The Neglected Role of Psychotherapy for Treatment-Resistant Depression
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.
1 : Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol 1999; 9:83–91Crossref, Medline, Google Scholar
2 : Treatment-resistant depression: resistant to definition? Acta Psychiatr Scand 2005; 112:302–309Crossref, Medline, Google Scholar
3 : Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord 2014; 156:1–7Crossref, Medline, Google Scholar
4 : Toward an evidence-based, operational definition of treatment-resistant depression: when enough is enough. JAMA Psychiatry 2017; 74:9–10Crossref, Medline, Google Scholar
5 : Current and common definitions of treatment-resistant depression: findings from a systematic review and qualitative interviews. Can J Psychiatry 2019; 64:380–387Crossref, Medline, Google Scholar
6 : Treatment-resistant major depressive disorder: Canadian expert consensus on definition and assessment. Depress Anxiety 2021; 38:456–467Crossref, Medline, Google Scholar
7 : The Dutch Measure for Quantification of Treatment Resistance in Depression (DM-TRD): an extension of the Maudsley Staging Method. J Affect Disord 2016; 205:365–371Crossref, Medline, Google Scholar
8 : Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 2003; 53:649–659Crossref, Medline, Google Scholar
9 : What is the meaning of treatment resistant/refractory major depression (TRD)? A systematic review of current randomized trials. Eur Neuropsychopharmacol 2007; 17:696–707Crossref, Medline, Google Scholar
10 : Staging methods for treatment resistant depression: a systematic review. J Affect Disord 2012; 137:35–45Crossref, Medline, Google Scholar
11 : The integrative management of treatment-resistant depression: a comprehensive review and perspectives. Psychother Psychosom 2014; 83:70–88Crossref, Medline, Google Scholar
12 : Cognitive therapy for anxious depression in STAR*D: what have we learned? J Affect Disord 2012; 142:213–218Crossref, Medline, Google Scholar
13 : Effectiveness of psychotherapy for treatment-resistant depression: a meta-analysis and meta-regression. Psychol Med 2019; 49:366–379Crossref, Medline, Google Scholar
14 : A meta-analysis of cognitive-behavioural therapy for adult depression, alone and in comparison with other treatments. Can J Psychiatry 2013; 58:376–385Crossref, Medline, Google Scholar
15 : Interpersonal psychotherapy for depression: a meta-analysis. Am J Psychiatry 2011; 168:581–592Link, Google Scholar
16 : A network meta-analysis of the effects of psychotherapies, pharmacotherapies and their combination in the treatment of adult depression. World Psychiatry 2020; 19:92–107Crossref, Medline, Google Scholar
17 :
18 : Psychological therapies for treatment-resistant depression in adults. Cochrane Database Syst Rev 2018; 5:CD010558Medline, Google Scholar
19 : Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry 2007; 68:935–940Crossref, Medline, Google Scholar
20 : Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry 2009; 166:980–991Link, Google Scholar
21 : Towards an international expert consensus for defining treatment response, remission, recovery and relapse in obsessive-compulsive disorder. World Psychiatry 2016; 15:80–81Crossref, Medline, Google Scholar
22 : Neurosurgery for intractable obsessive-compulsive disorder and depression: critical issues. Neurosurg Clin N Am 2003; 14:199–212Crossref, Medline, Google Scholar
23 : Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma. Proc Natl Acad Sci USA 2003; 100:14293–14296Crossref, Medline, Google Scholar
24 : Patient preference for psychological vs pharmacologic treatment of psychiatric disorders: a meta-analytic review. J Clin Psychiatry 2013; 74:595–602Crossref, Medline, Google Scholar
25 : National trends in the treatment for depression from 1998 to 2007. Arch Gen Psychiatry 2010; 67:1265–1273Crossref, Medline, Google Scholar
26 : 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; 70:354–361Crossref, Medline, Google Scholar
27 : 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; 77:294–302Crossref, Medline, Google Scholar
28 : Behavioral activation therapy for remediating persistent social deficits in medication-responsive chronic depression. J Psychiatr Pract 2011; 17:161–169Crossref, Medline, Google Scholar
29 : Depressed outpatients: results one year after treatment with drugs and/or interpersonal psychotherapy. Arch Gen Psychiatry 1981; 38:51–55Crossref, Medline, Google Scholar
30 : Treatment resistance in psychiatry: state of the art and new directions. Mol Psychiatry (Online ahead of print, July 13, 2021) Google Scholar
31 : Optimizing treatment of complicated grief: a randomized clinical trial. JAMA Psychiatry 2016; 73:685–694Crossref, Medline, Google Scholar
32 : 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; 18:33Crossref, Medline, Google Scholar
33 : Loss of antidepressant efficacy during maintenance therapy: possible mechanisms and treatments. J Clin Psychiatry 1998; 59:279–288Crossref, Medline, Google Scholar
34 : Tachyphylaxis in major depressive disorder: a review of the current state of research. J Affect Disord 2019; 245:488–497Crossref, Medline, Google Scholar
35 : 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; 342:1462–1470Crossref, Medline, Google Scholar
36 : Patient adherence in the treatment of depression. Br J Psychiatry 2002; 180:104–109Crossref, Medline, Google Scholar
37 : Simultaneous rTMS and psychotherapy in major depressive disorder: clinical outcomes and predictors from a large naturalistic study. Brain Stimul 2018; 11:337–345Crossref, Medline, Google Scholar
38 : Computer-assisted cognitive behavior therapy to prevent relapse following electroconvulsive therapy. J ECT 2017; 33:52–57Crossref, Medline, Google Scholar
39 : Cognitive-behavioral therapy as continuation treatment to sustain response after electroconvulsive therapy in depression: a randomized controlled trial. Biol Psychiatry 2014; 76:194–202Crossref, Medline, Google Scholar
40 : Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl) 2018; 235:399–408Crossref, Medline, Google Scholar
41 : Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry 2021; 78:481–489Crossref, Medline, Google Scholar
42 : Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013; 170:1134–1142Link, Google Scholar
43 : Esketamine for treatment resistant depression. Expert Rev Neurother 2019; 19:899–911Crossref, Medline, Google Scholar
44 : Ketamine and treatment-resistant depression. AANA J 2019; 87:411–419Medline, Google Scholar
45 : When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 1997; 58(suppl 13):23–29Medline, Google Scholar
46 : Psychotherapy and medication in the treatment of adult and geriatric depression: which monotherapy or combined treatment? J Clin Psychiatry 2005; 66:455–468Crossref, Medline, Google Scholar
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&Google Scholar
48 : Hardnekkige of therapieresistente depressie: what’s in a name? Tijdschr Psychiatr 2021; 63:260–262Medline, Google Scholar
49 : 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; 7:692–702Crossref, Medline, Google Scholar
50 : NIMH’s straight and neural path: the road to killing clinical psychiatric research. Psychiatr Serv 2020; 71:1096–1097Link, Google Scholar
51 : Using the NIH research, condition and disease categorization database for research advocacy: schizophrenia research at NIMH as an example. PLoS One 2020; 15:e0241062Crossref, Medline, Google Scholar
