Antianhedonic Effect of Repeated Ketamine Infusions in Patients With Treatment Resistant Depression

Alina Wilkowska, Mariusz Stanisław Wiglusz, Maria Gałuszko-Wegielnik, Adam Włodarczyk, Wiesław Jerzy Cubała, Alina Wilkowska, Mariusz Stanisław Wiglusz, Maria Gałuszko-Wegielnik, Adam Włodarczyk, Wiesław Jerzy Cubała

Abstract

Anhedonia constitutes one of the main symptoms of depressive episode. It correlates with suicidality and significantly effects the quality of patient's lives. Available treatments are not sufficient against this group of symptoms. Ketamine is a novel, rapid acting strategy for treatment resistant depression. Here we report the change in symptoms of anhedonia measured by Snaith-Hamilton Pleasure Scale as an effect of eight ketamine infusions as an add-on treatment in 42 patients with treatment resistant depression. We also determined the effect of this change on the severity of depressive symptoms measured by Inventory for Depression Symptomatology-Self Report 30-Item (IDS-SR 30). We have observed statistically significant decrease in the level of anhedonia during ketamine treatment. After adjusting for potential confounders we have found that significant reduction in Snaith-Hamilton Pleasure Scale (SHAPS) after each infusion and 1 week post treatment was observed only among patients who did not use benzodiazepines. The reduction in symptoms of anhedonia mediates the antidepressive effect of ketamine. The results need replication in a larger randomized placebo controlled trial.

Keywords: anhedonia; antianhedonic; benzodiazepines; ketamine; treatment resistant depression.

Conflict of interest statement

AWi has received research support from Angelini, Biogen, Eli Lilly and Company, Janssen- Cilag, Lundbeck, Polpharma, Sanofi and Valeant. MW has received research support from Acadia, Apodemus, Alkermes, Auspex Pharmaceuticals, Cephalon, Ferrier, Forest Laboratories, Gedeon Richter, GWPharma-ceuticals, Janssen, Lundbeck, Orion, Otsuka, Servier; Speaker s Bureau: Lundbeck, Servier. MG-W has received research support from: Janssen, Servier, Alkermes, KCR, Lilly, Biogen, Celon. AWł has received research support from Actavis, Eli Lilly, Minerva Neurosci-ences, Sunovion Pharmaceuticals, KCR, Janssen, Otsuka, Apodemus, Cortexyme, Acadia. WC has received research support from Actavis, Alkermes, Allergan, Angelini, Auspex, Biogen, Bristol-Myers Squibb, Cephalon, Eli Lilly, Ferrier, Forest Laboratories, Gedeon Richter, GW Pharmaceuticals, Janssen, KCR, Lundbeck, Orion, Otsuka, Sanofi, and Ser-vier; he has served on speakers bureaus for Adamed, Angelini, AstraZeneca, Bristol-Myers Squibb, Celon, GlaxoSmithKline, Janssen, Krka, Lekam, Lundbeck, Novartis, Orion, Pfizer, Polfa Tarchomin, Sanofi, Servier, and Zentiva; and he has served as a consultant for GW Pharmaceu-ticals, Janssen, KCR, Quintiles, and Roche.

Copyright © 2021 Wilkowska, Wiglusz, Gałuszko-Wegielnik, Włodarczyk and Cubała.

Figures

Figure 1
Figure 1
Snaith–Hamilton Pleasure Scale (SHAPS) score change during ketamine treatment. ***p < 0.001 in comparison with baseline scores (pre-infusion).
Figure 2
Figure 2
Snaith–Hamilton Pleasure Scale (SHAPS) score change during ketamine treatment in patients using benzodiazepines compared with the rest of the study group. *p < 0.05, **p < 0.01, ***p < 0.001 in comparison with baseline scores (pre-infusion).
Figure 3
Figure 3
The 30-item inventory for Depressive Symptomatology—Self Report (IDS-SR 30) score during ketamine treatment. *p < 0.05, ***p < 0.001 in comparison with baseline scores (pre-infusion).
Figure 4
Figure 4
The mediating effect of anhedonia in the relationship between ketamine treatment and the 30-item Inventory for Depressive Symptomatology—Self Report (IDS-SR 30) score. Snaith–Hamilton Pleasure Scale (SHAPS). #The model presents unstandardized effects.

References

    1. Nutt D, Demyttenaere K, Janka Z, Aarre T, Bourin M, Canonico PL, et al. . The other face of depression, reduced positive affect: the role of catecholamines in causation and cure. J Psychopharmacol. (2007) 21:461–71. 10.1177/0269881106069938
    1. Ducasse D, Loas G, Dassa D, Gramaglia C, Zeppegno P, Guillaume S, et al. . Anhedonia is associated with suicidal ideation independently of depression: a meta-analysis. Depress Anxiety. (2018) 35:382–92. 10.1002/da.22709
    1. Fawcett J, Scheftner WA, Fogg L, Clark DC, Young MA, Hedeker D, et al. . Time related predictors of suicide in major affective disorder. Am J Psychiatry. (1990) 147:1189–94. 10.1176/ajp.147.9.1189
    1. Uher R, Perlis RH, Henigsberg N, Zobel A, Rietschel M, Mors O, et al. . Depression symptom dimensions as predictors of antidepressant treatment outcome: replicable evidence for interest-activity symptoms. Psychol Med. (2012) 42:967–80. 10.1017/S0033291711001905
    1. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. . Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. (2000) 47:351–4. 10.1016/S0006-3223(99)00230-9
    1. Zarate CA, Jaskaran BS, 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) 63:856–64. 10.1001/archpsyc.63.8.856
    1. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, et al. . A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. (2010) 67:793–802. 10.1001/archgenpsychiatry.2010.90
    1. Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, et al. . The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. (2018) 175:150–8. 10.1176/appi.ajp.2017.17040472
    1. Okada D. Synaptic modulation in the effect of ketamine. In: Hashimoto K, Ide S, Ikeda K. eds. Ketamine From Abused Drug to- Rapid-Acting Antidepressant. Singapore: Springer Nature Singapore Pte Ltd.) (2020). p. 70–2.
    1. Abdallah CG, Averill CL, Salas R, Averill LA, Baldwin PR, Krystal JH, et al. . Prefrontal connectivity and glutamate transmission: relevance to depression pathophysiology and ketamine treatment. Biol Psychiatry Cogn Neurosci Neuroimaging. (2017) 2:566–74. 10.1016/j.bpsc.2017.04.006
    1. Rincón-Cortés M, Grace AA. Antidepressant effects of ketamine on depression-related phenotypes and dopamine dysfunction in rodent models of stress. Behav Brain Res. (2020) 379:112367. 10.1016/j.bbr.2019.112367
    1. Kokkinou M, Ashok AH, Howes OD. The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders. Mol Psychiatry. (2018) 23:59–69. 10.1038/mp.2017.190
    1. Kapur S, Seeman P. NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia. Mol Psychiatry. (2002) 7:837–44. 10.1038/sj.mp.4001093
    1. Vollenweider FX, Vontobel P, Oye I, Hell D, Leenders KL. Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans. J Psychiatr Res. (2000) 34:35–43. 10.1016/S0022-3956(99)00031-X
    1. Bechtholt-Gompf AJ, Walther HV, Adams MA, Carlezon WA, Jr, Ongür D, Cohen BM. Blockade of astrocytic glutamate uptake in rats induces signs of anhedonia and impaired spatial memory. Neuropsychopharmacology. (2010) 35:2049–59. 10.1038/npp.2010.74
    1. Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA. Antianhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl. Psychiatry. (2014) 4:e469. 10.1038/tp.2014.105
    1. Lally N, Nugent AC, Luckenbaugh DA, Niciu MJ, Roiser JP, Zarate CA, Jr. Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. J Psychopharmacol. (2015) 29:596–607. 10.1177/0269881114568041
    1. Rodrigues NB, McIntyre RS, Lipsitz O, Cha DS, Lee Y, Gill H, et al. . Changes in symptoms of anhedonia in adults with major depressive or bipolar disorder receiving IV ketamine: results from the Canadian Rapid Treatment Center of Excellence. J Affect Disord. (2020) 276:570–5. 10.1016/j.jad.2020.07.083
    1. Słupski J, Cubała WJ, Górska N, Słupska A, Gałuszko-Wegielnik M. Copper and anti-anhedonic effect of ketamine in treatment-resistant depression. Med Hypotheses. (2020) 144:110268. 10.1016/j.mehy.2020.110268
    1. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. (1996) 19:179–200. 10.1016/S0193-953X(05)70283-5
    1. Poon SH, Sim K, Baldessarini RJ. Pharmacological approaches for treatment-resistant bipolar disorder. Curr Neuropharmacol. (2015) 13:592–604. 10.2174/1570159X13666150630171954
    1. Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. (1995) 167:99–103. 10.1192/bjp.167.1.99
    1. Trivedi MH, Rush AJ, Ibrahim HM, Carmody TJ, Biggs MM, Suppes T, et al. . The inventory of depressive symptomatology, clinician rating (IDS-C) and self-report (IDS-SR), and the quick inventory of depressive symptomatology, clinician rating (QIDS-C) and self-report (QIDS-SR) in public sector patients with mood disorders: a psychometric evaluation. Psychol Med. (2004) 34:73–82. 10.1017/S0033291703001107
    1. Ballard ED, Wills K, Lally N, Richards EM, Luckenbaugh DA, Walls T, et al. . Anhedonia as a clinical correlate of suicidal thoughts in clinical ketamine trials. J Affect Disord. (2017) 218:195–200. 10.1016/j.jad.2017.04.057
    1. Ford N, Ludbrook G, Galletly C. Benzodiazepines may reduce the effectiveness of ketamine in the treatment of depression. Aust N Z J Psychiatry. (2015) 49:1227. 10.1177/0004867415590631
    1. Frye MA, Blier P, Tye SJ. Concomitant benzodiazepine use attenuates ketamine response: implications for large scale study design and clinical development. J Clin Psychofarmacol. (2015) 35:334–6. 10.1097/JCP.0000000000000316
    1. Andrashko V, Novak T, Brunovsky M, Klirova M, Sos P, Horacek J. The antidepressant effect of ketamine is dampened by concomitant benzodiazepine medication. Front Psychiatry. (2020) 28;11:844. 10.3389/fpsyt.2020.00844
    1. Kokane SS, Armant RJ, Bolaños-Guzmán CA, Perrotti LI. Overlap in the neural circuitry and molecular mechanisms underlying ketamine abuse and its use as an antidepressant. Behav Brain Res. (2020) 384:112548. 10.1016/j.bbr.2020.112548
    1. Michelini S, Cassano GB, Frare F, Perugi G. Long-term use of benzodiazepines: tolerance, dependence and clinical problems in anxiety and mood disorders. Pharmacopsychiatry. (1996) 29:127–34. 10.1055/s-2007-979558
    1. Parker GB, Graham RK. Determinants of treatment-resistant depression: the salience of benzodiazepines. J Nerv Ment Dis. (2015) 203:659–63. 10.1097/NMD.0000000000000348
    1. Parker GB, Graham RK. Clinical characteristics associated with treatment-resistant bipolar disorder. J Nerv Ment Dis. (2017) 205:188–91. 10.1097/NMD.0000000000000517
    1. McShane R, Baldwin DS, McAllister-Williams RH, Stone JM, Taylor D, Winstock AR, et al. . Esketamine and the need for a new type of registry for drugs with abuse potential. Am J Psychiatry. (2019) 176:966. 10.1176/appi.ajp.2019.19060631
    1. Wajs E, Aluisio L, Holder R, Daly EJ, Lane R, Lim P, et al. . Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. (2020) 81:19m12891. 10.4088/JCP.19m12891
    1. Taipale H, Tiihonen J. Registry-based studies: what they can tell us, and what they cannot. Eur Neuropsychopharmacol. (2021) 45:35–7. 10.1016/j.euroneuro.2021.03.005

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit