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Multiple-therapy-resistant major depressive disorder: a clinically important concept

  • R. H. McAllister-Williams (a1), D. M. B. Christmas (a2), A. J. Cleare (a3), A. Currie (a4), J. Gledhill (a5), L. Insole (a6), A. L. Malizia (a7), M. McGeever (a8), R. Morriss (a9), L. J. Robinson (a1), M. Scott (a10), P. R. A. Stokes (a3), P. S. Talbot (a11) and A. H. Young (a12)...


Many novel therapeutic options for depression exist that are either not mentioned in clinical guidelines or recommended only for use in highly specialist services. The challenge faced by clinicians is when it might be appropriate to consider such ‘non-standard’ interventions. This analysis proposes a framework to aid this decision.

Declaration of interest

In the past 3 years R.H.M.W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, LivaNova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. D.M.B.C. has received fees from LivaNova for attending an advisory board. In the past 3 years A.J.C. has received fees for lecturing from Astra Zeneca and Lundbeck; fees for consulting from LivaNova, Janssen and Allergan; and research grant support from Lundbeck.

In the past 3 years A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. In the past 3 years A.L.M. has received support for attending seminars and fees for consultancy work (including advisory board) from Medtronic Inc and LivaNova. R.M. holds joint research grants with a number of digital companies that investigate devices for depression including Alpha-stim, Big White Wall, P1vital, Intel, Johnson and Johnson and Lundbeck through his mindTech and CLAHRC EM roles. M.S. is an associate at Blueriver Consulting providing intelligence to NHS organisations, pharmaceutical and devices companies. He has received honoraria for presentations and advisory boards with Lundbeck, Eli Lilly, URGO, AstraZeneca, Phillips and Sanofi and holds shares in Johnson and Johnson. In the past 3 years P.R.A.S. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending an advisory board) from life sciences companies including Corcept Therapeutics, Indivior and LivaNova. In the past 3 years P.S.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has received funding for investigator initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth.


Corresponding author

Correspondence: R. H. McAllister-Williams, Wolfson Research Centre, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5LP, UK. Email:


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1National Institute for Health and Care Excellence. Depression: The Treatment and Management of Depression in Adults (update). Clinical Guideline 91. NICE, 2009
2Cleare, A, Pariante, CM, Young, AH, Anderson, IM, Christmas, D, Cowen, PJ, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol 2015; 29: 459525.
3de Diego-Adelino, J, Portella, MJ, Puigdemont, D, Perez-Egea, R, Alvarez, E, Perez, V. A short duration of untreated illness (DUI) improves response outcomes in first-depressive episodes. J Affect Disord 2010; 120: 221–5.
4Rhebergen, D, Beekman, AT, De, GR, Nolen, WA, Spijker, J, Hoogendijk, WJ et al. Trajectories of recovery of social and physical functioning in major depression, dysthymic disorder and double depression: a 3-year follow-up. J Affect Disord 2010; 124: 148–56.
5Bauer, M, Pretorius, HW, Constant, EL, Earley, WR, Szamosi, J, Brecher, M. Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo-controlled, double-blind study. J Clin Psychiatry 2009; 70: 540–9.
6Dunner, DL, Rush, AJ, Russell, JM, Burke, M, Woodard, S, Wingard, P, Allen, J. Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. J Clin Psychiatry 2006; 67: 688–95.
7Dunlop, BW, Kelley, ME, Aponte-Rivera, V, Mletzko-Crowe, T, Kinkead, B, Ritchie, JC, et al. Effects of Patient Preferences on Outcomes in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) Study. Am J Psychiatry 2017; 174: 546–56.
8Gaynes, 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. Psychiatr Serv 2009; 60: 1439–45.
9Conway, CR, George, MS, Sackeim, HA. Toward an evidence-based, operational definition of treatment-resistant depression: when enough is enough. JAMA Psychiatry 2017; 74: 910.
10Haddad, PM, Talbot, PS, Anderson, IM, McAllister-Williams, RH. Managing inadequate antidepressant response in depressive illness. Br Med Bull 2015; 115: 183201.
11Arnow, BA, Steidtmann, D, Blasey, C, Manber, R, Constantino, MJ, Klein, DN, et al. The relationship between the therapeutic alliance and treatment outcome in two distinct psychotherapies for chronic depression. J Consult Clin Psychol 2013; 81: 627–38.
12DeRubeis, RJ, Cohen, ZD, Forand, NR, Fournier, JC, Gelfand, LA, Lorenzo-Luaces, L. The Personalized Advantage Index: translating research on prediction into individualized treatment recommendations. A demonstration. PLoS One 2014; 9: e83875.
13Weck, F, Grikscheit, F, Jakob, M, Hofling, V, Stangier, U. Treatment failure in cognitive-behavioural therapy: therapeutic alliance as a precondition for an adherent and competent implementation of techniques. Br J Clin Psychol 2015; 54: 91108.
14Scottish ECT Audit Network. Annual Report 2015: A Summary of ECT in Scotland for 2014. Scottish ECT Audit Network, 2015.
15Pae, CU, Lim, HK, Han, C, Neena, A, Lee, C, Patkar, AA. Selegiline transdermal system: current awareness and promise. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 1153–63.
16Wiersma, JE, Van Schaik, DJ, Hoogendorn, AW, Dekker, JJ, Van, HL, Schoevers, RA, et al. The effectiveness of the cognitive behavioral analysis system of psychotherapy for chronic depression: a randomized controlled trial. Psychother Psychosom 2014; 83: 263–69.
17Goss, AJ, Kaser, M, Costafreda, SG, Sahakian, BJ, Fu, CH. Modafinil augmentation therapy in unipolar and bipolar depression: a systematic review and meta-analysis of randomized controlled trials. J Clin Psychiatry 2013; 74: 1101–7.
18Kleeblatt, J, Betzler, F, Kilarski, LL, Bschor, T, Kohler, S. Efficacy of off-label augmentation in unipolar depression: a systematic review of the evidence. Eur Neuropsychopharmacol 2017; 27: 423–41.
19Strejilevich, SA, Martino, DJ, Igoa, A, Manes, F. Pathological gambling in a bipolar patient treated with pramipexole. J Neuropsychiatry Clin Neurosci 2011; 23: E23.
20Bobo, WV, Voort, JL, Croarkin, PE, Leung, JG, Tye, SJ, Frye, MA. Ketamine for treatment-resistant unipolar and bipolar major depression: critical review and implications for clinical practice. Depress Anxiety 2016; 33: 698710.
21National Institute for Health and Care Excellence. Repetitive Transcranial Magnetic Stimulation for Depression. NICE Interventional Procedure Guidance (IPG542) NICE, 2015.
22National Institute for Health and Care Excellence. Vagus Nerve Stimulation for Treatment Resistent Depression. NICE Interventional Procedure Guidance (IPG 330). NICE: 2009.
23Aaronson, ST, Sears, P, Ruvuna, F, Bunker, M, Conway, CR, Dougherty, DD, et al. A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: comparison of response, remission, and suicidality. Am J Psychiatry 2017; 174: 640–8.
24American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder (5th edn) (DSM-5). APA, 2013.
25Cuijpers, P, Berking, M, Andersson, G, Quigley, L, Kleiboer, A, Dobson, KS. A meta-analysis of cognitive-behavioural therapy for adult depression, alone and in comparison with other treatments. Can J Psychiatry 2013; 58: 376–85.
26Morriss, R, Garland, A, Nixon, N, Guo, B, James, M, Kaylor-Hughes, C, et al. Efficacy and cost-effectiveness of a specialist depression service versus usual specialist mental health care to manage persistent depression: a randomised controlled trial. Lancet Psychiatry 2016; 3: 821–31.
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Multiple-therapy-resistant major depressive disorder: a clinically important concept

  • R. H. McAllister-Williams (a1), D. M. B. Christmas (a2), A. J. Cleare (a3), A. Currie (a4), J. Gledhill (a5), L. Insole (a6), A. L. Malizia (a7), M. McGeever (a8), R. Morriss (a9), L. J. Robinson (a1), M. Scott (a10), P. R. A. Stokes (a3), P. S. Talbot (a11) and A. H. Young (a12)...
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