The substantive delay (often 4–6 weeks) between the commencement of an antidepressant and any discernible improvement in depressive symptoms is an ongoing concern in the management of depressive disorders. This delay incurs the risk of cessation of medication, self-harm/suicide and ongoing ‘damage’ to the brain caused by the illness. Both historically and now, off-label polypharmacy has been used in clinical practice in an attempt to facilitate both immediate- and long-term relief from symptoms. While somewhat effective, this strategy was unregulated and associated with severe adverse side effects for patients. In this article we proffer an alternative paradigm to achieve a more rapid antidepressant response by conceptualising the gap in terms of windows of response. The Windows of Antidepressant Response Paradigm (WARP) frames treatment response as windows of time in which a clinical response can be expected following initiation of an antidepressant. The paradigm defines three distinct windows—the immediate-response window (1–2 days), fast-response window (up to 1 week) and slow-response window (from 1 week onwards). Newer agents such as rapid-acting antidepressants are considered to act within the immediate-response window, whereas atypical antipsychotic augmentation strategies are captured within the fast-response window. The slow-response window represents the delay experienced with conventional antidepressant monotherapy. Novel agents such as esketamine and brexpiprazole are discussed as examples to better understand the clinical utility of WARP. This framework can be used to guide research in this field and aide the development of newer, more effective antidepressant agents as well as providing a strategy to guide the prescription of multiple agents in clinical practice.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
World Health Organization. Depression. Fact sheet No. 369. 2017. Accessed Apr 2017.
Lim GY, Tam WW, Lu Y, Ho CS, Zhang MW, Ho RC. Prevalence of depression in the community from 30 countries between 1994 and 2014. Sci Rep. 2018;8(1):2861.
Sinyor M, Rezmovitz J, Zaretsky A. Screen all for depression. British Medical Journal Publishing Group; 2016.
Malhi GS, Bassett D, Boyce P, Bryant R, Fitzgerald PB, Fritz K, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2015;49(12):1087–206.
NICE Depression: Treatment and Management of Depression in Adults. Clinical Guideline 90: London: National Institute for Health and Clinical Excellence; 2009.
Malhi GS, Mann JJ. Depression. Lancet. 2018;392(10161):2299–312.
Middleton H, Shaw I, Hull S, Feder G. NICE guidelines for the management of depression. British Medical Journal Publishing Group; 2005.
Malhi GS, Das P, Mannie Z, Irwin L. Treatment-resistant depression: problematic illness or a problem in our approach? Br J Psychiatry. 2019;214(1):1–3.
Malhi GS, Bell E. Make news: treatment-resistant depression—an irreversible problem in need of a reversible solution? Aust N Z J Psychiatry. 2020;54(1):111–3.
Mojtabai R, Olfson M. National trends in psychotropic medication polypharmacy in office-based psychiatry. Arch Gen Psychiatry. 2010;67(1):26–36.
Rhee TG, Rosenheck RA. Psychotropic polypharmacy reconsidered: between-class polypharmacy in the context of multimorbidity in the treatment of depressive disorders. J Affect Disord. 2019;252:450–7.
Rhee TG, Mohamed S, Rosenheck RA. Antipsychotic prescriptions among adults with major depressive disorder in office-based outpatient settings: national trends from 2006 to 2015. J Clin Psychiatry. 2018;79(2).
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR* D report. Am J Psychiatry. 2006;163(11):1905–17.
Gaynes BN, Warden D, Trivedi MH, Wisniewski SR, Fava M, Rush AJ. What did STAR* D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatric Serv. 2009;60(11):1439–45.
Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, Mohr DC, Schatzberg AF. Major depressive disorder. Nat Rev Dis Primers. 2016;2(1):1–20.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®): American Psychiatric Pub; 2013.
Ferguson JM. SSRI antidepressant medications: adverse effects and tolerability. Prim Care Companion J Clin Psychiatry. 2001;3(1):22.
Predictable S. Side effects of antidepressants: an overview. Clevel Clin J Med. 2006;73:351.
López-Muñoz F, Ucha-Udabe R, Alamo C. The history of barbiturates a century after their clinical introduction. Neuropsychiatr Dis Treat. 2005;1(4):329.
Fang S-Y, Chen C-Y, Chang I-S, Wu EC-H, Chang C-M, Lin K-M. Predictors of the incidence and discontinuation of long-term use of benzodiazepines: a population-based study. Drug Alcohol Depend. 2009;104(1–2):140–6.
Fassaert T, Dorn T, Spreeuwenberg PM, Van Dongen MC, Van Gool CJ, Yzermans CJ. Prescription of benzodiazepines in general practice in the context of a man-made disaster: a longitudinal study. Eur J Public Health. 2007;17(6):612–7.
Cunningham CM, Hanley GE, Morgan S. Patterns in the use of benzodiazepines in British Columbia: examining the impact of increasing research and guideline cautions against long-term use. Health Policy. 2010;97(2–3):122–9.
Bridges P. … and a small dose of an antidepressant might help. Br J Psychiatry. 1983;142(6):626–8.
Stroup TS, Gray N. Management of common adverse effects of antipsychotic medications. World Psychiatry. 2018;17(3):341–56.
Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC. Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes. PLoS Med. 2013;10(3):e1001403.
Carney S. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet. 2003;361(9360):799–808.
Lisanby SH. Electroconvulsive therapy for depression. N Engl J Med. 2007;357(19):1939–45.
Isacsson G, Bergman U, Rich CL. Epidemiological data suggest antidepressants reduce suicide risk among depressives. J Affect Disord. 1996;41(1):1–8.
Isacsson G, Rich CL, Jureidini J, Raven M. The increased use of antidepressants has contributed to the worldwide reduction in suicide rates. Br J Psychiatry. 2010;196(6):429–33.
Hennen J, Baldessarini RJ. Suicidal risk during treatment with clozapine: a meta-analysis. Schizophr Res. 2005;73(2–3):139–45.
Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646.
McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379(9817):721–8.
Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2018;175(7):620–30.
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.
Machado-Vieira R, Henter ID, Zarate CA Jr. New targets for rapid antidepressant action. Prog Neurobiol. 2017;152:21–37.
Witkin JM, Knutson DE, Rodriguez GJ, Shi S. Rapid-acting antidepressants. Curr Pharm Des. 2018;24(22):2556–633.
Alt A, Nisenbaum ES, Bleakman D, Witkin JM. A role for AMPA receptors in mood disorders. Biochem Pharmacol. 2006;71(9):1273–88.
Molero P, Ramos-Quiroga J, Martin-Santos R, Calvo-Sánchez E, Gutiérrez-Rojas L, Meana J. Antidepressant efficacy and tolerability of ketamine and esketamine: a critical review. CNS Drugs. 2018;32(5):411–20.
Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, Thase ME, Winokur A, Van Nueten L, Manji H, Drevets WC. 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.
Correia-Melo FS, Leal GC, Vieira F, Jesus-Nunes AP, Mello RP, Magnavita G, Caliman-Fontes AT, Echegaray MV, Bandeira ID, Silva SS, Cavalcanti DE. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: a randomized, double-blind, non-inferiority study. J Affect Disord. 2020;264:527–34.
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.
Zarate CA, 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.
Shelton RC, Papakostas GI. Augmentation of antidepressants with atypical antipsychotics for treatment-resistant major depressive disorder. Acta Psychiatr Scand. 2008;117(4):253–9.
Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166(9):980–91.
Zhou X, Keitner GI, Qin B, Ravindran AV, Bauer M, Del Giovane C, et al. Atypical antipsychotic augmentation for treatment-resistant depression: a systematic review and network meta-analysis. Int J Neuropsychopharmacol. 2015;18(11):pyv060.
Croxtall JD, Scott LJ. Olanzapine/fluoxetine. CNS Drugs. 2010;24(3):245–62.
Pae C-U, Forbes A, Patkar AA. Aripiprazole as adjunctive therapy for patients with major depressive disorder. CNS Drugs. 2011;25(2):109–27.
Pae C-U, Sohi MS, Seo H-J, Serretti A, Patkar AA, Steffens DC, et al. Quetiapine XR: current status for the treatment of major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(7):1165–73.
Covvey JR, Crawford AN, Lowe DK. Intravenous ketamine for treatment-resistant major depressive disorder. Ann Pharmacother. 2012;46(1):117–23.
Moaddel R, Abdrakhmanova G, Kozak J, Jozwiak K, Toll L, Jimenez L, et al. Sub-anesthetic concentrations of (R, S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors. Eur J Pharmacol. 2013;698(1–3):228–34.
Wajs E, Leah A, Morrison R, Daly E, Lane R, Lim P, et al. Long-term safety of esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: SUSTAIN-2 phase 3 study. Eur Neuropsychopharmacol. 2019;29:S44–S45.
Anderson RH. Intranasal esketamine. Curr Psychiatry. 2019;18(5):31–8.
Turner EH. Esketamine for treatment-resistant depression: seven concerns about efficacy and FDA approval. Lancet Psychiatry. 2019;6(12):977–9.
Fornaro M, Fusco A, Anastasia A, Cattaneo CI, De Berardis D. Brexpiprazole for treatment-resistant major depressive disorder. Expert Opin Pharmacother. 2019;20(16):1925–33.
McKeage K. Adjunctive brexpiprazole: a review in major depressive disorder. CNS Drugs. 2016;30(2):91–9.
Thase ME, Youakim JM, Skuban A, Hobart M, Augustine C, Zhang P, et al. Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. J Clin Psychiatry. 2015;76(9):1224–311.
Thase ME, Youakim JM, Skuban A, Hobart M, Zhang P, McQuade RD, et al. Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study. J Clin Psychiatry. 2015;76(9):1232–40.
G.S.M. has received grant or research support from National Health and Medical Research Council, Australian Rotary Health, NSW Health, American Foundation for Suicide Prevention, Ramsay Research and Teaching Fund, Elsevier, AstraZeneca, Janssen-Cilag, Lundbeck, Otsuka and Servier; and has been a consultant for AstraZeneca, Janssen-Cilag, Lundbeck, Otsuka and Servier.
Conflict of interest
The authors EB, GM and AH declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors received no financial support for the research, authorship, and/or publication of this article.
Rights and permissions
About this article
Cite this article
Malhi, G.S., Morris, G., Bell, E. et al. A New Paradigm for Achieving a Rapid Antidepressant Response. Drugs 80, 755–764 (2020). https://doi.org/10.1007/s40265-020-01303-1