A clinical approach to treatment resistance in depressed patients: What to do when the usual treatments don’t work well enough?

Abstract

Background

Major depressive disorder is a common, recurrent, disabling and costly disorder that is often severe and/or chronic, and for which non-remission on guideline concordant first-line antidepressant treatment is the norm. A sizeable percentage of patients diagnosed with MDD do not achieve full remission after receiving antidepressant treatment. How to understand or approach these ‘refractory’, ‘TRD’ or ‘difficult to treat’ patients need to be revisited. Treatment resistant depression (TRD) has been described elsewhere as failure to respond to adequate treatment by two different antidepressants. This definition is problematic as it suggests that TRD is a subtype of major depressive disorder (MDD), inferring a boundary between TRD and depression that is not treatment resistant. However, there is scant evidence to suggest that a discrete TRD entity exists as a distinct subtype of MDD, which itself is not a discrete or homogeneous entity. Similarly, the boundary between TRD and other forms of depression is predicated at least in part on regulatory and research requirements rather than biological evidence or clinical utility.

Aim

This paper aims to investigate the notion of treatment failure in order to understand (i) what is TRD in the context of a broader formulation based on the understanding of depression, (ii) what factors make an individual patient difficult to treat, and (iii) what is the appropriate and individualised treatment strategy, predicated on an individual with refractory forms of depression?

Method

Expert contributors to this paper were sought internationally by contacting representatives of key professional societies in the treatment of MDD – World Federation of Societies for Biological Psychiatry, Australasian Society for Bipolar and Depressive Disorders, International Society for Affective Disorders, Collegium Internationale Neuro-Psychopharmacologium and the Canadian Network for Mood and Anxiety Treatments. The manuscript was prepared through iterative editing.

Outcomes

The concept of TRD as a discrete subtype of MDD, defined by failure to respond to pharmacotherapy, is not supported by evidence. Between 15 and 30% of depressive episodes fail to respond to adequate trials of 2 antidepressants, and 68% of individuals do not achieve remission from depression after a first-line course of antidepressant treatment. Failure to respond to antidepressant treatment, somatic therapies or psychotherapies may often reflect other factors including; biological resistance, diagnostic error, limitations of current therapies, psychosocial variables, a past history of exposure to childhood maltreatment or abuse, job satisfaction, personality disorders, co-morbid mental and physical disorders, substance use or non-adherence to treatment. Only a subset of patients not responding to antidepressant treatment can be explained through pharmacokinetic or pharmacodynamics mechanisms. We propose that non remitting MDD should be personalised, and propose a strategy of ‘deconstructing depression’. By this approach, the clinician considers which factors contribute to making this individual both depressed and ‘resistant’ to previous therapeutic approaches. Clinical formulation is required to understand the nature of the depression. Many predictors of response are not biological, and reflect a confluence of biological, psychological, and sociocultural factors, which may influence the illness in a particular individual. After deconstructing depression at a personalised level, a personalised treatment plan can be constructed. The treatment plan needs to address the factors that have contributed to the individual’s hard to treat depression. In addition, an individual with a history of illness may have a lot of accumulated life issues due to consequences of their illness, and these should be addressed in a recovery plan.

Limitations

A ‘deconstructing depression’ qualitative rubric does not easily provide clear inclusion and exclusion criteria for researchers wanting to investigate TRD.

Conclusions

MDD is a polymorphic disorder and many individuals who fail to respond to standard pharmacotherapy and are considered hard to treat. These patients are best served by personalised approaches that deconstruct the factors that have contributed to the patient’s depression and implementing a treatment plan that adequately addresses these factors. The existence of TRD as a discrete and distinct subtype of MDD, defined by two treatment failures, is not supported by evidence.

Keywords:

• Depression; resistance; therapy; psychiatry; mental health; neuroscience

Acknowledgements

None.

Statement of interest

SD has received grant support from Stanley Medical Research Institute, NHMRC, Beyond Blue, ARHRF, Simons Foundation, Geelong Medical Research Foundation, Fondation FondaMental, Eli Lilly, Glaxo SmithKline, Organon, Mayne Pharma and Servier. He has received speaker’s fees from Eli Lilly, advisory board fees from Eli Lilly and Novartis and conference travel support from Servier. MBerk has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Astra Zeneca, Lundbeck, Merck, Pfizer, and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Lundbeck Merck, Pfizer and Servier. HE is an employee of PRODEO LLC, PreActive Technologies Inc and Altoida LLC. He serves as a consultant and receives fees from the American Psychological Association and PCORI. He has received fees from CNSdose LLC. AY is funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. SK received grants/research support, consulting fees and/or honoraria within the last three years from Angelini, AOP Orphan Pharmaceuticals AG, Celgene GmbH, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sage, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd., Sun Pharmaceutical Industries Ltd. and Takeda. MF received grants/research support from Acadia Pharmaceuticals, Allergan, Alkermes, Inc., Aptinyx, Avanir Pharmaceuticals Inc., Axsome, Benckiser Pharmaceuticals, Inc., BioClinica, Inc, Biogen, BioHaven, Cambridge Science Corporation, Cerecor, Gate Neurosciences, Inc., GenOmind, LLC, Gentelon, LLC, Happify, Johnson & Johnson, Lundbeck Inc., Marinus Pharmaceuticals, Methylation Sciences, Inc., Millennium Pharmaceutics, Inc. Minerva Neurosciences, Neuralstem, NeuroRX Inc., Novartis, Otsuka, Pfizer, Premiere Research International, Relmada Therapeutics Inc., Reckitt, Shenox Pharmaceuticals, Stanley Medical Research Institute (SMRI), Taisho, Takeda, Vistagen, National Institute of Drug Abuse (NIDA); National Institutes of Health (NIH), National Institute of Mental Health (NIMH), and PCORI. He has not done any personal consulting. Any consulting he has done has been on behalf of Massachusetts General Hospital. He declares Stock/Other Financial Options including: Equity Holdings: Compellis; Psy Therapeutics, Royalty/patent, other income: Patents for Sequential Parallel Comparison Design (SPCD), licenced by MGH to Pharmaceutical Product Development, LLC (PPD) (US_7840419, US_7647235, US_7983936, US_8145504, US_8145505); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licenced by MGH to Biohaven. Patents for pharmacogenomics of Depression Treatment with Folate (US_9546401, US_9540691). Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte.Ltd. MET has been a consultant for Acadia, Akili, Alkermes, Allergan, Clexio, Gerson Lehrman Group, Guidepoint Global, Janssen Pharmaceuticals, Jazz Pharmaceuticals, H. Lundbeck A/S, Otsuka Pharmaceutical Co., Pfizer, Sage Pharmaceuticals, Seelos Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company, his spouse, Dr. Diane Sloan, is Senior Medical Director of Peloton Advantage, which does business with several pharmaceutical companies, he has received Grant/Research Support from Acadia, Inc., Alkermes, Allergan, Axsome, Inc., Intracellular Inc., Janssen Pharmaceuticals, Inc., Myriad (AssureRx), National Institute of Mental Health, Otsuka, Patient Centred Outcomes Research Institute, and has received Royalties from the American Psychiatric Foundation, Guilford Publications, Herald House, W.W. Norton & Company, Inc., Wolters Kluwer Health. MHT has received Grant/Research Support from NIMH, NIDA, Patient-Centred Outcomes Research Institute (PCORI), and Cancer Prevention Research Institute of Texas (CPRIT). He has served as a consultant to Acadia Pharmaceuticals, Inc., Allergan, Alto Neuroscience Inc, Axsome Therapeutics, Boegringer Ingelheim, Engage Health Media, GreenLight VitalSign6 Inc, Janssen, Merck Sharp & Dohme Corp., Myriad Neuroscience, Navitor Pharmaceutical Inc, Otsuka, Perception Neuroscience, Pharmerit International, SAGE Therapeutics, Signant Health, and he has received Editorial Compensation from American Psychiatric Association (Deputy Editor for American Journal of Psychiatry), and Oxford University Press. LNY has been on speaker/advisory boards for, or has received research grants from Abbvie, Alkermes, Allergan, CANMAT, CIHR, DSP, Intracellular Therapeutics, Merck, Sanofi and Sunovion. TS in the past 36 months, has reported: Grants from Merck, National Institute on Drug Abuse, National Institute of Health, VA Cooperative Studies Program, and VA OR&D PRIME Care, Palo Alto Health Sciences, Stanley Medical Research Institute, Pathways Genomics. Consulting fees from Allergan, Inc., Intracellular Therapies, Sunovion Pharmaceuticals, Inc., and Impel NeuroPharma Inc. Honoraria from CME Institute (Physicians Postgraduate Press, Inc.) and CMEology. Royalties from American Psychiatric Association Publishing, Hogrefe Publishing, Jones and Bartlett, and Wolters Kluwer Health (UpToDate). Travel reimbursement from Sunovion Pharmaceuticals, Inc. RM has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Minerva, Intra-Cellular, Abbvie. Dr. Roger McIntyre is a shareholder and CEO of Champignon. JK has received research support, educational grants, travel/meeting sponsorship, speaking honoraria and/or paid consultancy from Alkermes, AstraZeneca; Bionomics, Bristol-Myers Squibb; Eli Lilly; GlaxoSmithKline; Janssen; Lundbeck; Pfizer; Sanofi-Aventis; Servier; and Wyeth. PM received remuneration from Sanofi (Hangzhou) for lectures on bipolar disorder research in China in 2019. MBauer has received grant support from the Deutsche Forschungsgemeinschaft, the Bundesministerium für Bildung und Forschung, and the European Commission. He serves as a consultant to Janssen-Cilag, neuraxpharm, Novartis, Shire International, and Takeda, and receives fees from Aristo, Hexal, Janssen-Cilag, and Sunovion. All other authors have no conflicts of interest in the past 3 years to report or have reported conflicts of interest in their author statement.

Additional information

Funding

MB is supported by a NHMRC Senior Principal Research Fellowship (1059660 and 1156072).