This review was concerned with further-line treatment for those with depression, and included people with coexisting personality disorders, psychotic depression, and chronic depression. The committee recognised that these were overlapping populations in the context of further-line treatment, and agreed that a broader evidence base would more accurately reflect the complexities that may be associated with non-response to initial treatment. Further-line treatments for depression may be required when people with depression have not responded to first-line treatments or are unable to tolerate them, and an alternative treatment is required, or in cases where people have not responded to multiple treatments.
FAILURE OR INTOLERANCE OF FIRST-LINE TREATMENT: First-line treatments for depression do not lead to remission in approximately two-thirds of people and therefore the choice of further-line treatment is a common clinical dilemma for patients and professionals. In addition, there will be people who cannot tolerate the original choice of first-line treatment, and these people will also require selection of an appropriate second-line option. Further-line treatment strategies can include switching to a different medication or psychological therapy, switching from medication to a psychological therapy, or vice versa, using dose escalation, or using combinations of treatments. In addition, choice of second-line therapy may be informed by personal preference, although patient characteristics including previous history of treatment response, type of depressive syndrome and comorbidities can be helpful in guiding the choice. For the people who remain depressed despite second-line treatment, the terms ‘treatment resistance’ or ‘treatment resistant depression’ (TRD) are often used.
Treatment resistant depression (TRD) is usually defined as a failure to respond to 2 adequate courses of antidepressants within a specified episode of depression. There does not appear to be a similarly accepted definition of failure to 2 adequate courses of psychological therapy. Recent models of TRD (such as the Massachusetts General Hospital and the Maudsley Staging Method) consider the duration of depression, the severity of the illness and the number and types of treatments. A systematic review of all of these approaches identified that the Maudsley Staging Method had the best predictive utility in assessing resistance. However, all of these staging methods remain limited through their focus on assessing resistance to treatments within the current episode. Recent clinical trials and functional neuroimaging studies have suggested that some types of psychotherapy may have an important place in overcoming treatment resistance, and further clarifying this role, particularly at later stages of treatment failure, may help in developing fuller models of treatment resistance and likelihood of future remission. Alongside efforts to more clearly delineate treatment resistance there has been greater acknowledgement of so-called ‘pseudo-resistance’, where lack of response relates to misdiagnosis (for example, of bipolar depression) or under-treatment (for example, through inadequate dosage or length of treatment), rather than true treatment resistance. Understanding this problem of ‘pseudo-resistance’ (and avoiding incorrectly labelling an individual as genuinely treatment resistant) should remain a significant concern in day-to-day clinical practice in order to improve treatment outcomes. Genuine treatment resistance has been linked to a number of demographic and illness characteristics, including: living alone; lower income; unemployment; male gender; lower education; higher complexity through associated physical or psychiatric disorder; and a longer, more severe current episode. Several approaches to overcoming treatment resistant depression have been evaluated, including pharmacology, physical interventions and psychological therapy. Pharmacological next-step options include switching within a class of antidepressants (for example, different SSRIs); switching between different classes of antidepressants (for example, from an SSRI to a SNRI); combining different antidepressants together (for example, SSRI plus mirtazapine); or augmenting an antidepressant with an agent that is not antidepressant in its own right (for example, lithium). Given the lack of convincing superiority of one agent over another at group level, part of the therapeutic advantage of switching between antidepressants may come through ‘pharmacogenomics’, indicating the genetic factors that may make people differentially liable to the beneficial or adverse effects of particular pharmacological agents. Evidence indicates that people continue to achieve remission when further treatment steps are used but that even with this approach around one third of people will remain treatment resistant at one year. After a period of treatment resistance there is some evidence that remission is less stable, associated with higher subsequent relapse and shorter average time to relapse, indicating over the longer term that those people who find it difficult to get well may also then find it more difficult to stay well. The aim of this review is to identify the most effective interventions for people who have had no or limited response to previous treatment(s) for the current episode of depression, have not tolerated previous treatment(s) for the current episode of depression, or who have treatment-resistant depression.
