Ketamine and Other Glutamate Receptor Modulating Agents for Treatment-Resistant Depression: A Systematic Review of Randomized Controlled Trials
Objective: Available treatments of depression have limited efficacy and unsatisfactory remission rates. This study aims to review randomized controlled trials (RCTs) investigating effects of glutamate receptor modulators in treating patients with resistant depression.
Method: The study protocol was registered in PROSPERO (CRD42021225516). Scopus, ISI Web of Science, Embase, Cochrane Library, Google Scholar, and three trial registries were searched up to September 2020 to find RCTs evaluating glutamate receptor modulators for resistant depression. The difference between intervention and control groups in changing depression scores from baseline to endpoint was considered the primary outcome. Version 2 of the Cochrane risk-of-bias tool for randomized trials was used to assess the quality of the RCTs. No funding was received.
Results: Thirty-eight RCTs were included. Based on the included studies, compelling evidence was found for ketamine (with or without electroconvulsive therapy, intravenous or other forms), nitrous oxide, amantadine, and rislenemdaz (MK-0657); the results for MK-0657, amantadine, and nitrous oxide were only based on one study for each. Lithium, lanicemine, D-cycloserine, and decoglurant showed mixed results for efficacy, and, riluzole, and 7-chlorokynurenic acid were mostly comparable to placebo. A limited number of studies were available that addressed drugs other than ketamine.
Conclusion: The study cannot determine the difference between statistical and clinical significance between the agents and placebo due to high heterogeneity among the RCTs. Nevertheless, ketamine could be used as an efficacious drug in TRD; still, additional studies are needed to delineate the optimum dosage, duration of efficacy, and intervals. Further studies are also recommended on the effectiveness of glutamatergic system modulators other than ketamine on treatment-resistant depression.
2. Gutiérrez-Rojas L, Porras-Segovia A, Dunne H, Andrade-González N, Cervilla JA. Prevalence and correlates of major depressive disorder: a systematic review. Braz J Psychiatry. 2020;42(6):657-72.
3. Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015;76(2):155-62.
4. Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative Efficacy and Acceptability of 21 Antidepressant Drugs for the Acute Treatment of Adults With Major Depressive Disorder: A Systematic Review and Network Meta-Analysis. Focus (Am Psychiatr Publ). 2018;16(4):420-9.
5. Malhi GS, Mann JJ. Depression. Lancet. 2018 Nov 24;392(10161):2299-2312.
6. McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1531-41; quiz 666.
7. Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-52.
8. Dome P, Tombor L, Lazary J, Gonda X, Rihmer Z. Natural health products, dietary minerals and over-the-counter medications as add-on therapies to antidepressants in the treatment of major depressive disorder: a review. Brain Res Bull. 2019;146:51-78.
9. Beekman AT, Geerlings SW, Deeg DJ, Smit JH, Schoevers RS, de Beurs E, et al. The natural history of late-life depression: a 6-year prospective study in the community. Arch Gen Psychiatry. 2002;59(7):605-11.
10. Hengartner MP, Passalacqua S, Andreae A, Heinsius T, Hepp U, Rössler W, et al. Antidepressant Use During Acute Inpatient Care Is Associated With an Increased Risk of Psychiatric Rehospitalisation Over a 12-Month Follow-Up After Discharge. Front Psychiatry. 2019;10:79.
11. Hengartner MP, Plöderl M. Statistically Significant Antidepressant-Placebo Differences on Subjective Symptom-Rating Scales Do Not Prove That the Drugs Work: Effect Size and Method Bias Matter! Front Psychiatry. 2018;9:517.
12. Hassamal S, Spivey M, Pandurangi AK. Augmentation Therapy With Serial Intravenous Ketamine Over 18 Months in a Patient With Treatment Resistant Depression. Clin Neuropharmacol. 2015;38(5):212-6.
13. Pérez-Esparza R. Ketamine for Treatment-Resistant Depression: a New Advocate. Rev Invest Clin. 2018;70(2):65-7.
14. Zarate CA, Jr., Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004;161(1):171-4.
15. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-4.
16. Albott CS, Lim KO, Forbes MK, Erbes C, Tye SJ, Grabowski JG, et al. Efficacy, Safety, and Durability of Repeated Ketamine Infusions for Comorbid Posttraumatic Stress Disorder and Treatment-Resistant Depression. J Clin Psychiatry. 2018;79(3).
17. Fond G, Loundou A, Rabu C, Macgregor A, Lançon C, Brittner M, et al. Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology (Berl). 2014;231(18):3663-76.
18. Serafini G, Howland RH, Rovedi F, Girardi P, Amore M. The role of ketamine in treatment-resistant depression: a systematic review. Curr Neuropharmacol. 2014;12(5):444-61.
19. McCloud TL, Caddy C, Jochim J, Rendell JM, Diamond PR, Shuttleworth C, et al. Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults. Cochrane Database Syst Rev. 2015(9):Cd011611.
20. Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46(D1):D1074-d82.
21. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. Bmj. 2019;366:l4898.
22. Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, Iqbal S, Pillemer S, Foulkes A, Shah A, Charney DS, Mathew SJ. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013 Oct;170(10):1134-42.
23. Zarate CA, Jr., Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-64.
24. Dwyer JB, Landeros-Weisenberger A, Johnson JA, Londono Tobon A, Flores JM, Nasir M, et al. Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression: A Randomized Midazolam-Controlled Trial. Am J Psychiatry. 2021;178(4):352-62.
25. Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2020;25(7):1592-603.
26. Chen MH, Li CT, Lin WC, Hong CJ, Tu PC, Bai YM, et al. Cognitive function of patients with treatment-resistant depression after a single low dose of ketamine infusion. J Affect Disord. 2018;241:1-7.
27. Lai R, Katalinic N, Glue P, Somogyi AA, Mitchell PB, Leyden J, et al. Pilot dose-response trial of i.v. ketamine in treatment-resistant depression. World J Biol Psychiatry. 2014;15(7):579-84.
28. Singh JB, Fedgchin M, Daly EJ, De Boer P, Cooper K, Lim P, et al. A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression. Am J Psychiatry. 2016;173(8):816-26.
29. Loo CK, Gálvez V, O'Keefe E, Mitchell PB, Hadzi-Pavlovic D, Leyden J, et al. Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression. Acta Psychiatr Scand. 2016;134(1):48-56.
30. Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A, et al. Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial. Am J Psychiatry. 2019;176(5):401-9.
31. Ionescu DF, Bentley KH, Eikermann M, Taylor N, Akeju O, Swee MB, et al. Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial. J Affect Disord. 2019;243:516-24.
32. Shiroma PR, Thuras P, Wels J, Albott CS, Erbes C, Tye S, et al. A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression. Transl Psychiatry. 2020;10(1):206.
33. Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry. 2019;176(6):428-38.
34. Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018;75(2):139-48.
35. Fedgchin M, Trivedi M, Daly EJ, Melkote R, Lane R, Lim P, et al. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616-30.
36. Singh JB, Fedgchin M, Daly E, Xi L, Melman C, De Bruecker G, et al. Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study. Biol Psychiatry. 2016;80(6):424-31.
37. Domany Y, Bleich-Cohen M, Stoppelman N, Hendler T, Tarrasch R, Schreiber S, et al. Oral Ketamine for Treatment Resistant Major Depression - A double blind randomized controlled trial. Int J Neuropsychopharmacol. 2016;19:82-.
38. Domany Y, Bleich-Cohen M, Tarrasch R, Meidan R, Litvak-Lazar O, Stoppleman N, et al. Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study. Br J Psychiatry. 2019;214(1):20-6.
39. Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry. 2014;76(12):970-6.
40. Salehi B, Mohammadbeigi A, Kamali AR, Taheri-Nejad MR, Moshiri I. Impact comparison of ketamine and sodium thiopental on anesthesia during electroconvulsive therapy in major depression patients with drug-resistant; a double-blind randomized clinical trial. Ann Card Anaesth. 2015;18(4):486-90.
41. Dong J, Min S, Qiu H, Chen Q, Ren L. Intermittent administration of low dose ketamine can shorten the course of electroconvulsive therapy for depression and reduce complications: A randomized controlled trial. Psychiatry Res. 2019;281:112573.
42. Altinay M, Karne H, Anand A. Administration of Sub-anesthetic Dose of Ketamine and Electroconvulsive Treatment on Alternate Week Days in Patients with Treatment Resistant Depression: A Double Blind Placebo Controlled Trial. Psychopharmacol Bull. 2019;49(1):8-16.
43. Kuşçu Ö, Karacaer F, Biricik E, Güleç E, Tamam L, Güneş Y. Effect of Ketamine, Thiopental and Ketamine-Thiopental Combination during Electroconvulsive Therapy for Depression. Turk J Anaesthesiol Reanim. 2015;43(5):313-7.
44. Järventausta K, Chrapek W, Kampman O, Tuohimaa K, Björkqvist M, Häkkinen H, et al. Effects of S-ketamine as an anesthetic adjuvant to propofol on treatment response to electroconvulsive therapy in treatment-resistant depression: a randomized pilot study. J ect. 2013;29(3):158-61.
45. Baumann P, Nil R, Souche A, Montaldi S, Baettig D, Lambert S, et al. A double-blind, placebo-controlled study of citalopram with and without lithium in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic investigation. J Clin Psychopharmacol. 1996;16(4):307-14.
46. Costi S, Soleimani L, Glasgow A, Brallier J, Spivack J, Schwartz J, et al. Lithium continuation therapy following ketamine in patients with treatment resistant unipolar depression: a randomized controlled trial. Neuropsychopharmacology. 2019;44(10):1812-9.
47. Ruiz-Chow A, Ramirez-Bermudez J, Alviso-de la Serna L, Rios C. P.2.a.032 Amantadine: a treatment for major depressive disorder. Eur Neuropsychopharmacol. 2010;20:S352.
48. Salardini E, Zeinoddini A, Mohammadinejad P, Khodaie-Ardakani MR, Zahraei N, Zeinoddini A, et al. Riluzole combination therapy for moderate-to-severe major depressive disorder: A randomized, double-blind, placebo-controlled trial. J Psychiatr Res. 2016;75:24-30.
49. Mathew SJ, Gueorguieva R, Brandt C, Fava M, Sanacora G. A Randomized, Double-Blind, Placebo-Controlled, Sequential Parallel Comparison Design Trial of Adjunctive Riluzole for Treatment-Resistant Major Depressive Disorder. Neuropsychopharmacology. 2017;42(13):2567-74.
50. Mathew SJ, Murrough JW, aan het Rot M, Collins KA, Reich DL, Charney DS. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int J Neuropsychopharmacol. 2010;13(1):71-82.
51. Ibrahim L, Diazgranados N, Franco-Chaves J, Brutsche N, Henter ID, Kronstein P, et al. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology. 2012;37(6):1526-33.
52. Park LT, Kadriu B, Gould TD, Zanos P, Greenstein D, Evans JW, et al. A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression. Int J Neuropsychopharmacol. 2020;23(7):417-25.
53. Zarate CA, Jr., Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, et al. A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression. Biol Psychiatry. 2013;74(4):257-64.
54. Sanacora G, Johnson MR, Khan A, Atkinson SD, Riesenberg RR, Schronen JP, et al. Adjunctive Lanicemine (AZD6765) in Patients with Major Depressive Disorder and History of Inadequate Response to Antidepressants: A Randomized, Placebo-Controlled Study. Neuropsychopharmacology. 2017;42(4):844-53.
55. Heresco-Levy U, Javitt DC, Gelfin Y, Gorelik E, Bar M, Blanaru M, et al. Controlled trial of D-cycloserine adjuvant therapy for treatment-resistant major depressive disorder. J Affect Disord. 2006;93(1-3):239-43.
56. Heresco-Levy U, Gelfin G, Bloch B, Levin R, Edelman S, Javitt DC, et al. A randomized add-on trial of high-dose D-cycloserine for treatment-resistant depression. Int J Neuropsychopharmacol. 2013;16(3):501-6.
57. Umbricht D, Niggli M, Sanwald-Ducray P, Deptula D, Moore R, Grünbauer W, et al. Randomized, Double-Blind, Placebo-Controlled Trial of the mGlu2/3 Negative Allosteric Modulator Decoglurant in Partially Refractory Major Depressive Disorder. J Clin Psychiatry. 2020;81(4).
58. Ibrahim L, Diaz Granados N, Jolkovsky L, Brutsche N, Luckenbaugh DA, Herring WJ, 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. 2012;32(4):551-7.
59. Nagele P, Duma A, Kopec M, Gebara MA, Parsoei A, Walker M, et al. Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial. Biol Psychiatry. 2015;78(1):10-8.
60. Snyder SH, Ferris CD. Novel neurotransmitters and their neuropsychiatric relevance. Am J Psychiatry. 2000;157(11):1738-51.
61. Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012;62(1):63-77.
62. Zhu S, Paoletti P. Allosteric modulators of NMDA receptors: multiple sites and mechanisms. Curr Opin Pharmacol. 2015;20:14-23.
63. Hardingham GE, Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci. 2010;11(10):682-96.
64. Danbolt NC. Glutamate uptake. Prog Neurobiol. 2001;65(1):1-105.
65. Pittenger C, Coric V, Banasr M, Bloch M, Krystal JH, Sanacora G. Riluzole in the treatment of mood and anxiety disorders. CNS Drugs. 2008;22(9):761-86.
66. Kalivas PW. The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci. 2009;10(8):561-72.
67. Hashimoto K. Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res Rev. 2009;61(2):105-23.
68. Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J, Drevets WC. Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry. 2007;64(2):193-200.
69. Campbell S, MacQueen G. An update on regional brain volume differences associated with mood disorders. Curr Opin Psychiatry. 2006;19(1):25-33.
70. Koolschijn PC, van Haren NE, Lensvelt-Mulders GJ, Hulshoff Pol HE, Kahn RS. Brain volume abnormalities in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Hum Brain Mapp. 2009;30(11):3719-35.
71. Lorenzetti V, Allen NB, Fornito A, Yücel M. Structural brain abnormalities in major depressive disorder: a selective review of recent MRI studies. J Affect Disord. 2009;117(1-2):1-17.
72. Musazzi L, Milanese M, Farisello P, Zappettini S, Tardito D, Barbiero VS, et al. Acute stress increases depolarization-evoked glutamate release in the rat prefrontal/frontal cortex: the dampening action of antidepressants. PLoS One. 2010;5(1):e8566.
73. Gorman JM, Docherty JP. A hypothesized role for dendritic remodeling in the etiology of mood and anxiety disorders. J Neuropsychiatry Clin Neurosci. 2010;22(3):256-64.
74. Holmes A, Wellman CL. Stress-induced prefrontal reorganization and executive dysfunction in rodents. Neurosci Biobehav Rev. 2009;33(6):773-83.
75. Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008;7(5):426-37.
76. Li W, Ju K, Li Z, He K, Chen J, Wang Q, et al. Significant association of GRM7 and GRM8 genes with schizophrenia and major depressive disorder in the Han Chinese population. Eur Neuropsychopharmacol. 2016;26(1):136-46.
77. Pearlman DM, Najjar S. Meta-analysis of the association between N-methyl-d-aspartate receptor antibodies and schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder. Schizophr Res. 2014;157(1-3):249-58.
78. Steiner J, Bogerts B, Sarnyai Z, Walter M, Gos T, Bernstein HG, et al. Bridging the gap between the immune and glutamate hypotheses of schizophrenia and major depression: Potential role of glial NMDA receptor modulators and impaired blood-brain barrier integrity. World J Biol Psychiatry. 2012;13(7):482-92.
79. Innes S, Pariante CM, Borsini A. Microglial-driven changes in synaptic plasticity: A possible role in major depressive disorder. Psychoneuroendocrinology. 2019;102:236-47.
80. McNally L, Bhagwagar Z, Hannestad J. Inflammation, glutamate, and glia in depression: a literature review. CNS Spectr. 2008;13(6):501-10.
81. Bliss TV, Collingridge GL. Expression of NMDA receptor-dependent LTP in the hippocampus: bridging the divide. Mol Brain. 2013;6:5.
82. Pittenger C. Disorders of memory and plasticity in psychiatric disease. Dialogues Clin Neurosci. 2013;15(4):455-63.
83. Amidfar M, Woelfer M, Réus GZ, Quevedo J, Walter M, Kim YK. The role of NMDA receptor in neurobiology and treatment of major depressive disorder: Evidence from translational research. Prog Neuropsychopharmacol Biol Psychiatry. 2019;94:109668.
84. Yang Y, Maher DP, Cohen SP. Emerging concepts on the use of ketamine for chronic pain. Expert Rev Clin Pharmacol. 2020;13(2):135-46.
85. Kavalali ET, Monteggia LM. Targeting Homeostatic Synaptic Plasticity for Treatment of Mood Disorders. Neuron. 2020;106(5):715-26.
86. Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci. 2010;11(9):642-51.
87. Amidfar M, Réus GZ, Quevedo J, Kim YK. The role of memantine in the treatment of major depressive disorder: Clinical efficacy and mechanisms of action. Eur J Pharmacol. 2018;827:103-11.
88. Zarate CA, Manji HK. Riluzole in psychiatry: a systematic review of the literature. Expert Opin Drug Metab Toxicol. 2008;4(9):1223-34.
89. Frizzo ME, Dall'Onder LP, Dalcin KB, Souza DO. Riluzole enhances glutamate uptake in rat astrocyte cultures. Cell Mol Neurobiol. 2004;24(1):123-8.
90. McNally L, Bhagwagar Z, Hannestad J. Inflammation, glutamate, and glia in depression: a literature review. CNS Spectr. 2008;13(6):501-10.
91. Li KX, Loshak H. Intravenous Ketamine for Adults with Treatment-Resistant Depression or Post-Traumatic Stress Disorder: A Review of Clinical Effectiveness, Cost-Effectiveness and Guidelines. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; October 24, 2019.
92. Cavenaghi VB, da Costa LP, Lacerda ALT, Hirata ES, Miguel EC, Fraguas R. Subcutaneous Ketamine in Depression: A Systematic Review. Front Psychiatry. 2021;12:513068.
93. Bahr R, Lopez A, Rey JA. Intranasal Esketamine (Spravato(TM)) for Use in Treatment-Resistant Depression In Conjunction With an Oral Antidepressant. P t. 2019;44(6):340-75.
94. Kessler RC, Soukup J, Davis RB, Foster DF, Wilkey SA, Van Rompay MI, et al. The use of complementary and alternative therapies to treat anxiety and depression in the United States. Am J Psychiatry. 2001;158(2):289-94.
95. Ernst E. Herbal medicines--they are popular, but are they also safe? Eur J Clin Pharmacol. 2006;62(1):1-2.
96. Süer C, Dolu N, Artis S, Aydogan S. Effects of carnosine on long-term plasticity of medial perforant pathway/dentate gyrus synapses in urethane-anesthetized rats: an in vivo model. Exp Brain Res. 2009;197(2):135-42.
97. Hipkiss AR. Possible Benefit of Dietary Carnosine towards Depressive Disorders. Aging Dis. 2015;6(5):300-3.
98. Araminia B, Shalbafan M, Mortezaei A, Shirazi E, Ghaffari S, Sahebolzamani E, et al. L-Carnosine combination therapy for major depressive disorder: A randomized, double-blind, placebo-controlled trial. J Affect Disord. 2020;267:131-6.
99. Georgiadou G, Grivas V, Tarantilis PA, Pitsikas N. Crocins, the active constituents of Crocus Sativus L., counteracted ketamine-induced behavioural deficits in rats. Psychopharmacology (Berl). 2014;231(4):717-26.
100. Lechtenberg M, Schepmann D, Niehues M, Hellenbrand N, Wünsch B, Hensel A. Quality and functionality of saffron: quality control, species assortment and affinity of extract and isolated saffron compounds to NMDA and sigma1 (sigma-1) receptors. Planta Med. 2008;74(7):764-72.
101. Khazdair MR, Boskabady MH, Hosseini M, Rezaee R, A MT. The effects of Crocus sativus (saffron) and its constituents on nervous system: A review. Avicenna J Phytomed. 2015;5(5):376-91.
102. Hariton E, Locascio JJ. Randomised controlled trials - the gold standard for effectiveness research: Study design: randomised controlled trials. Bjog. 2018;125(13):1716.
103. Hengartner MP, Plöderl M. Statistically Significant Antidepressant-Placebo Differences on Subjective Symptom-Rating Scales Do Not Prove That the Drugs Work: Effect Size and Method Bias Matter! Front Psychiatry. 2018;9:517.
104. Wasserstein RL, Lazar NA. The ASA Statement on p-Values: Context, Process, and Purpose. Am Stat. 2016;70(2):129-33.
105. Moncrieff J, Kirsch I. Empirically derived criteria cast doubt on the clinical significance of antidepressant-placebo differences. Contemp Clin Trials. 2015;43:60-2.
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