Complexities of treatment-resistant depression: cautionary notes and promising avenues.

Abstract

419 treatments that are needed for response in all patients (>3). And many patients who respond or remit would have actually re­ sponded or remitted with pill placebo as well. This all means that TRD is simply the logical result of the limited effects of treat­ ments. The concept of TRD suggests that there is a threshold that patients should pass (two unsuccessful treatments), while in fact there is no threshold. There is only a limited number of patients who will respond to the next treatment, just as only a limited num­ ber responds to the first treatment. There are many pharmacological, psy­ chological and other treatments of depres­ sion and they all have comparable, but lim­ ited eff ects. At the same time, hardly any­ thing is known about who benefits from which treat ment. Very little is known about the first treat ment that should be offered to a patient. Any treatment is as good as an­ other. That means that we very much need research on who ben efits from which treat­ ment. But we also need research on sequen­ tial treatments. If a patient does not re spond to one treatment, what treatment should be offered next, and which one if the second treatment also does not work, and the third and the fourth? From this perspective, re­ search on TRD is very useful, because that is exactly the focus of this research: what should we do if patients do not respond to several treatments? So, although the concept of TRD is based on a misunderstanding of the effects of treatments, the research on interventions for TRD is very much need ed. Unfortunately, there is another major prob lem with research on TRD: the almost complete absence of psychological treat­ ments. In one systematic overview, a total of 148 dif ferent definitions of TRD were collected from the literature. All defini­ tions included at least one failed treatment with antidepressants, but only six defini­ tions (4%) included one failed treatment with psychotherapy. This is remarkable, because there is not only much evidence that psychotherapy overall is as effective as antidepressants in the short term, but also that psychotherapy is more effective in the longer term, and that combined treatment is more effective than either phar­ macotherapy or psychotherapy, in the short and longer term. Also, almost all treatment guid elines for depression not only recom­ mend antidepressants but also psychother­ apy as first line treatment. This suggests that almost all people who meet one of the cur­ rent definitions of TRD have not received the best available treatments. Fortunately, the review by McIntyre et al tries to repair this omission in the literature. But it still means that most of the other literature on TRD is flawed and biased towards pharma­ cological treatments of depression. There is also some evidence that phar­ macotherapy and psychotherapy work in­ dependently from each other, and that their effects are additive, without interfering with each other. At the same time, there is some evidence that prior use of antidepressants results in lower response rates when an­ other antidepressant is used. This makes it even less understandable why previous definitions of TRD usually do not include psychotherapies. It further illustrates the biased nature of this research area, and that many patients with TRD just received sub­ optimal treatments before being defined as having TRD. Taken together, one could argue that the concept of TRD should be abandoned, be­ cause it is based on a misconception of the effects of treatments of depression, and we should move towards an agenda for re­ search on sequential treatments. The cur­ rent research on TRD fits very well into this agenda, but also has serious limitations, es ­ pecially the focus on antidepressants and the exclusion of psychological and combined treatments. Such an agenda should also include oth­ er research questions. For example, there is very little research on sequential psycho­ logical treatments of depression. Although there are now almost 1,000 randomized controlled trials on these treatments, hardly anything is known about which treatment should be used when a patient does not re­ spond. The same is true for combined treat­ ments. Although it is clear from a consider­ able number of trials that combined treat­ ment is more effective than either psycho­ therapy or pharmacother apy alone, very little is known about what to do when a patient does not respond to that treatment. Should we change the antidepres sant, the psychotherapy, or both? We simply do not know, while these are the questions that need to be answered if we want to help as many patients as possible. It is time that we move away from the concept of TRD and focus on research on sequential treatments, because that is what patients need most.