With respect to depression, the term “treatment resistant” is used to describe patients who do not achieve adequate therapeutic response after multiple treatment interventions. However, there is no consensus on the definition of treatment resistance in depression. Part of the issue is that clinical trials and other studies report both response rates and remission rates. Response is usually defined as having a greater than 50% reduction from baseline scores on a validated depression rating scale such as the Hamilton Depression Scale (HAM-D). Remission, however, is defined as achieving a post-treatment score below a certain cutoff score on a validated depression scale (e.g. less than or equal to 7 on the HAM-D scale).
Even when antidepressant therapies work, they may not result in full remission of the entire complement of depressive symptoms, which span cognitive, emotional, psychomotor, motivational and somatic symptoms. Patients who are “partial responders” often live with significant residual symptoms of depression and suffer from functional impairments.
In fact, it’s possible to be suicidally depressed and still achieve a HAM-D score of 7 or less, qualifying for “remission” in many research studies.
Definitions of treatment resistance vary in their conceptualization of requiring response versus remission. Definitions of treatment resistance also vary according to the number of therapeutic failures to antidepressant medications and augmentation strategies.
There are different “staging” models for treatment-resistant depression, including the Thase and Rush model, the European Staging model, the Massachusetts General Hospital Staging model and the Maudsley Staging model. These attempt to stratify the severity of treatment resistance.
You might wonder what the best estimate of the prevalence of treatment resistant depression is in the population. The largest study done to date on the treatment of major depression in the community setting was the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study conducted by the National Institute of Mental Health from 2001 to 2006.
In this study, 4 separate stages of intervention, based upon expert guidelines at the time, were employed to try to treat depressed patients to full remission, defined at the outset as a HAM-D score of less than or equal to 7. Data from this study, which were published between 2006 and 2013, suggested that after 4 separate stages of intervention, an estimated 67% of patients achieved remission. After the first stage of intervention (prescription of Celexa or citalopram), approximately 37% of patients remitted. After the second stage of intervention (which included patients who were switched to a different antidepressant and those who were augmented by adding a second medication or cognitive behavior therapy to citalopram), between 50-55% of patients remitted.
Initially, these result were seen as encouraging to the psychiatrists and primary care physicians who treat depressed patients in their practices. It suggested that we could get the majority of depressed patients remitted.
However, the papers that were published from the STAR*D trial have received their fair share of criticism. For example, other researchers who examined the data from the trial found that the published results gave a misleading picture of efficacy. One such researcher, having examined the data from the study and applying the criteria originally established in the study protocol , suggested that only 38% of patients who were initially enrolled in the study remitted after 4 stages of treatment, a number far lower than the 67% originally published.
Thus, anywhere from 33% to 62% of patients with depression may have a treatment-resistant form of the condition (at least to the interventions studied in the STAR*D trial).
So, why is it that patients with depression do not achieve full remission of their symptoms with the array of available FDA-approved antidepressants and evidence-based psychotherapies such as cognitive behavioral therapy?
To me, this question is a fascinating one and one for which we don’t have clear cut answers. But, my guess is that a number of factors are at play:
We don’t have a clear cut understanding of the pathophysiology of depression
We don’t have the technology yet to effectively normalize dysfunctional activity in the various brain regions responsible for the symptoms of depression, even though we have a better understanding now of the various brain regions involved in depression.
Morphological changes in certain areas of the brain that accompany long-standing severe depression may not be reversible.
The FDA-approved antidepressants work largely by a similar mechanism. They are all monoamine modulating medications, targeting, in various degrees, serotonin, norepinephrine and dopamine neurotransmission.
Even though we know about other neurotransmitter systems involved in the pathophysiology of depression, we don’t have, as of yet, large scale clinical trials assessing the efficacy of medications that target those neurotransmitters (e.g. glutamate and opioid receptors).
Major Depressive Disorder may well comprise a heterogenous group of depressive disorders with differing pathophysiology in different individuals.
Certain factors that promote the persistence of depression may well not be able to be targeted by a primarily biological intervention (e.g. the chronic inability to form and maintain healthy interpersonal relationships).
Researchers have examined factors that may contribute to treatment resistance. Some factors that have been reported in the professional literature include the duration and severity of the current episode, the presence of significant anxiety, and comorbid personality disorders.
Clearly, there is a need to better understand why some patients express treatment-resistant forms of depression while others do not, and how to best treat these individuals.