Skip to main content Accessibility help
×
×
Home

Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition

  • Diego Hidalgo-Mazzei (a1), Michael Berk (a2), Andrea Cipriani (a3), Anthony J. Cleare (a4), Arianna Di Florio (a5), Daniel Dietch (a6), John R. Geddes (a7), Guy M. Goodwin (a8), Heinz Grunze (a9), Joseph F. Hayes (a10), Ian Jones (a11), Siegfried Kasper (a12), Karine Macritchie (a13), R. Hamish McAllister-Williams (a14), Richard Morriss (a15), Sam Nayrouz (a16), Sofia Pappa (a17), Jair C. Soares (a18), Daniel J. Smith (a19), Trisha Suppes (a20), Peter Talbot (a21), Eduard Vieta (a22), Stuart Watson (a23), Lakshmi N. Yatham (a24), Allan H. Young (a25) and Paul R. A. Stokes (a26)...
  • Please note a correction has been issued for this article.

Abstract

Background

Most people with bipolar disorder spend a significant percentage of their lifetime experiencing either subsyndromal depressive symptoms or major depressive episodes, which contribute greatly to the high levels of disability and mortality associated with the disorder. Despite the importance of bipolar depression, there are only a small number of recognised treatment options available. Consecutive treatment failures can quickly exhaust these options leading to treatment-resistant bipolar depression (TRBD). Remarkably few studies have evaluated TRBD and those available lack a comprehensive definition of multi-therapy-resistant bipolar depression (MTRBD).

Aims

To reach consensus regarding threshold definitions criteria for TRBD and MTRBD.

Method

Based on the evidence of standard treatments available in the latest bipolar disorder treatment guidelines, TRBD and MTRBD criteria were agreed by a representative panel of bipolar disorder experts using a modified Delphi method.

Results

TRBD criteria in bipolar depression was defined as failure to reach sustained symptomatic remission for 8 consecutive weeks after two different treatment trials, at adequate therapeutic doses, with at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination treatment. MTRBD included the same initial definition as TRBD, with the addition of failure of at least one trial with an antidepressant, a psychological treatment and a course of electroconvulsive therapy.

Conclusions

The proposed TRBD and MTRBD criteria may provide an important signpost to help clinicians, researchers and stakeholders in judging how and when to consider new non-standard treatments. However, some challenging diagnostic and therapeutic issues were identified in the consensus process that need further evaluation and research.

Declaration of interest

In the past 3 years, M.B. has received grant/research support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, Mayne Pharma, Servier, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Eli Lilly, Grunbiotics, Glaxo SmithKline, Janssen Cilag, LivaNova, Lundbeck, Merck, Mylan, Otsuka, Pfizer and Servier. A.J.C. has in the past 3 years received honoraria for speaking from Astra Zeneca and Lundbeck, honoraria for consulting from Allergan, Janssen, Lundbeck and LivaNova and research grant support from Lundbeck. G.M.G. holds shares in P1Vital and has served as consultant, advisor or CME speaker for Allergan, Angelini, Compass pathways, MSD, Lundbeck, Otsuka, Takeda, Medscape, Minervra, P1Vital, Pfizer, Servier, Shire and Sun Pharma. J.G. has received research funding from National Institute for Health Research, Medical Research Council, Stanley Medical Research Institute and Wellcome. H.G. received grants/research support, consulting fees or honoraria from Gedeon Richter, Genericon, Janssen Cilag, Lundbeck, Otsuka, Pfizer and Servier. 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, Liva Nova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. R.M. has received research support from Big White Wall, Electromedical Products, Johnson and Johnson, Magstim and P1Vital. S.N. received honoraria from Lundbeck, Jensen and Otsuka. J.C.S. has received funds for research from Alkermes, Pfizer, Allergan, J&J, BMS and been a speaker or consultant for Astellas, Abbott, Sunovion, Sanofi. S.W has, within the past 3 years, attended advisory boards for Sunovion and LivaNova and has undertaken paid lectures for Lundbeck. D.J.S. has received honoraria from Lundbeck. T.S. has reported grants from Pathway Genomics, Stanley Medical Research Institute and Palo Alto Health Sciences; consulting fees from Sunovion Pharamaceuticals Inc.; honoraria from Medscape Education, Global Medical Education and CMEology; and royalties from Jones and Bartlett, UpToDate and Hogrefe Publishing. S.P. has served as a consultant or speaker for Janssen, and Sunovion. P.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. E.V. received grants/ research support, consulting fees or honoraria from Abbott, AB-Biotics, Allergan, Angelini, Dainippon Sumitomo, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka and Sunovion. L.N.Y. has received grants/research support, consulting fees or honoraria from Allergan, Alkermes, Dainippon Sumitomo, Janssen, Lundbeck, Otsuka, Sanofi, Servier, Sunovion, Teva and Valeant. 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 also previously received funding for investigator-initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth. P.R.A.S. has received research funding support from Corcept Therapeutics Inc. Corcept Therapeutics Inc fully funded attendance at their internal conference in California USA and all related expenses. He has received grant funding from the Medical Research Council UK for a collaborative study with Janssen Research and Development LLC. Janssen Research and Development LLC are providing non-financial contributions to support this study. P.R.A.S. has received a presentation fee from Indivior and an advisory board fee from LivaNova.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition
      Available formats
      ×

Copyright

Corresponding author

Correspondence: Paul R. A. Stokes, Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Room E2.06, 2nd floor, Main Building, De Crespigny Park, London SE5 8AF, UK. Email: paul.r.stokes@kcl.ac.uk

References

Hide All
1Kupka, RW, Altshuler, LL, Nolen, WA, Suppes, T, Luckenbaugh, DA, Leverich, GS, et al. Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder. Bipolar Disord 2007; 9: 531–5.
2Post, RM. The impact of bipolar depression. J Clin Psychiatry 2005; 66 (suppl 5): 510.
3Tondo, L, Vázquez, GH, Baldessarini, RJ. Options for pharmacological treatment of refractory bipolar depression. Curr Psychiatry Rep 2014; 16: 431.
4Li, C-T, Bai, Y-M, Huang, Y-L, Chen, Y-S, Chen, T-J, Cheng, J-Y, et al. Association between antidepressant resistance in unipolar depression and subsequent bipolar disorder: cohort study. Br J Psychiatry 2012; 200: 4551.
5Sienaert, P, Lambrichts, L, Dols, A, De Fruyt, J. Evidence-based treatment strategies for treatment-resistant bipolar depression: a systematic review. Bipolar Disord 2013; 15: 61–9.
6Suppes, T, Webb, A, Paul, B, Carmody, T, Kraemer, H, Rush, AJ. Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania. Am J Psychiatry 1999; 156: 1164–9.
7Pacchiarotti, I, Mazzarini, L, Colom, F, Sanchez-Moreno, J, Girardi, P, Kotzalidis, GD, et al. Treatment-resistant bipolar depression: towards a new definition. Acta Psychiatr Scand 2009; 120: 429–40.
8Sachs, GS. Treatment-resistant bipolar depression. Psychiatr Clin North Am 1996; 19: 215–36.
9Poon, SH, Sim, K. Evidence-based pharmacological approaches for treatment-resistant bipolar disorder. Treat mood Disord 2015: 8393.
10McAllister-Williams, RH, Christmas, DMB, Cleare, AJ, Currie, A, Gledhill, J, Insole, L, et al. Multiple-therapy-resistant major depressive disorder: a clinically important concept. Br J Psychiatry 2018; 212: 274–8.
11Goodwin, GM, Haddad, PM, Ferrier, IN, Aronson, JK, Barnes, TRH, Cipriani, A, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2016; 30: 495553.
12The National Institute for Health and Care Excellence. Bipolar Disorder: Assessment and Management. NICE Clinical Guideline 185. NICE, 2014.
13Dalkey, NC. The Delphi Method: An Experimental Study of Group Opinion. RAND Corporation, 1969.
14Jorm, AF. Using the Delphi expert consensus method in mental health research. Aust New Zeal J Psychiatry 2015; 49: 887–97.
15Donaldson, L. Expert patients usher in a new era of opportunity for the NHS. BMJ 2003; 326: 1279–80.
16Pacchiarotti, I, Bond, DJ, Baldessarini, RJ, Nolen, WA, Grunze, H, Licht, RW, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry 2013; 170: 1249–62.
17Medicines and Healthcare Products Regulatory Agency. Valproate Medicines (Epilim , Depakote ): Contraindicated in Women and Girls of Childbearing Potential Unless Conditions of Pregnancy Prevention Programme are Met. Medicines and Healthcare Products Regulatory Agency, 2018 (https://www.gov.uk/drug-safety-update/valproate-medicines-epilim-depakote-contraindicated-in-women-and-girls-of-childbearing-potential-unless-conditions-of-pregnancy-prevention-programme-are-met).
18Forty, L, Smith, D, Jones, L, Jones, I, Caesar, S, Cooper, C, et al. Clinical differences between bipolar and unipolar depression. Br J Psychiatry 2008; 192: 388–9.
19Young, AH, McElroy, SL, Bauer, M, Philips, N, Chang, W, Olausson, B, et al. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry 2010; 71: 150–62.
20Hirschfeld, RM, Calabrese, JR, Frye, MA, Lavori, PW, Sachs, G, Thase, ME, et al. Defining the clinical course of bipolar disorder: response, remission, relapse, recurrence, and roughening. Psychopharmacol Bull 2007; 40: 714.
21Calabrese, JR, Huffman, RF, White, RL, Edwards, S, Thompson, TR, Ascher, JA, et al. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord 2008; 10: 323–33.
22Yatham, LN, Kennedy, SH, Parikh S, V, Schaffer, A, Bond, DJ, Frey, BN, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord 2018; 20: 97170.
23Samalin, L, Vieta, E, Okasha, TA, Uddin, MJ, Ahmadi Abhari, SA, Nacef, F, et al. Management of bipolar disorder in the intercontinental region: an international, multicenter, non-interventional, cross-sectional study in real-life conditions. Sci Rep 2016; 6: 25920.
24Tondo, L, Baldessarini, RJ, Vázquez, G, Lepri, B, Visioli, C. Clinical responses to antidepressants among 1036 acutely depressed patients with bipolar or unipolar major affective disorders. Acta Psychiatr Scand 2013; 127: 355–64.
25McGirr, A, Vöhringer, PA, Ghaemi, SN, Lam, RW, Yatham, LN. Safety and efficacy of adjunctive second-generation antidepressant therapy with a mood stabiliser or an atypical antipsychotic in acute bipolar depression: a systematic review and meta-analysis of randomised placebo-controlled trials. Lancet Psychiatry 2016; 3: 1138–46.
26Jauhar, S, McKenna, PJ, Laws, KR. NICE guidance on psychological treatments for bipolar disorder: searching for the evidence. Lancet Psychiatry 2016; 3: 386–8.
27Kemp, DE, Gao, K, Chan, PK, Ganocy, SJ, Findling, RL, Calabrese, JR. Medical comorbidity in bipolar disorder: relationship between illnesses of the endocrine/metabolic system and treatment outcome. Bipolar Disord 2010; 12: 404–13.
28Lee, JH, Dunner, DL. The effect of anxiety disorder comorbidity on treatment resistant bipolar disorders. Depress Anxiety 2008; 25: 91–7.
29Deckersbach, T, Peters, AT, Sylvia, L, Urdahl, A, Magalhães, PVS, Otto, MW, et al. Do comorbid anxiety disorders moderate the effects of psychotherapy for bipolar disorder? Results from STEP-BD. Am J Psychiatry 2014; 171: 178–86.
30Swartz, HA, Pilkonis, PA, Frank, E, Proietti, JM, Scott, J. Acute treatment outcomes in patients with bipolar I disorder and co-morbid borderline personality disorder receiving medication and psychotherapy. Bipolar Disord 2005; 7: 192–7.
31Zimmerman, M. A Review of 20 years of research on overdiagnosis and underdiagnosis in the rhode Island methods to improve diagnostic assessment and services (MIDAS) project. Can J Psychiatry 2016; 61: 71–9.
32Goikolea, JM, Colom, F, Torres, I, Capapey, J, Valentí, M, Undurraga, J, et al. Lower rate of depressive switch following antimanic treatment with second-generation antipsychotics versus haloperidol. J Affect Disord 2013; 144: 191–8.
33Sachs, GS, Thase, ME, Otto, MW, Bauer, M, Miklowitz, D, Wisniewski, SR, et al. Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry 2003; 53: 1028–42.
34Cooper, SJ, Reynolds, GP, Barnes, T, England, E, Haddad, P, Heald, A, et al. BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment. J Psychopharmacol 2016; 30: 717–48.
35Taylor, G, McNeill, A, Girling, A, Farley, A, Lindson-Hawley, N, Aveyard, P. Change in mental health after smoking cessation: systematic review and meta-analysis. BMJ 2014; 348: g1151.
36American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder (5th edn) (DSM-5). APA, 2013.
37McIntyre, RS, Soczynska, JK, Cha, DS, Woldeyohannes, HO, Dale, RS, Alsuwaidan, MT, et al. The prevalence and illness characteristics of DSM-5-defined ‘mixed feature specifier’ in adults with major depressive disorder and bipolar disorder: results from the International Mood Disorders Collaborative Project. J Affect Disord 2015; 172: 259–64.
38Grunze, H, Vieta, E, Goodwin, GM, Bowden, C, Licht, RW, Azorin, J-M, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: acute and long-term treatment of mixed states in bipolar disorder. World J Biol Psychiatry 2018; 19: 258.
39Verdolini, N, Hidalgo-Mazzei, D, Murru, A, Pacchiarotti, I, Samalin, L, Young, AH, et al. Mixed states in bipolar and major depressive disorders: systematic review and quality appraisal of guidelines. Acta Psychiatr Scand 2018; 138: 196222.
40Goldberg, JF, Allen, MH, Miklowitz, DA, Bowden, CL, Endick, CJ, Chessick, CA, et al. suicidal ideation and pharmacotherapy among STEP-BD patients. Psychiatr Serv 2005; 56: 1534–40.
41Wilkinson, 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.
42Sharma, V, Sharma, S. Peripartum management of bipolar disorder: what do the latest guidelines recommend? Expert Rev Neurother 2017; 17: 335–44.
43Graham, RK, Tavella, G, Parker, GB. Is there consensus across international evidence-based guidelines for the psychotropic drug management of bipolar disorder during the perinatal period? J Affect Disord 2018; 228: 216–21.
44National Institute for Health and Care Excellence (NICE). Antenatal and Postnatal Mental Health. NICE, 2016 (https://www.nice.org.uk/guidance/qs115).
45National Institute for Health and Care Excellence. Falls in Older People: Assessing Risk and Prevention. NICE, 2013.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The British Journal of Psychiatry
  • ISSN: 0007-1250
  • EISSN: 1472-1465
  • URL: /core/journals/the-british-journal-of-psychiatry
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords

Type Description Title
WORD
Supplementary materials

Hidalgo-Mazzei et al. supplementary material
Appendix

 Word (133 KB)
133 KB
WORD
Supplementary materials

Hidalgo-Mazzei et al. supplementary material
Table S1

 Word (13 KB)
13 KB

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed

Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition

  • Diego Hidalgo-Mazzei (a1), Michael Berk (a2), Andrea Cipriani (a3), Anthony J. Cleare (a4), Arianna Di Florio (a5), Daniel Dietch (a6), John R. Geddes (a7), Guy M. Goodwin (a8), Heinz Grunze (a9), Joseph F. Hayes (a10), Ian Jones (a11), Siegfried Kasper (a12), Karine Macritchie (a13), R. Hamish McAllister-Williams (a14), Richard Morriss (a15), Sam Nayrouz (a16), Sofia Pappa (a17), Jair C. Soares (a18), Daniel J. Smith (a19), Trisha Suppes (a20), Peter Talbot (a21), Eduard Vieta (a22), Stuart Watson (a23), Lakshmi N. Yatham (a24), Allan H. Young (a25) and Paul R. A. Stokes (a26)...
  • Please note a correction has been issued for this article.
Submit a response

eLetters

No eLetters have been published for this article.

×

Reply to: Submit a response


Your details


Conflicting interests

Do you have any conflicting interests? *