Does treatment‐resistant depression need psychotherapy?

Congratulations are well deserved for this review by 27 psychiatric leaders, representing 14 countries, including 294 references ¹ . This highly researched, well‐written paper describes the characteristics of treatment‐resistant depression (TRD), including prevalence, risks, clinical features, costs, public health burden, management and treatments. Despite the wealth of information provided, lingering throughout the paper is mention of the instability and inconsistency of the TRD definition. Since the paper is about TRD, the reader is left uneasy about what to assume. In fact, the criticism of the term TRD could be a major conclusion of the review.

The authors state that “a consensus definition of TRD with predictive utility does not currently exist” and that “this is a major limitation from the viewpoints of translational research, treatment development, as well as clinical and policy decision making” ¹ . Comments like this permeate the paper. At first, only the reader is uneasy, but, as the paper progresses, it is clear that the authors may be as well. They conclude with many suggestions for this dilemma, which make this a landmark paper on a shifting topic.

As reviewed by the authors, the most common definition of TRD is the failure to respond to two or more antidepressants despite adequate dose, duration and adherence. This definition – the authors say – does not operationalize response, ignores partial response, does not take social functioning into account, is based on the use of standard medications, and usually does not include psychotherapy.

Quite discouragingly, the authors note that most individuals meeting the criteria for major depressive disorder with access to high‐quality measurement‐based care will meet the criteria for TRD. Hence, treatment resistance is one of the most commonly encountered therapeutic outcomes in persons prescribed conventional antidepressants.

Despite this pessimism, the report provides at least two suggestions for improving the situation: the inclusion of evidence‐based psychotherapy and the implementation of more nuanced clinical approaches, which may improve treatment selection and patient adherence, and may even be therapeutic (what is often called the therapeutic alliance).

The authors note that, according to several studies, psychotherapy is preferred over pharmacotherapy by most people with a lived experience of depression, and, when combined with medication, facilitates coping and resilience. With this encouragement, I started to follow up on their treatment guideline references to check what has been said about psychotherapy.

Indeed, psychotherapy is included as a first line intervention in the practice guidelines for treatment of depression by both the American Psychiatric Association and the American Psychological Association ² , ³ . Can we classify patients as resistant to treatment if the guidelines for recommended treatments are not included in the definition?

One can understand historically the reluctance to include psychotherapy in the TRD definition due to the old belief that you cannot test psychotherapy because every situation is unique. But there has been a revolution in psychotherapy development and research over the last 30 years, which has challenged that belief. Psychotherapy is now precisely defined in manuals used for training of therapists with different backgrounds. These manualized psychotherapies have been tested in numerous clinical trials in different populations and settings. The formats of treatment have evolved, and there are now individual, group and digital forms. The treatments are no longer interminable, but are time limited in frequency and duration.

Evidence‐based psychotherapies for depression are now recommended by treatment guidelines in the US, Canada and Australia. In 2019, the US Preventive Task Force recommended two evidence‐based psychotherapies for treatment and prevention of depression during pregnancy ⁴ . The World Health Organization (WHO), in its Mental Health Gap Action Plan (mhGAP) Intervention Guide, included evidence‐based psychotherapy ⁵ . These treatments are being widely disseminated throughout the world, and recently also in low‐income countries. For example, a large‐scale clinical trial of interpersonal psychotherapy was carried out in Uganda ⁶ .

Let's glance at the substantial database of clinical trials. In 2021, a meta‐analysis of efficacy, acceptability and long‐term outcomes of psychotherapies was published in this journal ⁷ . This meta‐analysis included cognitive behavioral therapy (CBT), interpersonal psychotherapy (IPT), problem‐solving, behavioral activation, and non‐directive supportive counseling, compared with each other or to usual care, waiting list, or pill placebos. Three hundred and thirty‐one randomized clinical trials with over 34,000 patients with depression were included. A 50% reduction in symptoms was the primary outcome. The authors found that all psychotherapies were more efficacious than usual care or waiting list. There were no consistent differences between psychotherapies, with a few exceptions. The effects for most psychotherapies were still evident at one‐year follow‐up.

In a separate report also published in this journal ⁸ , a network meta‐analysis of the effects of psychotherapies, pharmacotherapies and their combination for adult depression was conducted. Included were 101 clinical trials and 11,010 patients with moderate or severe major depression. In general, combined treatment was more effective than psychotherapy alone or pharmacotherapy alone in achieving response (50% reduction in symptoms) and remission. There were no significant differences between psychotherapy alone and pharmacotherapy alone. Patient found combined treatment or psychotherapy alone as more acceptable than pharmacotherapy alone.

Thus, the exclusion of evidence‐based psychotherapy in the evaluation of treatment resistance may be a significant omission in the TRD definition ⁹ .

Let's consider the second issue raised about TRD, which is adherence to the implemented pharmacological treatments. Patients may be prescribed correct medications at proper doses, may even fill the prescriptions, but may not be taking the drugs. The authors note that 30 to 50% of patients are non‐adherent to medication in the acute phase of treatment. The patient may be resistant to taking the treatment prescribed and not necessarily resistant to the treatment itself.

Accurate information to ensure adherence may revolve on the therapeutic relationship. The time spent with the patient (by the physician or a trusted team member) in a supportive manner might allow a more comprehensive assessment of the patients' symptoms, social situations surrounding the symptom onset, attitudes and knowledge, experience and fears about medications, treatment options, costs, family attitudes, lifestyle barriers, and a whole host of factors which may potentially be leading to non‐adherence or non‐recovery. This is not formal psychotherapy, but it can be therapeutic. The information obtained could unlock the mystery of patient resistance. What is involved may be misinformation, misunderstanding, mistrust, or mistaken treatment, rather than resistance to a treatment.

The possible addition of an evidence‐based psychotherapy or the time spent to obtain a comprehensive patient evaluation may reduce the high rate of TRD. This is not a recommendation for long‐term psychotherapy. Most evidence‐based treatments are time‐limited. It is not even a call for evidence‐based psychotherapy for everyone, but it does suggest the need for a thorough evaluation and a therapeutic relationship as a beginning. Before the patient, the disease or the treatment is blamed for resistance, a therapeutic alliance and perhaps psychotherapy may be worth a try. Indeed, TRD may need psychotherapy.