Confounding Factors in TRD (Part 1): The Role of Subtyping and Bipolarity

Confounding Factors in TRD (Part 1): The Role of Subtyping and Bipolarity

In psychiatric practice, treatment-resistant depression (TRD) is not unusual. In his 2008 review of the various definitions for TRD, including that of adequate clinical trials of at least 1 antidepressant, and perhaps 2, Barbee1concluded with the view that the simplest definition of TRD is “failure to achieve a response to a medication to any degree short of remission.” We can gain much by stepping back from a patient with TRD and doing a careful assessment for complicating factors that can prevent remission of depressive symptoms.

In this 2-part article (see "Confounding Factors in TRD Part 2: Comorbidities and Treatment Resistance"), we discuss a number of the most common confounding factors of TRD. Here we look at subtyping and bipolarity and their role in TRD. Personality factors also affect treatment response in patients with depression. Unrecognized (or ignored) comorbid Axis II pathology, such as borderline personality disorder (BPD), can closely mimic various Axis I depression diagnoses, to the point where the clinician questions whether persistent or lingering dysphoric states are truly “depression.” In Part 2, we will discuss comorbidities in depression and their role in treatment resistance.

Outcomes are worse for patients with a history of childhood adversity or for patients who are in stressful or untenable psychosocial situations (eg, an abusive relationship, an ongoing custody battle). Depressive illnesses are both common and difficult to eradicate in such patients without attention to the “whole picture.” Poor treatment responsiveness is also associated with lack of social supports. Likewise, when the incentives, conscious or unconscious, for the “sick role” and psychiatric disability are greater than the rewards of euthymia, clinicians can easily find themselves thwarted in their treatment attempts.


Melancholic features in TRD

Treatment resistance can occur when subtyping of depression is inaccurate or disregarded. This can be seen with melancholic features, which are presented as a specifier for major depression in DSM-IV-TR. The criteria for the melancholic features specifier are, in some measure, exaggerations of the neurovegetative symptoms of depression (Table).


Melancholic features specifier for major depressive episode

“Melancholia” has been suggested as a separate diagnostic category for DSM-5; the criteria would include2:

• Disturbed mood of apprehension, worry, or despondency

• Psychomotor disturbance of agitation, retardation (including stupor or catatonia or both)

• At least 2 vegetative signs: poor sleep, poor appetite, disturbed libido, problems with cognition

• At least 1 of the following: abnormal dexamethasone suppression test or high nighttime cortisol levels; or decreased REM latency or other sleep abnormalities

Independent of the classification issues with respect to melancholic features, findings suggest differential responses to treatment when major depression is accompanied by melancholic signs and symptoms. These differences include a more favorable response profile with medications, especially with TCAs and other dual-action antidepressant classes, than with psychotherapies, as well as an increased response to ECT.3

Catatonic features in TRD

Catatonic subtyping involves considerations similar to those for melancholic features. Signs of catatonia are easily missed and are often mistaken for the less ominous “psychomotor slowing” seen so commonly with many depressions. The basic catatonic features are motoric immobility or overactivation (catatonic excitement), negativism, mutism, posturing, and echophenomena. Many psychiatric residents and even some experienced practitioners are not well versed in examining patients for catatonia, even though the condition is relatively common on psychiatric inpatient units, where many patients with refractory depressions are admitted.

Patients with psychotic features and/or melancholic features are more likely to have accompanying catatonic features as well, which is consistent with the notion that all of those specifiers point to a more severe biological process than that seen in uncomplicated major depression. When catatonic features are recognized by elicited history or on examination, special treatment considerations come into play. These include the need for high-dose benzodiazepines; consideration of ECT; and special care with use of antipsychotic medications (especially high-potency conventional antipsychotics) because of their tendency to worsen catatonic symptoms.4


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