Psychotherapy for Treatment-Resistant Depression Is Overlooked, Underused

Psychiatric TimesVol 40, Issue 11

"Evidence indicates that psychotherapy may yield greater durability of treatment gains than pharmacotherapy."

brainwashed 4 you_AdobeStock

brainwashed 4 you_AdobeStock


When initial treatments for depression do not work, patients often feel responsible. They blame themselves, feel stigmatized, and think they are not trying hard enough. Family relationships and work suffer. Life becomes still more constricted and cold. Suicide risk is an ongoing concern. Thus, patients who suffer from treatment-resistant depression (TRD) need and deserve the full range of the best available treatments.

An oft-neglected treatment for TRD, both in research studies and in clinical practice, is evidence-based psychotherapy. Indeed, many definitions of TRD focus on medications and somatic treatments and do not even consider psychotherapies.1

There is a solid research base for the effectiveness of varied psychologically based antidepressant treatments in general. A meta-analysis of 101 studies and more than 11,000 patients found that several psychotherapies are as effective as medication for adult depression, and that combining psychotherapy and pharmacotherapy provides greater effects than either treatment alone.2

Some evidence indicates that psychotherapy may yield greater durability of treatment gains than pharmacotherapy3 and that sequential treatment with medication followed by psychotherapy extends durability.4-8

In a meta-analysis of 21 studies specifically targeting TRD, psychotherapy added to treatment as usual (TAU) was more effective than TAU alone.9 Another meta-analysis of 18 studies of psychotherapy for treatment nonresponders for any mood or anxiety disorder showed that psychotherapy decreased symptoms and improved quality of life.10

Among the psychotherapies investigated for TRD, multiple randomized controlled trials have demonstrated the effectiveness of cognitive behavior therapy (CBT) and mindfulness-based cognitive therapy.9,11 Other therapies that have fared well in general antidepressant studies but have not had extensive testing for TRD effectiveness include interpersonal psychotherapy (IPT) and brief psychodynamic psychotherapy.

Although more research is needed, available evidence suggests that psychotherapy is well worth considering as part of a comprehensive approach to TRD.

Key Principles for TRD

Several identified mediators of TRD are problems psychotherapy typically addresses. Building hope, resolving interpersonal difficulties, normalizing negative affects instead of regarding them as bad feelings, generating positive attributions, teaching problem-solving, and behavioral activation are the bread and butter of CBT and IPT treatment. Many such targets may not fully respond to somatic interventions.

In addition, individuals with chronic depression may have had the illness since childhood or early adult life, and therefore not have developed necessary psychological and social skills that psychotherapy can help them learn. When residual symptoms such as depressed mood or anxiety persist despite medication, evidence-based psychotherapy may reduce these and increase the likelihood of recovery.

The therapeutic alliance deserves particular attention in work with patients who have long-standing illness. Acknowledgement of the demoralization and hopelessness that often accompany TRD may improve the relationship with the patient. The scientific literature is rife with implications that treatment resistance means “the patient failing the treatment” when, in fact, it is the other way around.

Many patients (and, on occasion, their families) have the sense that there is no hope for a good life. Because such beliefs can counteract recovery, the therapist needs to convey a message of respect for the patient’s efforts and an attitude that one can live a meaningful and productive life, even with residual depressive symptoms.


CBT for TRD focuses on labeling hopelessness a belief and highlighting every new accomplishment as due to efforts by the patient to gradually improve a sense of self-efficacy. Another important aspect of CBT for TRD is helping patients to recognize when they begin to engage in the thinking associated with a negative mood state.

Patients may then learn to employ tools that help them disengage from those overlearned mental habits—using thought records, activity scheduling, or mindfulness. Considering these thoughts as a depression mindset that occurs after stressors and can be managed without accelerating a negative mood can be a powerful tool in helping patients with TRD.

Planning and managing activity are very important for patients with TRD. Often patients avoid rewarding and meaningful activities because of negative predictions about the outcome. Behavioral activation therapy, employed alone or as part of CBT, encourages the patient to experiment with small increments of activity in pursuit of meaningful goals or potential sources of enjoyment to increase positive affect.

In addition, it provides a normalizing rationale for lack of motivation and illustrates the consequences of inactivity.12 Patients can learn to recognize and manage ruminative negative thinking and boost positive moods by augmenting behavioral activation with tools taught in psychotherapy to help them anticipate positive experiences and attend to positive emotions.13


IPT focuses on patient emotions and their link to environmental circumstances and relationships.14 Acute treatment is time-limited, typically 12 weekly sessions. The IPT therapist helps the patient define depression as a temporary, treatable (if, for TRD, difficult-to-treat) illness that is not the patient’s fault. This maneuver helps to distinguish the disorder from the patient’s sense of self and relieves guilt.

As in CBT, the patient has depression rather than being the depression. Exploring patient history, including previous treatments, yields a therapeutic focus for acute IPT treatment: complicated grief following death of a significant other; a role dispute or struggle with a significant other; a role transition or major life upheaval. The goal of acute treatment is to resolve this crisis.

IPT sessions focus on recent interpersonal encounters and how the patient felt during them and handled them. Evoked feelings are explored as useful signals about the environment rather than the bad personal qualities patients often perceive them to be.

Normalizing negative affects like anger removes an uncomfortable internal pressure and helps the patient gauge how to read and handle situations more effectively. Role play promotes assertiveness and the use of anger as self-defense in confrontations.

No homework is assigned: patient autonomy and the pressure of the time limit determine when the patient acts on items learned in treatment. If IPT, with or without pharmacotherapy, yields acute response or remission, continuation IPT is often warranted to further strengthen functioning and forestall relapse.15

Short-term psychodynamic psychotherapies have been manualized, tested, and shown to benefit patients with major depression.16 So has brief supportive psychotherapy.17 All these treatments deserve further research, although the National Institute of Mental Health has unfortunately lost interest in funding clinical trials.18

Concluding Thoughts

Patients with TRD live with an ongoing, debilitating disorder for this all-too-frequent condition. Although effective psychotherapy is not a panacea, it deserves more attention as an important contributor to the relief of TRD than it currently receives as well as an increased focus for research for more effective treatments.

Dr Sudak is professor of psychiatry and vice chair for education at Drexel University College of Medicine in Philadelphia, Pennsylvania. She is also the general psychiatry residency program director at Tower Health-Phoenixville Hospital.

Dr Markowitz is a professor of clinical psychiatry at the Columbia University College of Physicians and Surgeons and a research psychiatrist at the New York State Psychiatric Institute, both in New York, New York.

Dr Wright is Kolb Endowed Chair of Outpatient Psychiatry and director of the Depression Center at the University of Louisville in Kentucky. He was founding president of the Academy of Cognitive and Behavioral Therapies, is a fellow of the American College of Psychiatrists, and received the Distinguished Educator of the Year Award from the University of Louisville.


1. Markowitz JC, Wright JH, Peeters F, et al. The neglected role of psychotherapy for treatment-resistant depression. Am J Psychiatry. 2022;179(2):90-93.

2. 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(1):92-107.

3. Furukawa TA, Shinohara K, Sahker E, et al. Initial treatment choices to achieve sustained response in major depression: a systematic review and network meta-analysis. World Psychiatry. 2021;20(3):387-396. 

4. Paykel ES, Scott J, Teasdale JD, et al. Prevention of relapse in residual depression by cognitive therapy. Arch Gen Psychiatry. 1999;56(9):829-835.

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6. Fava GA, Grandi S, Zielezny M, et al. Four-year outcome for cognitive behavioral treatment of residual symptoms in major depression. Am J Psychiatry. 1996;153(7):945-947.

7. Fava GA, Rafanelli C, Grandi S, et al. Prevention of recurrent depression with cognitive behavioral therapy. Arch Gen Psychiatry. 1998;55(9):816-820.

8. Fava GA, Ruini C, Rafanelli C, et al. Six-year outcome of cognitive behavior therapy for prevention of recurrent depression. Am J Psychiatry. 2004;161(10):1872-1876.

9. 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(3):366-379.

10. Gloster AT, Rinner MTB, Ioannou M, et al. Treating treatment non-responders: a meta-analysis of randomized controlled psychotherapy trials. Clin Psychol Rev. 2020;75:101810.

11. Wright JH, Markowitz JC, Wood J, et al. Evidence-based psychotherapy for treatment-resistant depression. In: Quevedo J, Riva-Posse P, Bobo WV, eds. Managing Treatment-Resistant Depression: Road to Novel Therapeutics. Academic Press; 2022:369-376.

12. Martell CR, Addis ME, Jacobson NS. Depression in Context: Strategies for Guided Action. W.W. Norton & Company; 2001.

13. Craske MG, Meuret AE, Ritz T, et al. Positive affect treatment for depression and anxiety: a randomized clinical trial for a core feature of anhedonia. J Consult Clin Psychol. 2019;87(5):457-471. 

14. Weissman MM, Markowitz JC, Klerman GL. The Guide to Interpersonal Psychotherapy. Oxford University Press; 2018.

15. Markowitz JC. Interpersonal Psychotherapy for Dysthymic Disorder. American Psychiatric Press; 1998.

16. Driessen E, Hegelmaier LM, Abbass AA, et al. The efficacy of short-term psychodynamic psychotherapy for depression: a meta-analysis update. Clin Psychol Rev. 2015;42:1-15.

17. Markowitz JC. Supportive evidence: brief supportive psychotherapy as active control and clinical intervention. Am J Psychother. 2022;75(3):122-128.

18. Markowitz JC, Milrod BL. Lost in translation: the value of psychiatric clinical trials. J Clin Psychiatry. 2022;83(6):22com14647

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