Pharmacological Approaches to Treatment-Resistant Depression

Overview

Treatment-resistant depression (TRD) refers to an inadequate response to adequate antidepressant treatment. TRD is common in clinical settings. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D), only 36.8% of patients with major depressive disorder (MDD) who were initially treated with citalopram achieved remission. A recent meta-analytic study reviewed 91 antidepressant monotherapy randomized controlled trials and showed an average remission rate of 44%.

TRD leads to poorer psychosocial functioning and raises the risk of suicide, which increases the disease burden of MDD. Cases of TRD tend to be highly recurrent, with up to 80% of patients requiring multiple treatments. The clinical outcomes of patients who fail to remit are usually worse than those of first-episode patients.

Definition of Treatment-Resistant Depression

Although it appears simple, defining “inadequate response” and “adequate antidepressant treatment” remains contro­versial.

Inadequate response typically means failure to achieve remission; patients who improve but who fail to remit with initial treatment are more likely to have a recurrence. In clinical trials, remission is usually defined by scores on depression symptom severity scales (e.g., a Hamilton Depression Rating Scale-17 < 7). Several researchers have suggested that functional recovery also needs to be taken into consideration when defining adequate response.

At least one trial with an antidepressant with established efficacy in MDD (with sufficient duration and doses) is considered to be “adequate antidepressant treatment.” However, defining sufficient duration and dose is difficult. Sufficient dose is either the minimum dosage that will produce the expected effect or the maximum dosage that the patient can tolerate until the expected effect is achieved. Typically, sufficient duration of an antidepressant is considered to be long enough to produce a robust therapeutic effect. In clinical trials 4–6 weeks has been used as the threshold for sufficient duration, but some researchers suggest using a longer period, up to 8–12 weeks. In STAR*D, many patients who initially failed to achieve remission or response, eventually achieved remission or a response by 14 weeks.

Staging Models of Treatment-Resistant Depression

Another important characteristic of TRD is the number of failed trials. As previously mentioned, most clinical studies use a definition of TRD as failure to remit to at least one antidepressant. In other words, those with TRD can fail a number of antidepressant trials. Although there is no clear method of defining the severity of TRD, it is generally thought that as the number of failed trials increases, the chance of remission will diminish. In STAR*D, 30.6% of patients achieved remission at Level 2 and about 13% of subjects achieved remission at Level 3.

Several staging models have been suggested involving the number of non-response to adequate treatment strategies and the types of antidepressants used. However, several factors have not been fully studied. In the staging models, non-response to two agents of different classes has been thought to be more difficult to treat than non-response to two agents of the same class. In addition, there is an implicit hierarchy of antidepressant treatments, with monoamine oxidase inhibitors (MAOIs) being considered as superior to tricyclic antidepressants (TCAs) and SSRIs, and TCAs being considered as more effective than SSRIs in some populations. These two concepts have never been fully investigated. A recent study showed no significant difference in remission rates between venlafaxine-treated and sertraline-treated patients who had not responded to other SSRIs. Similarly, a meta-analysis of antidepressants and a cross-over trial of imipramine and setraline did not prove superior to TCAs.

Clinical Features Associated with Treatment-Resistant Depression

Several clinical conditions (e.g., substance abuse and co-morbid anxiety disorder) have been associated with TRD. Co-morbid personality disorders, subtypes of depression (including atypical depression, melancholic depression, and chronic depression) have also been associated with worse response to antidepressants; however, the studies have had mixed results. Co-morbid personality disorders also have been associated with poorer outcome, but not all studies support these findings. Medical co-morbidities also contribute to a poorer response to antidepressants.

Clinical Approach to Treatment-Resistant Depression

Pseudo-resistance refers to non-response associated with inadequate treatment. When patients with MDD show an inadequate response (i.e., not achieving remission) with adequate antidepressant treatment, clinicians should consider the possibility of pseudo-resistance.

Misdiagnosis of mood disorders is a relatively common problem in clinical practice. This may involve recall bias associated with retrospective evaluations. When remission does not occur, we recommend that clinicians re-do the diagnostic evaluation using a structured clinical interview. Psychiatric co-morbid conditions also need to be examined thoroughly.

It is also important to assess whether a patient actually receives an “adequate antidepressant treatment.” Clinicians need to evaluate whether an antidepressant was used in an adequate dose for a sufficient amount of time and whether the patient actually took medication as prescribed. Medical co-morbidities (including hypothyroidism, fibromyalgia, and neurologic conditions) can also confound the treatment response. Conducting routine blood work and a physical examination can provide additional clues. Also, co-administered medication can affect antidepressant metabolism (via inducing cytochrome P450 enzymes). In some cases, a patient might be a rapid metabolizer of a drug and result in a lower blood level.

Common Treatment Strategies for Treatment-Resistant Depression

Once TRD is confirmed, more rigorous treatment is necessary. Various strategies have been investigated, although the best sequence of treatment has not been established. In general, switching antidepressants, combining two antidepressants, and using augmenting strategies are the most reasonable for TRD. However, the optimal method has not been determined. A retrospective analysis from STAR*D showed no significant differences (in terms of remission rate, response rate, time to remission, and time to response) between switching and augmentation strategies.