Confounding Factors in Treatment-Resistant Depression (Part 2): Comorbidities and Treatment Resistance

Confounding Factors in Treatment-Resistant Depression (Part 2): Comorbidities and Treatment Resistance

treatment-resistant depressionIn psychiatric practice, many depressed patients lack an optimal course of treatment—ie, a “simple” antidepressant medication, with or without psychotherapy—that results in complete symptom remission. The simplest definition of treatment-resistant depression (TRD) is “failure to achieve a response to a medication to any degree short of remission.”1 Addressing the complicating factors that may be responsible for TRD early may improve treatment outcomes.

The role of subtyping and bipolarity in TRD was discussed in Part 1 of this 2-part article2 (See: "Confounding Factors in TRD Part 1: The Role of Subtyping and Bipolarity). Here we review a number of the most common confounding factors of TRD but limit our scope to comorbidities that can be directly addressed and treated by psychiatrists. Subtle maladaptive personality traits or inherent temperamental factors may play a role in sustaining depression in certain individuals. Axis I diagnoses, such as eating disorders, anxiety disorders, and sleep disorders, complicate the treatment of depression unless they are directly addressed. Dissociative disorders may also complicate the treatment of depression.

The role of anxiety and anxiety disorders in TRD

Clinicians have long recognized that treatment of depression may be unsuccessful if accompanying anxiety disorders are not recognized and addressed. Even comorbid subsyndromal anxiety symptoms can complicate the treatment of depression and lead to TRD. Anxiety and depression co-occur frequently, sometimes with one or the other as the primary and preceding diagnosis, but often with a mixture of depressive and anxiety symptoms that is difficult to disentangle historically or clinically.

In their examination of generalized anxiety disorder (GAD) and its association with major depression, Moffitt and colleagues3 followed a group of approximately 1000 New Zealanders from birth to age 32. In this cohort, either MDD or GAD presented as the initial illness. High comorbidity of the two illnesses was demonstrated: 72% of patients with GAD had lifetime MDD, and 48% of MDD patients had lifetime GAD. The extent of the association between depression and anxiety disorders in general is further illustrated by the National Comorbidity Survey, which found that an anxiety disorder was present in 58% of the patients with a lifetime history of depression.4

Anxiety symptoms may make depression harder to treat. Studies have shown that comorbid anxiety in depression is associated with greater severity and longer time to recovery; poorer response to medication; multiple drug trials; more frequent relapses and recurrences; increased social and vocational disability; and perhaps most importantly, an increased rate of suicide, especially in the first year of treatment.5,6

One dissenting study found no association between GAD and TRD; however, this study had a small sample size, and it was a retrospective analysis of failed drug studies.7 Furthermore, this negative study focused narrowly on GAD, while confirmatory studies look more broadly at anxiety disorders and include subsyndromal symptoms, such as psychic anxiety, worry, phobic symptoms, and somatic anxiety.8 Subsyndromal symptoms can be debilitating, even when they do not meet DSM criteria. A comprehensive evaluation for an accompanying DSM-IV-TR anxiety disorder in patients with depression should include screening for agoraphobia, GAD, obsessive-compulsive disorder, panic disorder, PTSD, social phobia, and specific phobia (formerly simple phobia). Although any of these might accompany a specific depression diagnosis, the most commonly reported are social phobia, specific phobia, and PTSD.9

The increased risk of treatment resistance in depressed patients with anxiety symptoms has also been demonstrated in the geriatric population. A recent study of patients older than 70 years with major depression used a self-rating scale for anxiety and found that elevated scores on this scale were associated with poorer response to treatment, increased rate of recurrence in the first 2 years of illness, and increased rate of treatment drop-out.10 Anxiety was viewed in this population as creating a “brittle response” to standard antidepressant treatment. Interestingly, in this study, adjunctive lorazepam (added to paroxetine) did not improve outcomes. The authors suggest that further studies of adjunctive use of psychotherapies and atypical antipsychotic medications in the elderly are needed.

What are the implications of this strong association between anxiety and depression? The most dreaded outcome of depression is suicide, and the destabilizing effect of anxiety in patients who are struggling with suicidal impulses in the setting of major depression increases this risk. Fawcett8 exemplifies this with case reports of 3 patients who ultimately committed suicide and who serve as object lessons for those who care for patients with major depression in both inpatient and outpatient settings.

These cautionary tales illustrate the importance of monitoring for anxiety and agitation in depressed patients. Be particularly aware of escalating anxiety that can accompany the onset of treatment with antidepressants, including SSRIs and TCAs. Because patients with anxiety disorders tend to be very sensitive to the adverse effects of medications, consider beginning antidepressants at lower than usual dosages and slowly titrating the dosage in depressed patients with comorbid anxiety.


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