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Clinical and epidemiological predictors of treatment-resistant depression
Introduction
Treatment-resistant depression (TRD) is common among individuals with major depressive disorder (MDD), with over one-third of patients being unable to reach an adequate level of symptomatic improvement after trying an antidepressant (AD) treatment ( ). However, it is unclear which factors may lead to poor response to treatment, categorically defined as “treatment resistance.” It is also unclear whether the lack of response to a medication or to a class of medications has clinical implications for long-term prognosis, or whether it has implications for the choice of the next AD treatment. Possible predictors of TRD have been investigated with different methodologies, from prospective clinical trials to large epidemiological studies; however, most of the available data addressing predictors of TRD is derived from post hoc analysis of data from randomized trials. The predictors derived from post hoc studies have significant limitations, including difficulties with replicating positive results across studies, and very few predictors have been tested prospectively. One of the major causes of conflicting results is the use of different definitions of TRD across studies, as the number of failed AD trials required to meet the definition of TRD varies substantially from “nonresponse to one prior treatment” to “nonresponse to three or more prior ADs.” Additional factors such as type of treatment considered (i.e., medications, psychotherapy, ECT), duration, and adequacy of doses, may also differ across studies, further complicating the definition of TRD ( ).
The purpose of this chapter is to review and summarize the literature reporting clinical and epidemiological factors that have been associated with treatment resistance in patients with MDD. Each of those factors has been investigated for possible correlation with the presence of the categorical phenotypes of “non-response” or “non-remission.”
Clinical predictors of TRD that have been commonly explored include those related to the timeline of the illness, such as age of onset, duration and number of episodes, and chronicity (i.e., symptoms of depression persisting unabated for more than 2 years). Some of the other factors considered are related to markers of depression severity including, for example, psychiatric hospitalizations, suicide attempts, the presence of psychotic symptoms, or patterns of general medical or psychiatric comorbidity. Other factors investigated are related to specific features of MDD (i.e., melancholic, atypical, or anxious depression), family history, and personality features. Finally, epidemiological predictors of TRD include gender, ethnicity, psychosocial and environmental factors (i.e., employment, marital status, educational status, adverse life events), and global level of functioning.
Clinical predictors
Clinical subtypes
Although some studies have suggested that individuals with different depressive subtypes, including anxious, melancholic, atypical, mixed, and psychotic depression, respond differentially to ADs, there are inconsistencies in the literature ( ). For example, regarding the “atypical” subtype of depression, in the 1970s researchers reported superior efficacy of MAOI compared to tricyclics for patients with this subtype, and additional trials were conducted in the 1980s ( ); however, this association has not been investigated with more recently developed ADs and it is of limited utility for clinicians due to the infrequent use of MAOIs, as discussed in greater detail elsewhere in this volume. Regarding “melancholic” depression, some studies showed that patients with this subtype and higher depression severity may not respond as well to SSRIs compared to venlafaxine or tricyclic ADs ( ) and that melancholic features are associated with TRD (defined as failure to respond to at least two consecutive AD trials) ( ), but these observations were not supported by other studies ( ). In an uncontrolled parallel design study using sertraline, citalopram, and venlafaxine, there was no clear association between depressive subtype and clinical outcome ( ). It should be noted that, often, the percentage of patients classified as having a pure-form subtype (i.e., melancholic) or more than one subtype (mixed) is fairly similar (approximately one-third of the sample), further complicating the classification ( ). The presence of anxiety symptoms in the context of a major depressive episode, or so-called “anxious depression,” seems to confer increased risk for nonresponse to ADs in a manner that is similar to having a comorbid anxiety disorder, and several groups have found that anxiety symptoms at baseline predicted poorer or delayed response to treatment ( ; ; ; ).
Depression severity
Among individuals treated with antidepressants, the severity of illness itself is commonly considered a factor contributing to resistance ( ; ; ). In a prospective study that included multiple next-step stages of treatment for depressed antidepressant-treated patients, found that higher depression severity at baseline was associated with poorer response to SSRIs (fluoxetine and paroxetine). Similar results were reported by who found that higher levels of depression severity at the beginning of follow-up was associated with TRD in a European multicenter study, in addition to other factors including comorbid anxiety disorders, comorbid personality disorders, presence of recurrent episodes, number of psychiatric hospitalizations, early age at onset of index depressive episode, and a lifetime history of poor response to the first antidepressant prescribed. However, the association between depression severity and TRD has not been consistently replicated. For example, in a post hoc analysis of pooled data from three randomized trials of pharmacotherapy, psychotherapy, or combination therapy for depression, reported that lower baseline depression severity, and not higher severity, was associated with non-response to treatment. Other researchers explored the relationship between symptom severity at baseline and response to escitalopram, compared with response to several other SSRIs and SNRIs combined (citalopram, duloxetine, fluoxetine, paroxetine, sertraline, and venlafaxine) ( ). In that study, higher depression severity was associated with lower response rates to all the other antidepressants combined, while there was no association between baseline symptom severity and response to escitalopram.
Chronicity
One of the more commonly reported factors associated with non-response to ADs is chronicity, or duration of the MDD episode of more than 2 years ( ; ; ; ). These findings of duration of episode overlap with those of , reporting nonresponse to psychotherapy associated with a longer duration of depression. Interestingly, this study explored psychotherapy, pharmacotherapy, and the combination of the two, and showed that patients with chronic depression exhibited a lower response to psychotherapy alone. However, the predictive effect of duration of episode was no longer significant when considering pharmacotherapy only. In a more recent, large, single-blind, 7-month prospective randomized trial, chronicity of depression did not appear to differentially impact acute or longer-term outcome with SSRI monotherapy or with combination of antidepressants ( ). In other studies the number of previous hospitalizations, a possible marker of both severity and chronicity, was significantly associated with non-response, however, this may lead to circular definition, as non-response itself may lead to an increase in the rate of hospitalizations ( ; ).
Treatment adherence
It is intuitive that patients who prematurely self-discontinue treatment, or have poor compliance, may be at higher risk for depressive relapse or for developing a more chronic symptomatic course. A repeated pattern of interruptions of pharmacologic treatment may be due to several factors including poor access to care or financial barriers, and these may overall lead to worse prognosis or be correlated with other adverse prognostic factors in people with depression. In an interesting study that explored the relationship between adherence to depression treatment guidelines (4–9 months of AD therapy following acute symptom remission) and recurrence of depression in a sample of Medicaid beneficiaries with diagnosed depression ( ), patients who stopped their treatment prematurely were at higher risk of experiencing a relapse, while those who continued with their AD treatment were the least likely to relapse. Similar findings were reported in a more recent study that suggested a fivefold increase in nonresponse associated with nonadherence to psychotherapeutic treatment ( ). Another variable to consider that is related to care not consistent with prescription guidelines and may be considered parallel to the general principle of adherence is the prescribing of inadequate doses of antidepressant treatment, which has been consistently associated with non-response ( ; ; ). However, in most cases, treatment non-adherence or under-prescribing (i.e., inadequate doses or inadequate duration of trials) are generally considered to be causes of “pseudo-resistance,” apparent non-response due to inadequately conducted therapeutic trials, as opposed to depression that has responded poorly to vigorous, evidence-based, guideline-consistent treatment.
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