. Drug Discov. 15, 219-221 (2016).
130. Huang, C. C., et al. Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. Biol. Psychiatry 74, 734-741 (2013).
131. Durr, K. L., et al. Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, desensitized states. Cell 158, 778-792 (2014).
132. Ward, S. E., Bax, B. D., Harries, M. Challenges for and current status of research into positive modulators of AMPA receptors. Br. J. Pharmacol. 160, 181-190 (2010).
133. Nations, K. R., et al. Maximum tolerated dose evaluation of the AMPA modulator Org 26576 in healthy volunteers and depressed patients: A summary and method analysis of bridging research in support of phase II dose selection. Drugs R. D. 12, 127-139 (2012).
134. Nations, K. R., et al. Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: An exploratory, randomized, double-blind, placebo-controlled trial. J. Psychopharmacol. 26, 1525-1539 (2012).
135. Dwyer, J. M., Lepack, A. E., Duman, R. S. mGluR2/3 blockade produces rapid and long-lasting reversal of anhedonia caused by chronic stress exposure. J. Mol. Psychiatry 1, 15 (2013).
136. Witkin, J. M., et al. The rapidly acting antidepressant ketamine and the mGlu2/3 receptor antagonist LY341495 rapidly engage dopaminergic mood circuits. J. Pharmacol. Exp. Ther. 358, 71-82 (2016).
137. Hughes, Z. A., et al. Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression. Neuropharmacology 66, 202-214 (2013).
138. Quiroz, J. A., et al. Efficacy and safety of basimglurant as adjunctive therapy for major depression: A randomized clinical trial. JAMA Psychiatry 73, 675-684 (2016).
139. Jain, F. A., Hunter, A. M., Brooks, J. O. III & Leuchter, A. F. Predictive socioeconomic and clinical profiles of antidepressant response and remission. Depress. Anxiety 30, 624-630 (2013).
140. Miller, S., et al. Cognition-childhood maltreatment interactions in the prediction of antidepressant outcomes in major depressive disorder patients: Results from the iSPOT-D trial. Depress. Anxiety 32, 594-604 (2015).
141. Williams, L. M., et al. Amygdala reactivity to emotional faces in the prediction of general and medication-specific responses to antidepressant treatment in the randomized iSPOT-D trial. Neuropsychopharmacology 40, 2398-2408 (2015).
142. Breitenstein, B., et al. ABCB1 gene variants and antidepressant treatment outcome: A meta-analysis. Am. J. Med. Genet. B Neuropsychiatr. Genet. 168B, 274-283 (2015).
143. Zarate, C. A. Jr, et al. A randomized trial of a low-trapping nonselective N-methyl-d-aspartate channel blocker in major depression. Biol. Psychiatry 74, 257-264 (2013).
144. Tan, S., Lam, W. P., Wai, M. S., Yu, W. H., Yew, D. T. Chronic ketamine administration modulates midbrain dopamine system in mice. PLoS ONE 7, e43947 (2012).
145. Williams, N. R., Schatzberg, A. F. NMDA antagonist treatment of depression. Curr. Opin. Neurobiol. 36, 112-117 (2016).
146. Miller, A. H. Conceptual confluence: The kynurenine pathway as a common target for ketamine and the convergence of the inflammation and glutamate hypotheses of depression. Neuropsychopharmacology 38, 1607-1608 (2013).
147. Dale, O., Somogyi, A. A., Li, Y., Sullivan, T., Shavit, Y. Does intraoperative ketamine attenuate inflammatory reactivity following surgery A systematic review and meta-analysis. Anesth. Analg. 115, 934-943 (2012).
148. Choi, M., et al. Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats. Proc. Natl Acad. Sci. USA 112, 15755-15760 (2015).
149. Hayashi, Y., et al. Driving AMPA receptors into synapses by LTP and CaMKII: Requirement for GluR1 and PDZ domain interaction. Science 287, 2262-2267 (2000).
150. Kew, J. N., Kemp, J. A. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl. ) 179, 4-29 (2005).
151. Schoepp, D. D. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J. Pharmacol. Exp. Ther. 299, 12-20 (2001).
152. Trullas, R., Skolnick, P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur. J. Pharmacol. 185, 1-10 (1990).
153. Shors, T. J., Seib, T. B., Levine, S., Thompson, R. F. Inescapable versus escapable shock modulates long-term potentiation in the rat hippocampus. Science 244, 224-226 (1989).
154. Skolnick, P., Popik, P., Trullas, R. Glutamate-based antidepressants: 20 years on. Trends Pharmacol. Sci. 30, 563-569 (2009).
155. Skolnick, P., et al. Adaptation of N-methyl-d-aspartate (NMDA) receptors following antidepressant treatment: Implications for the pharmacotherapy of depression. Pharmacopsychiatry 29, 23-26 (1996).
156. Papp, M., Moryl, E. Antidepressant-like effects of 1-aminocyclopropanecarboxylic acid and d-cycloserine in an animal model of depression. Eur. J. Pharmacol. 316, 145-151 (1996).
157. Sos, P., et al. Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depression. Neuro Endocrinol. Lett. 34, 287-293 (2013).
158. Diazgranados, N., et al. A randomized add-on trial of an N-methyl-d-aspartate antagonist in treatment-resistant bipolar depression. Arch. Gen. Psychiatry 67, 793-802 (2010).
159. Zarate, C. A. Jr, et al. Replication of ketamine's antidepressant efficacy in bipolar depression: A randomized controlled add-on trial. Biol. Psychiatry 71, 939-946 (2012).