The Neglected Role of Psychotherapy for Treatment-Resistant Depression
Publication: American Journal of Psychiatry
The concept of treatment-resistant or treatment-refractory depression (TRD) has evolved over 40 years since the recognition that some patients minimally benefit from repeated antidepressant medication trials. No uniform definition exists for TRD (1–10). What constitutes TRD has unfortunately varied across settings and literature reviews, differing in defining trial adequacy, nonresponse, retrospectively versus (more rigorous) prospectively defined nonresponse, and threshold number of trials and medication classes. With infrequent exceptions (5, 7), definitions have been restricted to repeated nonresponse to medication, with or without neuromodulation therapy (e.g., transcranial magnetic stimulation [TMS], ECT) (1–4, 6, 8–11). The STAR*D study, the grandest TRD experiment, was unusual in including one psychotherapy—alone, or with pharmacotherapy—as one step among multitiered prospective trials (4, 12). More commonly, psychotherapy is ignored (13). Even TRD staging systems that include psychotherapies equate them interchangeably with pharmacotherapies, as if their prognostic impact and benefits were equivalent.
TRD definitions are overly narrow. Decades of research demonstrate that time-limited cognitive-behavioral therapy (CBT) (14), interpersonal psychotherapy (IPT) (15), and others treat mild to severe nonpsychotic major depression (16, 17) and—based on limited research—treatment-resistant depression comparably to medications (13, 18). Van Bronswijk and colleagues meta-analyzed the limited TRD psychotherapy literature, finding a moderate effect size (d=0.42) for improvement in psychotherapy plus usual treatment over usual treatment alone (13). This magnitude matches those in controlled studies of common adjunctive pharmacotherapies (19, 20). So why omit a whole treatment class from TRD definitions? Why not give psychotherapy a central role, as requiring exposure/response prevention therapy has in defining treatment-intractable obsessive-compulsive disorder (21, 22)?
Psychotherapies may have differential advantages for patients whose depressive episodes arise with particular outlooks or symptoms, or from particular stressors (7, 23). Although today pharmacotherapy is increasingly the primary intervention, three-quarters of depressed patients prefer psychotherapy (24). Prescribers often ignore patient preference (25) even though treatment preference can (26) (if variably [27]) influence treatment outcome.
Different modalities may target different symptoms or benefit different patients. When effective, antidepressant pharmacotherapy relieves mood and neurovegetative symptoms faster than psychotherapy but helps patients less in understanding and partnering in managing their illness. Medications do not help patients structure their lives and seek positive experiences, like behavioral therapy (28); recognize and test painful, distorted negative thinking, like cognitive therapy; or understand and use emotions to solve interpersonal difficulties and mobilize social support, like IPT (29). Psychotherapy may emotionally alter patients’ self-regard, distinguishing self from illness: recognizing they are not “defective,” as they often believe, but ill. This distinction is salient when beleaguered by TRD. Patients improving in psychotherapy credit themselves more than do those swallowing pills.
We lack firm evidence on whether matching patient characteristics to treatments yields differential outcomes. Treatment selection research is nascent and complex (30). Our experience in psychotherapy trials and clinical practice indicates that patients barraged by negative thinking, diminished pleasurable activities, and indecision may find CBT or behavioral activation useful; those depressed in the context of troubled marriages, career disappointments, or complicated bereavement may respond to IPT. A widow unable to grieve may partially improve on medication (31) but needs catharsis and outlook modulation to recover. Psychotherapy may temper the inherent depressive hopelessness and demoralization that repeated medication nonresponse reinforces (32). Patients complaining, “Nothing helps me” may be reporting treatment history, not distorted thinking.
Whether psychotherapies have advantages over medications in clinically defined subgroups remains untested. The reality may be nuanced. Some depressed individuals in bad marriages who respond to pharmacotherapy may strengthen their relationships. Others may respond but relapse despite medication adherence. In our experience, such “poop-out” (33) commonly occurs amid ongoing interpersonal difficulties. Nevertheless, this scenario, like TRD itself, often receives a purely biological description: “tachyphylaxis” (33, 34). Such patients might appear “treatment resistant” to medication but not to psychotherapy-enhancing interpersonal skills. Hence TRD evaluations should always assess the type, intensity, and quality of patients’ past psychotherapies.
Patients reporting prior ineffective psychotherapies critically need psychoeducation. As with pharmacotherapy, one psychotherapy may work when another has not. Clinicians can disclose that many effective options exist: sometimes finding a solution requires several attempts. A strong therapeutic alliance, balancing realistic therapeutic optimism with recognition of suffering, facilitates ongoing collaboration to weather unsuccessful trials. Often feeling like failures and expecting poor outcomes, TRD patients may need reminding: they have not “failed.” Rather, the treatments have failed them.
Combining or sequencing antidepressant psychotherapy with pharmacotherapy increases treatment acceptability (35), enhances medication adherence (36), and exploits treatment synergies (37). For advanced level TRD, psychotherapy can enhance TMS response (34) and reduce post-ECT relapse risk (38, 39). Recent TRD protocols build supportive psychotherapy into most psilocybin (40, 41) (but not ketamine [42–44]) trials. Experts recommend combined treatment for TRD (16, 45, 46).
Overhauling TRD is overdue (47). Peeters et al. developed a TRD staging method in 2016 including psychotherapy trials (7). So did Conway and colleagues in their 2017 two-stage model. Stage 1 TRD involved “failure of two adequate dose-duration antidepressants or psychotherapy from different classes (either in combination or succession) in the current episode”; stage 2 required a third trial. “Adequate” meant “eight attended sessions of a…psychotherapy with demonstrated MDD effectiveness (e.g., CBT or IPT)” (4, p. 10).
We propose that TRD staging require not only nonresponse to at least two prospective adequate antidepressant medication trials (sufficient dosage for sufficient duration), but also nonresponse to at least one adequate trial (trained therapist, completed 9–16 sessions) of an evidence-based antidepressant psychotherapy (17). Perhaps true TRD should further demand nonresponse to a combined psychotherapy/pharmacotherapy trial. Treatment algorithms should include evidence-based psychotherapies, which should partially define TRD.
TRD treatment outcome assessments might expand beyond symptomatic change to social functioning, quality of life, sense of purpose, and well-being, much as with any chronic illness (48, 49). The National Institute of Mental Health, historically the predominant American psychotherapy research funding source, unfortunately shows scant current interest in testing these outcomes (50, 51).
Funding psychotherapy research and training for TRD would benefit long-suffering individuals and their loved ones. The psychosocial framework of TRD development is woefully understudied, precluding judgment of the comparative merits of the relevant psychotherapies. Psychiatry needs clinical trials comparing pharmacotherapy to time-limited psychotherapy to assess predictive factors for differential therapeutics of TRD.
References
1.
Souery D, Amsterdam J, de Montigny C, et al: Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol 1999; 9:83–91
2.
Malhi GS, Parker GB, Crawford J, et al: Treatment-resistant depression: resistant to definition? Acta Psychiatr Scand 2005; 112:302–309
3.
McIntyre RS, Filteau MJ, Martin L, et al: Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord 2014; 156:1–7
4.
Conway CR, George MS, Sackeim HA: Toward an evidence-based, operational definition of treatment-resistant depression: when enough is enough. JAMA Psychiatry 2017; 74:9–10
5.
Brown S, Rittenbach K, Cheung S, et al: Current and common definitions of treatment-resistant depression: findings from a systematic review and qualitative interviews. Can J Psychiatry 2019; 64:380–387
6.
Rybak YE, Lai KSP, Ramasubbu R, et al: Treatment-resistant major depressive disorder: Canadian expert consensus on definition and assessment. Depress Anxiety 2021; 38:456–467
7.
Peeters FP, Ruhe HG, Wichers M, et al: The Dutch Measure for Quantification of Treatment Resistance in Depression (DM-TRD): an extension of the Maudsley Staging Method. J Affect Disord 2016; 205:365–371
8.
Fava M: Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 2003; 53:649–659
9.
Berlim MT, Turecki G: What is the meaning of treatment resistant/refractory major depression (TRD)? A systematic review of current randomized trials. Eur Neuropsychopharmacol 2007; 17:696–707
10.
Ruhé HG, van Rooijen G, Spijker J, et al: Staging methods for treatment resistant depression: a systematic review. J Affect Disord 2012; 137:35–45
11.
Carvalho AF, Berk M, Hyphantis TN, et al: The integrative management of treatment-resistant depression: a comprehensive review and perspectives. Psychother Psychosom 2014; 83:70–88
12.
Farabaugh A, Alpert J, Wisniewski SR, et al: Cognitive therapy for anxious depression in STAR*D: what have we learned? J Affect Disord 2012; 142:213–218
13.
van Bronswijk S, Moopen N, Beijers L, et al: Effectiveness of psychotherapy for treatment-resistant depression: a meta-analysis and meta-regression. Psychol Med 2019; 49:366–379
14.
Cuijpers P, Berking M, Andersson G, et al: A meta-analysis of cognitive-behavioural therapy for adult depression, alone and in comparison with other treatments. Can J Psychiatry 2013; 58:376–385
15.
Cuijpers P, Geraedts AS, van Oppen P, et al: Interpersonal psychotherapy for depression: a meta-analysis. Am J Psychiatry 2011; 168:581–592
16.
Cuijpers P, Noma H, Karyotaki E, et al: A network meta-analysis of the effects of psychotherapies, pharmacotherapies and their combination in the treatment of adult depression. World Psychiatry 2020; 19:92–107
17.
Wright J, Reis J, Wood J, et al: Psychotherapy for treatment resistant depression, in Managing Treatment-Resistant Depression: Road to Novel Therapeutics. Edited by Quevedo J, Riva Posse P, Bobo WV. Cambridge, Mass, Academic Press (in press)
18.
Ijaz S, Davies P, Williams CJ, et al: Psychological therapies for treatment-resistant depression in adults. Cochrane Database Syst Rev 2018; 5:CD010558
19.
Crossley NA, Bauer M: Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry 2007; 68:935–940
20.
Nelson JC, Papakostas GI: Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry 2009; 166:980–991
21.
Mataix-Cols D, Fernández de la Cruz L, Nordsletten AE, et al: Towards an international expert consensus for defining treatment response, remission, recovery and relapse in obsessive-compulsive disorder. World Psychiatry 2016; 15:80–81
22.
Greenberg BD, Price LH, Rauch SL, et al: Neurosurgery for intractable obsessive-compulsive disorder and depression: critical issues. Neurosurg Clin N Am 2003; 14:199–212
23.
Nemeroff CB, Heim CM, Thase ME, et al: Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma. Proc Natl Acad Sci USA 2003; 100:14293–14296
24.
McHugh RK, Whitton SW, Peckham AD, et al: Patient preference for psychological vs pharmacologic treatment of psychiatric disorders: a meta-analytic review. J Clin Psychiatry 2013; 74:595–602
25.
Marcus SC, Olfson M: National trends in the treatment for depression from 1998 to 2007. Arch Gen Psychiatry 2010; 67:1265–1273
26.
Kocsis JH, Leon AC, Markowitz JC, et al: Patient preference as a moderator of outcome for chronic depression treated with nefazodone, cognitive behavioral analysis system of psychotherapy, or their combination. J Clin Psychiatry 2009; 70:354–361
27.
Windle E, Tee H, Sabitova A, et al: Association of patient treatment preference with dropout and clinical outcomes in adult psychosocial mental health interventions: a systematic review and meta-analysis. JAMA Psychiatry 2020; 77:294–302
28.
Erickson G, Hellerstein DJ: Behavioral activation therapy for remediating persistent social deficits in medication-responsive chronic depression. J Psychiatr Pract 2011; 17:161–169
29.
Weissman MM, Klerman GL, Prusoff BA, et al: Depressed outpatients: results one year after treatment with drugs and/or interpersonal psychotherapy. Arch Gen Psychiatry 1981; 38:51–55
30.
Howes OD, Thase ME, Pillinger T: Treatment resistance in psychiatry: state of the art and new directions. Mol Psychiatry (Online ahead of print, July 13, 2021)
31.
Shear MK, Reynolds CF 3rd, Simon NM, et al: Optimizing treatment of complicated grief: a randomized clinical trial. JAMA Psychiatry 2016; 73:685–694
32.
Mago R, Fagiolini A, Weiller E, et al: Understanding the emotions of patients with inadequate response to antidepressant treatments: results of an international online survey in patients with major depressive disorder. BMC Psychiatry 2018; 18:33
33.
Byrne SE, Rothschild AJ: Loss of antidepressant efficacy during maintenance therapy: possible mechanisms and treatments. J Clin Psychiatry 1998; 59:279–288
34.
Kinrys G, Gold AK, Pisano VD, et al: Tachyphylaxis in major depressive disorder: a review of the current state of research. J Affect Disord 2019; 245:488–497
35.
Keller MB, McCullough JP, Klein DN, et al: The acute treatment of chronic major depression: a comparison of nefazodone, cognitive behavioral analysis system of psychotherapy, and their combination. N Engl J Med 2000; 342:1462–1470
36.
Pampallona S, Bollini P, Tibaldi G, et al: Patient adherence in the treatment of depression. Br J Psychiatry 2002; 180:104–109
37.
Donse L, Padberg F, Sack AT, et al: Simultaneous rTMS and psychotherapy in major depressive disorder: clinical outcomes and predictors from a large naturalistic study. Brain Stimul 2018; 11:337–345
38.
Wilkinson ST, Ostroff RB, Sanacora G: Computer-assisted cognitive behavior therapy to prevent relapse following electroconvulsive therapy. J ECT 2017; 33:52–57
39.
Brakemeier EL, Merkl A, Wilbertz G, et al: Cognitive-behavioral therapy as continuation treatment to sustain response after electroconvulsive therapy in depression: a randomized controlled trial. Biol Psychiatry 2014; 76:194–202
40.
Carhart-Harris RL, Bolstridge M, Day CMJ, et al: Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl) 2018; 235:399–408
41.
Davis AK, Barrett FS, May DG, et al: Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry 2021; 78:481–489
42.
Murrough JW, Iosifescu DV, Chang LC, et al: Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013; 170:1134–1142
43.
Swainson J, Thomas RK, Archer S, et al: Esketamine for treatment resistant depression. Expert Rev Neurother 2019; 19:899–911
44.
Lent JK, Arredondo A, Pugh MA, et al: Ketamine and treatment-resistant depression. AANA J 2019; 87:411–419
45.
Thase ME, Rush AJ: When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 1997; 58(suppl 13):23–29
46.
Hollon SD, Jarrett RB, Nierenberg AA, et al: Psychotherapy and medication in the treatment of adult and geriatric depression: which monotherapy or combined treatment? J Clin Psychiatry 2005; 66:455–468
47.
Centers for Medicare and Medicaid Services: Definition of Treatment-Resistant Depression in the Medicare Population. 2018. https://www.cms.gov/medicare-coverage-database/details/technology-assessments-details.aspx?TAId=105&bc=AAAQAAAAAAAA&
48.
Veraart JKE, van Belkum SM, Oostelbos PFJ, et al: Hardnekkige of therapieresistente depressie: what’s in a name? Tijdschr Psychiatr 2021; 63:260–262
49.
Chevance A, Ravaud P, Tomlinson A, et al: Identifying outcomes for depression that matter to patients, informal caregivers, and health-care professionals: qualitative content analysis of a large international online survey. Lancet Psychiatry 2020; 7:692–702
50.
Markowitz JC, Friedman RA: NIMH’s straight and neural path: the road to killing clinical psychiatric research. Psychiatr Serv 2020; 71:1096–1097
51.
Torrey EF, Knable MB, Rush AJ, et al: Using the NIH research, condition and disease categorization database for research advocacy: schizophrenia research at NIMH as an example. PLoS One 2020; 15:e0241062
Information & Authors
Information
Published In
History
Received: 26 May 2021
Revision received: 25 July 2021
Accepted: 23 August 2021
Published in print: February 2022
Published online: 2 February 2022
Authors
Competing Interests
Dr. Markowitz receives consultation fees from the U.S. Department of Defense and NIMH and royalties from American Psychiatric Association Publishing, Basic Books, and Oxford University Press. Dr. Wright reports equity interest and consulting with Mindstreet, Inc., and royalties from American Psychiatric Association Publishing, Guilford Press, and Simon and Schuster. Dr. Peeters receives royalties from Boom Publishers, Bohn Stafleu van Loghum, and Hogrefe Publishing Group, receives research grants from Zon-MW and the Mitialto Foundation, and received financial compensation as an independent symposium speaker for Janssen-Cilag and SCEM. Dr. Thase has served as an adviser or consultant for Acadia, Akili, Alkermes, Allergan (Forest, Naurex), Boehringer-Ingelheim, Clexio Biosciences, H. Lundbeck A/S, Jazz Pharmaceuticals, Janssen (Johnson & Johnson), Otsuka Pharmaceutical Company, Perception Neuroscience, Sage Therapeutics, Seelos Pharmaceuticals, and Takeda; he has received grant support from Acadia, Allergan (Forest, Naurex), Axsome Therapeutics, Intracellular, Johnson & Johnson (Janssen), Myriad (Assurex), Otsuka Pharmaceutical Company, and Takeda; he receives royalties from American Psychiatric Association Publishing, Guilford Publications, Herald House, and W.W. Norton & Company; and his spouse is employed by Open Health (formerly Peloton Advantage), which does business with a number of pharmaceutical companies. Dr. Kocsis reports no conflicts of interest. Dr. Sudak receives book royalties from American Psychiatric Association Publishing, John Wiley and Sons, and Wolters-Kluwer.
Metrics & Citations
Metrics
Citations
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
View Options
View options
PDF/EPUB
View PDF/EPUBGet Access
Login options
Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.
Personal login Institutional Login Open Athens loginNot a subscriber?
PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.
Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).