Refining the definition of treatment-resistant depression

TRD is a common clinical problem and public health concern.

Treatment-resistant depression (TRD) is a common clinical problem and public health concern.¹ Research into TRD is crucial. Malhi and Byrow recently reviewed the concept of TRD - a term that is commonly used but difficult to define.² This definition may need to be refined in order to better understand depression and its treatment. Specificity of response - defining response according to particular clinical domains - may be a step forward.

Patterns of response

The goal of antidepressant treatment includes improvement and return to functioning.^{3, 4} Response - clinically meaningful symptom reduction - is needed to achieve functional recovery. In clinical trials, response is generally considered a 50% or greater reduction of symptoms, as measured on a standard depression rating scale. While an ideal response is rapid and complete, patterns of response vary.⁴ Response can be delayed with slow improvement. Or it may be incomplete - partial response - when patients fail to achieve complete symptom remission. In some cases there is no discernible response.

Are all symptoms equal?

When measuring response using standard rating scales, there is no real distinction between the various symptoms of depression. Improvement across different symptom domains can yield similar response scores.² The improvement of sleep is numerically equal to improvement of suicidal thinking or guilt, although the consequences for patients are clearly very different.

The concept of treatment resistance - too broad a brush?

The definition of TRD involves two parts - response and therapy. It is an inadequate response to at least one⁵ or two⁶ trials of antidepressant given at adequate dose and duration. Inadequate response includes no response to treatment as well as partial response. Even the most sophisticated definitions of TRD are, however, difficult to apply to patients in the ‘real world’.^{5, 7}

Failure of successive treatments to achieve a satisfactory response leads to the recognition of treatment resistance.

Specificity of response - defining response according to particular clinical domains - may be a step forward in refining the definition of TRD.

Specificity of response - defining response according to particular clinical domains

TRD is defined according to the patient’s history of inadequate response. It also takes into account the patient’s clinical history: number and duration of previous episodes, previous history of response or nonresponse, family history and comorbidity. But would it be possible to further refine TRD by taking a patient’s symptom profile into account?

Groups of depressive symptoms are clinically very different. Distinguishing subgroups of response may highlight different kinds of treatment resistance.

This approach introduces the concept of specificity of response.² Subtypes of TRD could include patients that are responsive overall, but have little or no response in a specific domain of symptoms. These may include cognition or vegetative symptoms.

Lack of response to guide decision making.

Lack of response to guide decision making

TRD is associated with poorer quality of life and increased mortality, and accounts for a large proportion of the burden of depression.⁸ Many patients will experience a poor response to antidepressants at some point in the course of their illness. Response, and the lack of it, should be used to guide decision making. Options include changing dosage, switching treatment, combination treatments and the use of adjunctive therapy.