Interest-activity symptom severity predicts response to ketamine infusion in treatment-resistant depression



Interest and activity are part of the positive mood domain. Evidence suggests the symptom domain of interest-activity at baseline as a clinical predictor for treatment response to traditional antidepressants. However, whether this domain is related to the response to a single low-dose ketamine infusion remains unclear.


Seventy-one patients with treatment-resistant depression were randomized to 3 treatment groups: a single 0.5 or 0.2 mg/kg ketamine or normal saline placebo infusion. Depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale before infusions and at postinfusion period (at 40 min and up to 2 weeks). Low (mild) versus medium versus high (severe) interest-activity symptom domain groups were classified on the basis of the cutoff point of ± 0.4 standard deviation. The effect of baseline interest-activity symptoms on outcomes was tested using generalized estimating equation models.


The interest-activity symptom domain as a continuous variable (β = 8.413, p = .016) was related to the trajectory of depressive symptoms. Stratified by levels of the interest-activity symptom domain, in the low interest-activity, 0.2 mg/kg ketamine infusion (β = 0.013) demonstrated the greatest antidepressant effect (p < .01) compared with 0.5 mg/kg ketamine (β = 0.739) and placebo infusions; however, in the high interest-activity, 0.5 mg/kg ketamine infusion (β = 0.001) demonstrated the best antidepressant effect (p < .01) compared with 0.2 mg/kg ketamine (β = 1.372) and placebo infusions.


The symptom domain of interest-activity was an independent predictor for the treatment response to a single low-dose ketamine infusion.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2


  1. Beck AT, Steer RA, Ball R, Ranieri W (1996) Comparison of Beck depression inventories -IA and -II in psychiatric outpatients. J Pers Assess 67(3):588–597

    CAS  Article  Google Scholar 

  2. Bjorkholm C, Franberg O, Malmerfelt A, Marcus MM, Konradsson-Geuken A, Schilstrom B et al (2014) Adjunctive treatment with asenapine augments the escitalopram-induced effects on monoaminergic outflow and glutamatergic neurotransmission in the medial prefrontal cortex of the rat. Int J Neuropsychopharmacol 8(3):pyu068.

  3. Chen MH, Lin WC, Wu HJ, Bai YM, Li CT, Tsai SJ et al (2020) Efficacy of low-dose ketamine infusion in anxious vs nonanxious depression: revisiting the adjunctive ketamine study of Taiwanese patients with treatment-resistant depression. CNS Spectr 18;1–6.

  4. Demyttenaere K, Van Duppen Z (2019) The impact of (the concept of) treatment-resistant depression: an opinion review. Int J Neuropsychopharmacol 22(2):85–92

    Article  Google Scholar 

  5. Downar J, Geraci J, Salomons TV, Dunlop K, Wheeler S, McAndrews MP, Bakker N, Blumberger DM, Daskalakis ZJ, Kennedy SH, Flint AJ, Giacobbe P (2014) Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression. Biol Psychiatry 76(3):176–185

    Article  Google Scholar 

  6. Dunlop K, Rizvi SJ, Kennedy SH, Hassel S, Strother SC, Harris JK, Zamyadi M, Arnott SR, Davis AD, Mansouri F, Schulze L, Ceniti AK, Lam RW, Milev R, Rotzinger S, Foster JA, Frey BN, Parikh SV, Soares CN, Uher R, Turecki G, MacQueen GM, Downar J (2020) Clinical, behavioral, and neural measures of reward processing correlate with escitalopram response in depression: a Canadian Biomarker Integration Network in Depression (CAN-BIND-1) report. Neuropsychopharmacology 45(8):1390–1397

    CAS  Article  Google Scholar 

  7. Garcia LS, Comim CM, Valvassori SS, Reus GZ, Stertz L, Kapczinski F et al (2009) Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 33(3):450–455

    CAS  Article  Google Scholar 

  8. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62

    CAS  Article  Google Scholar 

  9. Iniesta R, Malki K, Maier W, Rietschel M, Mors O, Hauser J, Henigsberg N, Dernovsek MZ, Souery D, Stahl D, Dobson R, Aitchison KJ, Farmer A, Lewis CM, McGuffin P, Uher R (2016) Combining clinical variables to optimize prediction of antidepressant treatment outcomes. J Psychiatr Res 78:94–102

    Article  Google Scholar 

  10. Kadriu B, Ballard ED, Henter ID, Murata S, Gerlus N, Zarate CA Jr (2020) Neurobiological biomarkers of response to ketamine. Adv Pharmacol 89:195–235

    Article  Google Scholar 

  11. Krystal JH, Sanacora G, Duman RS (2013) Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry 73(12):1133–1141

    CAS  Article  Google Scholar 

  12. Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA (2014) Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry 4:e469

    CAS  Article  Google Scholar 

  13. Li CT, Chen MH, Juan CH, Huang HH, Chen LF, Hsieh JC, Tu PC, Bai YM, Tsai SJ, Lee YC, Su TP (2014) Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Brain 137(Pt 7):2088–2098

    Article  Google Scholar 

  14. Li CT, Chen MH, Lin WC, Hong CJ, Yang BH, Liu RS, Tu PC, Su TP (2016) The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: a randomized controlled study. Hum Brain Mapp 37(3):1080–1090

    Article  Google Scholar 

  15. Liu Q, He H, Yang J, Feng X, Zhao F, Lyu J (2020) Changes in the global burden of depression from 1990 to 2017: findings from the global burden of disease study. J Psychiatr Res 126:134–140

    Article  Google Scholar 

  16. Montgomery SA, Rani SJ, McAuley R, Roy D, Montgomery DB (1981) The antidepressant efficacy of zimelidine and maprotiline. Acta Psychiatr Scand Suppl 290:219–224

    CAS  Article  Google Scholar 

  17. Murrough JW, Burdick KE, Levitch CF, Perez AM, Brallier JW, Chang LC, Foulkes A, Charney DS, Mathew SJ, Iosifescu DV (2015) Neurocognitive effects of ketamine and association with antidepressant response in individuals with treatment-resistant depression: a randomized controlled trial. Neuropsychopharmacology 40(5):1084–1090

    CAS  Article  Google Scholar 

  18. Nakonezny PA, Morris DW, Greer TL, Byerly MJ, Carmody TJ, Grannemann BD, Bernstein IH, Trivedi MH (2015) Evaluation of anhedonia with the Snaith-Hamilton Pleasure Scale (SHAPS) in adult outpatients with major depressive disorder. J Psychiatr Res 65:124–130

    Article  Google Scholar 

  19. Rizvi SJ, Quilty LC, Sproule BA, Cyriac A, Michael Bagby R, Kennedy SH (2015) Development and validation of the Dimensional Anhedonia Rating Scale (DARS) in a community sample and individuals with major depression. Psychiatry Res 229(1–2):109–119

    Article  Google Scholar 

  20. Sinyor M, Schaffer A, Levitt A (2010) The sequenced treatment alternatives to relieve depression (STAR*D) trial: a review. Can J Psychiatr 55(3):126–135

    Article  Google Scholar 

  21. Souery D, Papakostas GI, Trivedi MH (2006) Treatment-resistant depression. J Clin Psychiatry 67(Suppl 6):16–22

    PubMed  Google Scholar 

  22. Su TP, Chen MH, Li CT, Lin WC, Hong CJ, Gueorguieva R, Tu PC, Bai YM, Cheng CM, Krystal JH (2017) Dose-related effects of adjunctive ketamine in Taiwanese patients with treatment-resistant depression. Neuropsychopharmacology 42(13):2482–2492

    CAS  Article  Google Scholar 

  23. Thomas RK, Baker G, Lind J, Dursun S (2018) Rapid effectiveness of intravenous ketamine for ultraresistant depression in a clinical setting and evidence for baseline anhedonia and bipolarity as clinical predictors of effectiveness. J Psychopharmacol 32(10):1110–1117

    CAS  Article  Google Scholar 

  24. Uher R, Farmer A, Maier W, Rietschel M, Hauser J, Marusic A, Mors O, Elkin A, Williamson RJ, Schmael C, Henigsberg N, Perez J, Mendlewicz J, Janzing JGE, Zobel A, Skibinska M, Kozel D, Stamp AS, Bajs M, Placentino A, Barreto M, McGuffin P, Aitchison KJ (2008) Measuring depression: comparison and integration of three scales in the GENDEP study. Psychol Med 38(2):289–300

    CAS  Article  Google Scholar 

  25. Uher R, Frey BN, Quilty LC, Rotzinger S, Blier P, Foster JA, Müller DJ, Ravindran AV, Soares CN, Turecki G, Parikh SV, Milev R, MacQueen G, Lam RW, Kennedy SH, on behalf of the CAN-BIND Investigator Team (2020) Symptom dimension of interest-activity indicates need for aripiprazole augmentation of escitalopram in major depressive disorder: a CAN-BIND-1 report. J Clin Psychiatry 16;81(4):20m13229.

  26. Uher R, Perlis RH, Henigsberg N, Zobel A, Rietschel M, Mors O, Hauser J, Dernovsek MZ, Souery D, Bajs M, Maier W, Aitchison KJ, Farmer A, McGuffin P (2012) Depression symptom dimensions as predictors of antidepressant treatment outcome: replicable evidence for interest-activity symptoms. Psychol Med 42(5):967–980

    CAS  Article  Google Scholar 

  27. Westbrook A, Braver TS (2016) Dopamine does double duty in motivating cognitive effort. Neuron 89(4):695–710

    CAS  Article  Google Scholar 

  28. Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, Hu H (2018) Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 554(7692):317–322

    CAS  Article  Google Scholar 

Download references


We thank all research assistants, physicians, pharmacist, and nursing staffs at D020 Unit of Taipei Veterans General Hospital for their assistance during the study process, without whom this work could have been possible. We thank Mr. I-Fan Hu for his support and friendship.


The study was supported by grant from Taipei Veterans General Hospital (V106B-020, V107B-010, V107C-181, V108B-012), Yen Tjing Ling Medical Foundation (CI-110-30) and Ministry of Science and Technology, Taiwan (107-2314-B-075-063-MY3, 108-2314-B-075 -037). The funding source had no role in any process of our study.

Author information



Corresponding authors

Correspondence to Wei-Chen Lin or Tung-Ping Su.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information


(DOCX 223 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chen, MH., Lin, WC., Wu, HJ. et al. Interest-activity symptom severity predicts response to ketamine infusion in treatment-resistant depression. Psychopharmacology 238, 857–865 (2021).

Download citation


  • Ketamine
  • Treatment-resistant depression
  • Interest-activity