Factors Associated with Antidepressant Effects of Ketamine: A Reanalysis of Double-Blind Randomized Placebo-Controlled Trial of Intravenous Ketamine for Treatment-Resistant Depression

Abstract

Introduction Predictors of treatment response to intravenous ketamine remain unclear in patients with treatment-resistant depression (TRD); therefore, this study aimed to clarify these predictors using the US National Institutes of Health database of clinical trials.

Methods Data from a placebo-controlled, double-blind, randomized controlled trial were used to assess the efficacy of intravenous ketamine in adult patients with TRD (NCT01920555). For the analysis, data were used from the participants who had received therapeutic doses of intravenous ketamine (i. e., 0.5 and 1.0 mg/kg). Logistic and multivariable regression analyses were conducted to explore the demographic and clinical factors associated with response to treatment or changes in the Hamilton Depression Rating Scale 6 items (HAM-D-6) total score.

Results This study included 31 patients with TRD (13 women; mean±standard deviation age, 48.4±10.9 years). Logistic regression analysis showed that the age of onset was positively correlated with treatment response after three days of ketamine administration (β=0.08, p=0.037); however, no association was observed between treatment response and age, sex, baseline HAM-D-6 total score, or dissociative score assessed with the Clinician-Administered Dissociative States Scale 40 min after ketamine infusion. Multiple regression analysis showed that no factors were correlated significantly with the percentage change in the HAM-D-6 total score three days after ketamine administration.

Discussion Later disease onset correlates with a better treatment response three days after ketamine infusion in patients with TRD. Glutamatergic signal transmission may be impaired in patients with an earlier onset of depression, resulting in decreased neuroplasticity, which diminishes ketamine response.

Key words

depression - human - ketamine - treatment-resistant

Publication History

Received: 30 July 2023
Received: 01 September 2023

Accepted: 13 September 2023

Article published online:
16 October 2023

• References

• 1 McIntyre RS, Carvalho IP, Lui LMW. et al. The effect of intravenous, intranasal, and oral ketamine in mood disorders: A meta-analysis. J Affect Disord 2020; 276: 576-584
• 2 Fava M, Freeman MP, Flynn M. et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry 2020; 25: 1592-1603
• 3 Singh JB, Fedgchin M, Daly EJ. 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: 816-826
• 4 Ritter P, Findeis H, Bauer M. Ketamine in the treatment of depressive episodes. Pharmacopsychiatry 2020; 53: 45-50
• 5 Sakurai H, Jain F, Foster S. et al. Long-term outcome in outpatients with depression treated with acute and maintenance intravenous ketamine: A retrospective chart review. J Affect Disord 2020; 276: 660-666
• 6 Wilkinson ST, Katz RB, Toprak M. et al. Acute and longer-term outcomes using ketamine as a clinical treatment at the Yale Psychiatric Hospital. J Clin Psychiatry 2018; 79
• 7 Rong C, Park C, Rosenblat JD. et al. Predictors of response to ketamine in treatment resistant major depressive disorder and bipolar disorder. Int J Environ Res Public Health 2018; 15
• 8 Luckenbaugh DA, Ibrahim L, Brutsche N. et al. Family history of alcohol dependence and antidepressant response to an N-methyl-D-aspartate antagonist in bipolar depression. Bipolar Disord 2012; 14: 880-887
• 9 Phelps LE, Brutsche N, Moral JR. et al. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol Psychiatry 2009; 65: 181-184
• 10 Niciu MJ, Luckenbaugh DA, Ionescu DF. et al. Clinical predictors of ketamine response in treatment-resistant major depression. J Clin Psychiatry 2014; 75: e417-23
• 11 Jesus-Nunes AP, Leal GC, Correia-Melo FS. et al. Clinical predictors of depressive symptom remission and response after racemic ketamine and esketamine infusion in treatment-resistant depression. Hum Psychopharmacol 2022; 37: e2836
• 12 Sakurai H, Hoeppner B, Jain F. et al. Use of staging models for treatment-resistant depression is not helpful in predicting nonresponse to acute intravenous ketamine treatment. J Clin Psychopharmacol 2022; 42: 140-145
• 13 Murrough JW, Wan L-B, Iacoviello B. et al. Neurocognitive effects of ketamine in treatment-resistant major depression: Association with antidepressant response. Psychopharmacology 2013;
• 14 Chen M-H, Lin W-C, Li C-T. et al. Baseline working memory predicted response to low-dose ketamine infusion in patients with treatment-resistant depression. Pharmacopsychiatry 2022; 55: 109-114
• 15 Machado-Vieira R, Gold PW, Luckenbaugh DA. et al. The role of adipokines in the rapid antidepressant effects of ketamine. Mol Psychiatry 2017; 22: 127-133
• 16 Haile CN, Murrough JW, Iosifescu DV. et al. Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression. Int J Neuropsychopharmacol 2014; 17: 331-336
• 17 Laje G, Lally N, Mathews D. et al. Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biol Psychiatry 2012; 72: e27-e28
• 18 Abdallah CG, Salas R, Jackowski A. et al. Hippocampal volume and the rapid antidepressant effect of ketamine. J Psychopharmacol 2015; 29: 591-595
• 19 Alnefeesi Y, Chen-Li D, Krane E. et al. Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis. J Psychiatr Res 2022; 151: 693-709
• 20 Chen M-H, Wu H-J, Li C-T. et al. Using classification and regression tree modelling to investigate treatment response to a single low-dose ketamine infusion: Post hoc pooled analyses of randomized placebo-controlled and open-label trials. J Affect Disord 2021; 281: 865-871
• 21 De Carlo V, Calati R, Serretti A. Socio-demographic and clinical predictors of non-response/non-remission in treatment resistant depressed patients: A systematic review. Psychiatry Res 2016; 240: 421-430
• 22 Petersen T, Hughes M, Papakostas GI. et al. Treatment-resistant depression and Axis II comorbidity. Psychother Psychosom 2002; 71: 269-274
• 23 Herzog DP, Wagner S, Engelmann J. et al. Early onset of depression and treatment outcome in patients with major depressive disorder. J Psychiatr Res 2021; 139: 150-158
• 24 Nelson JC, Delucchi KL, Schneider LS. Moderators of outcome in late-life depression: A patient-level meta-analysis. Am J Psychiatry 2013; 170: 651-659
• 25 Calati R, Salvina Signorelli M, Balestri M. et al. Antidepressants in elderly: Metaregression of double-blind, randomized clinical trials. J Affect Disord 2013; 147: 1-8
• 26 Kozel FA, Trivedi MH, Wisniewski SR. et al. Treatment outcomes for older depressed patients with earlier versus late onset of first depressive episode: A sequenced treatment alternatives to relieve depression (STAR*D) report. Am J Geriatr Psychiatry 2008; 16: 58-64
• 27 Zisook S, Lesser I, Stewart JW. et al. Effect of age at onset on the course of major depressive disorder. Am J Psychiatry 2007; 164: 1539-1546
• 28 Bukh JD, Bock C, Vinberg M. et al. Differences between early and late onset adult depression. Clin Pract Epidemiol Ment Health 2011; 7: 140-147
• 29 Mathai DS, Meyer MJ, Storch EA. et al. The relationship between subjective effects induced by a single dose of ketamine and treatment response in patients with major depressive disorder: A systematic review. J Affect Disord 2020; 264: 123-129
• 30 Ballard ED, Zarate CA. The role of dissociation in ketamine’s antidepressant effects. Nat Commun 2020; 11: 6431
• 31 Phillips JL, Norris S, Talbot J. et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: A randomized controlled trial. Am J Psychiatry 2019; 176: 401-409
• 32 Valentine GW, Mason GF, Gomez R. et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [1H]-MRS. Psychiatry Research: Neuroimaging 2011; 191: 122-127
• 33 Luckenbaugh DA, Niciu MJ, Ionescu DF. et al. Do the dissociative side effects of ketamine mediate its antidepressant effects?. J Affect Disord 2014; 159: 56-61
• 34 Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382-389
• 35 Bremner JD, Krystal JH, Putnam FW. et al. Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress 1998; 11: 125-136
• 36 Bech P, Allerup P, Gram LF. et al. The Hamilton depression scale. Evaluation of objectivity using logistic models. Acta Psychiatr Scand 1981; 63: 290-299
• 37 Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56-62
• 38 O’Sullivan RL, Fava M, Agustin C. et al. Sensitivity of the six-item Hamilton Depression Rating Scale. Acta Psychiatr Scand 1997; 95: 379-384
• 39 Bech P, Boyer P, Germain J-M. et al. HAM-D17 and HAM-D6 sensitivity to change in relation to desvenlafaxine dose and baseline depression severity in major depressive disorder. Pharmacopsychiatry 2010; 43: 271-276
• 40 American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-5.
• 41 Murphy JA, Byrne GJ. Prevalence and correlates of the proposed DSM-5 diagnosis of Chronic Depressive Disorder. J Affect Disord 2012; 139: 172-180
• 42 Negt P, Brakemeier E-L, Michalak J. et al. The treatment of chronic depression with cognitive behavioral analysis system of psychotherapy: A systematic review and meta-analysis of randomized-controlled clinical trials. Brain Behav 2016; 6: e00486
• 43 Kocsis JH. Pharmacotherapy for chronic depression. J Clin Psychol 2003; 59: 885-892
• 44 Cuijpers P, van Straten A, Schuurmans J. et al. Psychotherapy for chronic major depression and dysthymia: a meta-analysis. Clin Psychol Rev 2010; 30: 51-62
• 45 Kocsis JH, Gelenberg AJ, Rothbaum BO. et al. Cognitive behavioral analysis system of psychotherapy and brief supportive psychotherapy for augmentation of antidepressant nonresponse in chronic depression: the REVAMP Trial. Arch Gen Psychiatry 2009; 66: 1178-1188
• 46 Thapar A, Eyre O, Patel V. et al. Depression in young people. Lancet 2022; 400: 617-631
• 47 Reynolds CF, Dew MA, Frank E. et al. Effects of age at onset of first lifetime episode of recurrent major depression on treatment response and illness course in elderly patients. Am J Psychiatry 1998; 155: 795-799
• 48 Kautzky A, Möller H-J, Dold M. et al. Combining machine learning algorithms for prediction of antidepressant treatment response. Acta Psychiatr Scand 2021; 143: 36-49
• 49 Kautzky A, Baldinger-Melich P, Kranz GS. et al. A new prediction model for evaluating treatment-resistant depression. J Clin Psychiatry 2017; 78: 215-222
• 50 Sanacora G, Zarate CA, Krystal JH. et al. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 2008; 7: 426-437
• 51 Aleksandrova LR, Phillips AG, Wang YT. Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism. J Psychiatry Neurosci 2017; 42: 222-229
• 52 Beneyto M, Kristiansen LV, Oni-Orisan A. et al. Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacology 2007; 32: 1888-1902
• 53 Duric V, Banasr M, Stockmeier CA. et al. Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int J Neuropsychopharmacol 2013; 16: 69-82
• 54 Freudenberg F, Celikel T, Reif A. The role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in depression: Central mediators of pathophysiology and antidepressant activity?. Neurosci Biobehav Rev 2015; 52: 193-206
• 55 Qiao H, An S-C, Ren W. et al. Progressive alterations of hippocampal CA3-CA1 synapses in an animal model of depression. Behav Brain Res 2014; 275: 191-200
• 56 Arisawa T, Miyazaki T, Ota W. et al. [11C]K-2 image with positron emission tomography represents cell surface AMPA receptors. Neurosci Res 2021;
• 57 Hatano M, Miyazaki T, Ishiwata Y. et al. Biodistribution and radiation dosimetry of the positron emission tomography probe for AMPA receptor, [11C]K-2, in healthy human subjects. Sci Rep 2021; 11: 1598
• 58 Miyazaki T, Nakajima W, Hatano M. et al. Visualization of AMPA receptors in living human brain with positron emission tomography. Nat Med 2020; 26: 281-288
• 59 Miyazaki T, Abe H, Uchida H. et al. Translational medicine of the glutamate AMPA receptor. Proc Jpn Acad Ser B Phys Biol Sci 2021; 97: 1-21