Effects of Low-Dose Ketamine Infusion on the Positive and Negative Domains of Hopelessness and Suicidal Thoughts

Wei-Chen Lin, MD ; Mu-Hong Chen, MD, PhD ; Tung-Ping Su, MD ; Cheng-Ta Li, MD, PhD ; Hui-Ju Wu, BSN ; Shih-Jen Tsai, MD ; Ya-Mei Bai, MD PhD ; Wei-Chung Mao, MD, PhD ; Pei-Chi Tu, MD PhD

J Clin Psychiatry 2024;85(3):24m15257

Abstract

Background: Low-dose ketamine infusion has been demonstrated to exert antisuicidal effects on patients with treatment-resistant depression (TRD) and strong suicidal ideation. Although evidence suggests an association between hopelessness and suicidality, very few studies have investigated the antihopelessness effects of ketamine.

Methods: This study included 84 patients with TRD and strong suicidal ideation. The diagnosis of depression was based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, diagnostic criteria for major depressive disorder. They were randomly assigned to receive a single infusion of either 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. Hopelessness and suicidal symptoms were assessed at baseline, at 240 minutes postinfusion, and on Days 2, 3, 7, and 14 postinfusion. The assessments were performed using the self-report Beck Hopelessness Scale (BHS) and Positive and Negative Suicide Ideation Inventory (PANSI). The analysis focused on the positive and negative domains of the BHS and PANSI, respectively. The clinical trial was conducted between August 15, 2018, and November 30, 2021.

Results: Statistical analyses performed using a generalized linear model revealed that the ketamine group had significantly higher PANSI-positive (P = .008) and lower PANSI-negative (P = .015) suicidal ideation scores on Day 2 postinfusion than did the midazolam group. At 240 minutes postinfusion, the ketamine group had significantly lower BHS-negative domain scores than did the midazolam group (P = .031). Notably, the observed ketamine-induced reduction in hopelessness at 240 minutes postinfusion was associated with its antisuicidal effect on Day 2 postinfusion.

Discussion: A single infusion of low-dose ketamine resulted in a brief (∼4 hours) yet significant reduction in hopelessness. Subjective antisuicidal effects of ketamine were noted on Day 2 postinfusion. Further studies are needed to elucidate the neuromechanisms underlying the antihopelessness and antisuicidal effects of ketamine.

Trial Registration: UMIN Clinical Trials Registry identifiers: UMIN000033916 and UMIN000033760

J Clin Psychiatry 2024;85(3):24m15257

Author affiliations are listed at the end of this article.

Continue Reading...

Did you know members enjoy unlimited free PDF downloads as part of their subscription? Subscribe today for instant access to this article and our entire library in your preferred format. Alternatively, you can purchase the PDF of this article individually.

Subscribe Now

Already a member? Login

Buy PDF for $40

Please sign in or purchase this PDF for $40.

References (38)

Zheng Y, Molassiotis A, Tyrovolas S, et al. Epidemiological changes, demographic drivers, and global years of life lost from suicide over the period 1990–2019. Suicide Life Threat Behav. 2022;52(3):439–451. PubMed CrossRef
Fu TST, Lee CS, Gunnell D, et al. Changing trends in the prevalence of common mental disorders in Taiwan: a 20-year repeated cross-sectional survey. Lancet. 2013;381(9862):235–241. PubMed CrossRef
Price RB, Kissel N, Baumeister A, et al. International pooled patient-level meta analysis of ketamine infusion for depression: in search of clinical moderators. Mol Psychiatry. 2022;27(12):5096–5112. PubMed CrossRef
Su TP, Chen MH, Li CT, et al. Dose-related effects of adjunctive ketamine in Taiwanese patients with treatment-resistant depression. Neuropsychopharmacology. 2017;42(13):2482–2492. PubMed CrossRef
Su TP, Li CT, Lin WC, et al. A randomized, double-blind, midazolam-controlled trial of low-dose ketamine infusion in patients with treatment-resistant depression and prominent suicidal ideation. Int J Neuropsychopharmacol. 2023;26(5):331–339. PubMed CrossRef
Beck AT, Brown G, Steer RA. Prediction of eventual suicide in psychiatric inpatients by clinical ratings of hopelessness. J Consult Clin Psychol. 1989;57(2):309–310. PubMed CrossRef
Beck AT, Brown G, Berchick RJ, et al. Relationship between hopelessness and ultimate suicide: a replication with psychiatric outpatients. Am J Psychiatry. 1990;147(2):190–195. PubMed CrossRef
Li Y, Kwok SYCL. A longitudinal network analysis of the interactions of risk and protective factors for suicidal potential in early adolescents. J Youth Adolesc. 2023;52(2):306–318. PubMed
Ribeiro JD, Huang X, Fox KR, et al. Depression and hopelessness as risk factors for suicide ideation, attempts and death: meta-analysis of longitudinal studies. Br J Psychiatry. 2018;212(5):279–286. PubMed CrossRef
Qiu T, Klonsky ED, Klein DN. Hopelessness predicts suicide ideation but not attempts: a 10-year longitudinal study. Suicide Life Threat Behav. 2017;47(6):718–722. PubMed CrossRef
Ropaj E. Hope and suicidal ideation and behaviour. Curr Opin Psychol. 2023;49:101491. PubMed CrossRef
Grunebaum MF, Galfalvy HC, Choo TH, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry. 2018;175(4):327–335. PubMed CrossRef
Witte TK, Joiner TE Jr., Brown GK, et al. Factors of suicide ideation and their relation to clinical and other indicators in older adults. J Affect Disord. 2006;94(1–3):165–172. PubMed CrossRef
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. PubMed CrossRef
Domany Y, Shelton RC, McCullumsmith CB. Ketamine for acute suicidal ideation. An emergency department intervention: a randomized, double-blind, placebo controlled, proof-of-concept trial. Depress Anxiety. 2020;37(3):224–233. PubMed CrossRef
Osman A, Gutierrez PM, Kopper BA, et al. The positive and negative suicide ideation inventory: development and validation. Psychol Rep. 1998;82(3 Pt 1):783–793. PubMed CrossRef
Evers AG, Murrough JW, Charney DS, et al. Ketamine as a prophylactic resilience enhancing agent. Front Psychiatry. 2022;13:833259. PubMed CrossRef
Brachman RA, McGowan JC, Perusini JN, et al. Ketamine as a prophylactic against stress-induced depressive-like behavior. Biol Psychiatry. 2016;79(9):776–786. PubMed CrossRef
Montgomery SA. Maprotiline, nomifensine, mianserin, zimelidine: a review of antidepressant efficacy in in-patients. Neuropharmacology. 1980;19(12):1185–1190. PubMed CrossRef
Price RB, Nock MK, Charney DS, et al. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66(5):522–526. PubMed CrossRef
Kliem S, Lohmann A, Mößle T, et al. Psychometric properties and measurement invariance of the Beck hopelessness scale (BHS): results from a German representative population sample. BMC psychiatry. 2018;18(1):110. PubMed CrossRef
Chen W, Yang T, Gao R, et al. The factor structure and psychometric properties of the Chinese version of the Positive and Negative Suicide Ideation Inventory (PANSI-C) in a non-clinical sample of Chinese adolescents. Ann Gen Psychiatry. 2021;20(1):47. PubMed CrossRef
Sinniah A, Oei TPS, Chinna K, et al. Psychometric properties and validation of the positive and negative suicide ideation (PANSI) inventory in an outpatient clinical population in Malaysia. Front Psychol. 2015;6:1934. PubMed CrossRef
Horwitz AG, Berona J, Czyz EK, et al. Positive and negative expectations of hopelessness as longitudinal predictors of depression, suicidal ideation, and suicidal behavior in high-risk adolescents. Suicide Life Threat Behav. 2017;47(2):168–176. PubMed CrossRef
Lascelles K, Marzano L, Brand F, et al. Ketamine treatment for individuals with treatment-resistant depression: longitudinal qualitative interview study of patient experiences. BJPsych Open. 2020;7(1):e9. PubMed CrossRef
Ballard ED, Farmer CA, Gerner J, et al. Prospective association of psychological pain and hopelessness with suicidal thoughts. J Affect Disord. 2022;308:243–248. PubMed CrossRef
Papp M, Gruca P, Lason-Tyburkiewicz M, et al. Antidepressant, anxiolytic and procognitive effects of subacute and chronic ketamine in the chronic mild stress model of depression. Behav Pharmacol. 2017;28(1):1–8. PubMed CrossRef
Li CT, Chen MH, Lin WC, et al. The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: a randomized controlled study. Hum Brain Mapp. 2016;37(3):1080–1090. PubMed CrossRef
Chen MH, Li CT, Lin WC, et al. Persistent antidepressant effect of low-dose ketamine and activation in the supplementary motor area and anterior cingulate cortex in treatment-resistant depression: a randomized control study. J Affect Disord. 2018;225:709–714. PubMed CrossRef
Wu J, Dong D, Jackson T, et al. The neural correlates of optimistic and depressive tendencies of self-evaluations and resting-state default mode network. Front Hum Neurosci. 2015;9:618. PubMed CrossRef
Erthal F, Bastos A, Vilete L, et al. Unveiling the neural underpinnings of optimism: a systematic review. Cogn Affect Behav Neurosci. 2021;21(5):895–916. PubMed CrossRef
Morris LS, Costi S, Tan A, et al. Ketamine normalizes subgenual cingulate cortex hyper-activity in depression. Neuropsychopharmacology. 2020;45(6):975–981. PubMed CrossRef
McGhee LL, Maani CV, Garza TH, et al. The correlation between ketamine and posttraumatic stress disorder in burned service members. J Trauma. 2008;64(2 suppl):S195–S198. PubMed CrossRef
McGhee LL, Maani CV, Garza TH, et al. The relationship of intravenous midazolam and posttraumatic stress disorder development in burned soldiers. J Trauma. 2009;66(4 suppl):S186–S190. PubMed CrossRef
Du R, Han R, Niu K, et al. The multivariate effect of ketamine on PTSD: systematic review and meta-analysis. Front Psychiatry. 2022;13:813103. PubMed CrossRef
Abbar M, Demattei C, El-Hage W, et al. Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. BMJ. 2022;376:e067194. PubMed CrossRef
Kwok SYCL, Shek DTL. Hopelessness, parent-adolescent communication, and suicidal ideation among Chinese adolescents in Hong Kong. Suicide Life Threat Behav. 2010;40(3):224–233. PubMed CrossRef
Obayuwana AO, Collins JL, Carter AL, et al. Hope Index Scale: an instrument for the objective assessment of hope. J Natl Med Assoc. 1982;74:761–765. PubMed