Defining treatment-resistant depression, difficult-to-treat depression, and staging treatment intensity

Definition of TRD

TRD can be thought of as describing patients beyond a certain threshold in a course of serial treatment trials. There is, however, no universally accepted criterion for this threshold. A systematic review identified 150 randomized controlled trials, observational studies, and case series of patients defined as having “TRD” published between January 2016 and December 2017 ( ). The most common element of the definition used in these studies was a failure to respond to two different treatments, though this was the case in only just over half of the definitions (50.3%: ( ), see Fig. 1.1 ).

However, there is a complete lack of consensus regarding how different classes of medication are considered, the length and dose of treatment trial required, how nonpharmacological interventions are considered, whether the trials needed to be in the current episode or not, what the target outcomes of trials is, how this should be assessed, and whether trials in past episodes count or not ( ; ). A systematic review has also highlighted the observation that only 17% of interventional studies recruited populations of patients meeting the most frequently specified criteria of two failed trails ( ). This leads to a major issue with regard to the evidence base for the management of TRD. A systematic review of all psychological and pharmacological augmentation strategies was only able to evaluate 28 randomized controlled trials (RCTs) including just 18 different treatments in participants meeting the TRD criteria of prior failure of two previous treatments, despite a wide range being widely used clinically ( ).

So how should TRD be defined? One possible approach is to examine whether there is evidence of factors that distinguish patients with TRD compared with other patients with depression. Considering the data from the largest randomized trial in depression, the STAR*D study, it has been suggested that there is a marked change in remission rates between second and third step treatments supporting a view that TRD should be defined on the basis of two failed treatments ( ) (see Fig. 1.2 ).

However, in a meta-analysis of over 4500 patients, a dichotomous or even a highly variable response to antidepressants does not seem to be the case, challenging the notion that there are distinct subgroups of treatment-responsive and treatment-resistant patients with depression ( ). Big data sets can be used to identify factors associated with proxy markers of TRD, for example, the need for using ECT, vagus nerve stimulation (VNS), or deep brain stimulation (DBS). One such study identified that such patients could be defined by having received three or more antidepressants, or one or more antipsychotics, in the preceding year ( ). However, the argument is somewhat circular in defining TRD on the basis of use of certain (neurostimulatory) treatments, and the derived criteria will vary between different health care environments whose treatment algorithms differ. The reality is that there are likely to be a multitude of reasons why some patients respond to medication and others do not, including pharmacokinetic and pharmacodynamic differences, and there are no clearly defined symptomatology-based, phenotypic, or biological boundaries between TRD and depression that is not treatment resistant ( ), precluding this as an avenue through which to define TRD—at least at the present time.

What about from a regulatory perspective? While regulators do set out some outline criteria, what companies do is determined at least in part by business considerations. Intranasal esketamine has received a license in many parts of the world for augmentation of antidepressants in patients with TRD. This was on the basis of pivotal RCTs in which TRD was defined as a failure to respond to at least one antidepressant in the current episode assessed retrospectively, plus failure of a different antidepressant taken at an adequate dose for a total duration of at least 6 weeks observed prospectively ( ). No response was defined as less than a 25% improvement in symptoms and adequacy of dose of drug assessed using the Massachusetts General Hospital antidepressant treatment response questionnaire ( ). Currently, there are no other drugs licensed in Europe for TRD. An alternative approach was taken by the manufacturers of a long-acting formulation of quetiapine who obtained a license for its use in patients with “sub-optimal response” to antidepressants based on pivotal studies that recruited participants whose depression had failed to respond to just one or more antidepressants ( ). The decision between these two different positions is largely governed by marketing factors as well as a belief that the more previous treatments have been ineffective, the less likely a subsequent one is to work, based on the data from the STAR*D study ( ).

Ultimately, the definition of TRD is arbitrary. In an attempt to address this, a European-funded partnership with industry has drawn together a number of international experts in the management of depression from across the globe and, using a Delphi technique, attempted to arrive at a consensus definition of TRD particularly, but not exclusively, for regulatory studies ( ). There was strong consensus that the definition should be failure of at least two prior antidepressant treatments but only weak consensus that this should be based on treatments in the current episode or the last 2 years, whichever is longer. There was moderate consensus that an adequate trial of a medication was a minimum of 4 weeks at a minimally effective dose and that the minimum of two failed treatments needed to include two established treatments with different mechanisms of action, though how the latter is defined was not detailed. The consensus was that trials in TRD could include patients who had received psychotherapy or neurostimulation treatments, such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and ECT, but not VNS or DBS. There was also consensus that trials should exclude comorbid personality disorders, other mental disorders, and active and severe substance misuse ( ). If this consensus is adopted, then it will lead to more consistency in studies allowing for comparisons of treatments, but the downside is that the data will be less generalizable given high rates of comorbidity of all types in TRD populations ( ; ).

Most definitions of TRD focus exclusively on unipolar depression, though some studies in TRD do include patients with a bipolar diagnosis ( ). There is much less consistency regarding the definition of treatment-resistant bipolar depression (TRBD). The most common definition in the recent literature is failure of one treatment known to be effective ( ). However, a group of experts in the management of bipolar disorder, using a Delphi technique, arrived at a consensus definition of TRBD as failure to reach sustained symptomatic remission for eight consecutive weeks after two different treatment trials, at adequate therapeutic doses, with at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination treatment ( ). This has been operationalized in an ongoing trial as failure to respond to (or tolerate) two out of four treatments included in current guidelines for the treatment of bipolar depression ( ): quetiapine, olanzapine, lamotrigine, and lurasidone ( ).