Psychotic features in TRD
Failure to detect “hidden” psychosis accompanying depression or inattention to special considerations with known psychotic depression can lead to ineffective treatment with antidepressants alone. Even with optimal treatment, the presence of psychosis in patients with major depression is often associated with a more severe course and includes more repeated hospitalizations, decreased responsiveness to treatment, and higher relapse rates.5,6
Accurate subtyping of depression thus dictates that clinicians become adept at ferreting out psychotic symptoms in patients who do not have obvious delusions or hallucinations. This often requires a high index of suspicion and intensive interview techniques. Patients may not spontaneously mention, for instance, that they are seeing malevolent “shadowy figures” out of the corners of their eyes. Likewise, without probing questions in the interview, subtle evidence of a delusional thought process (eg, is the patient really financially broke or is he or she suffering from a delusion of poverty?) can easily be overlooked.
In a recent chart review, symptoms of psychosis in depression were missed 27% of the time in an aggregate of patients on the inpatient psychiatric units of 4 academic medical centers.7 Estimates of the incidence of psychosis in depression range from 14% to 20%, which represents a considerable number of patients who would be categorized as having TRD if the psychosis is not recognized and they subsequently fail to respond to antidepressant treatment. Current evidence supports the conclusion that psychotic depression responds best to ECT or, when that treatment is not available or feasible, to a combination of an antidepressant and antipsychotic medication.8
Atypical features in TRD
The atypical features of increase in appetite or weight and hypersomnia are sometimes referred to as “reverse vegetative signs,” but the full atypical syndrome also includes mood reactivity, a “leaden” feeling in the extremities, and exquisite sensitivity to social rejection. Earlier studies showed superiority of MAOIs to TCAs for atypical depression, but with the ascendancy of SSRIs and SNRIs, MAOIs have generally fallen out of favor.9 MAOIs are further disadvantaged by their associated diet and medication restrictions and less favorable adverse-effect profile. Nonetheless, recognition of atypical features of depression in a given patient should lead to consideration of use of an MAOI. Lack of recognition of atypical features may lead to an impression of TRD.
Missed bipolarity in TRD
Patients who have bipolar disorder may show poor, erratic, or even “paradoxical” responses to therapy with antidepressants alone.10 When subtle evidence of bipolarity is overlooked and patients subsequently have numerous unsuccessful trials of non–mood-stabilizing antidepressant agents, these patients are thought to have treatment-resistant unipolar depression. When a patient who presents with a depressive state reports a history of classic manic symptoms, such as spending sprees, elation, flight of ideas, and grandiosity, very few experienced clinicians would overlook a bipolar diagnosis.
Beginning with the work of Akiskal and Pinto,11 there has been heightened recognition that genotypic bipolarity may not fully manifest itself phenotypically. There are patients with bipolar spectrum illness who do not present obvious historical accounts of mania or hypomania. It is often only after a period of years of illness that a patient is recognized as having bipolar II disorder rather than unipolar depression. The Mood Disorder Questionnaire (MDQ), designed for use in primary care clinics, is useful in screening for bipolarity in patients with depression.12 The MDQ can be combined with a comprehensive clinical interview for detection of hidden bipolar variants. Once a bipolar component is strongly suspected, the pharmacological strategy should shift from use of pure antidepressant agents (eg, monotherapy with SSRIs, SNRIs, or TCAs) toward a predominance of mood-stabilizing agents or ECT.13
Personality factors in TRD
Most psychiatrists with extensive experience in treating depressed patients develop an intuitive sense that there are patients with “personality issues” who do not respond to treatment as readily as psychologically healthy peers with similar degrees of depression. One way that this is conceptualized is resistance directed toward or involving medication.14 Numerous studies have examined the comorbidity of Axis II disorders and depression, but fewer studies have looked at the impact of personality disorders on overall treatment responsiveness. Other studies have bypassed DSM categories altogether and have focused instead on more basic personality traits, attitudes, and/or temperament variables that create the “culture” in which depression can both germinate and sustain itself despite seemingly adequate treatments.
The relationship between personality factors and depression is complex and difficult to study for a number of reasons. Depression itself confounds the accurate assessment of personality. Patients in the throes of a depressive episode may appear to have—indeed, often meet criteria for—a personality disorder. Many patients who do meet criteria for an Axis II diagnosis during a mood episode no longer meet those criteria once their depression has been adequately treated. In short, depression can induce a psychological state that resembles a personality disorder.
Personality disorders are currently conceptualized not as static configurations of traits but rather as fluid constellations that can fluctuate with internal and external stressors.15 In this dynamic system, the development of a major depression would represent a “negative” internal factor that could disrupt personality homeostasis to the point where a personality disorder emerges. Further complicating the relationship between depression and personality is the observation that evidence of personality pathology in late adolescence or early adulthood may actually represent the early signs of a mood disorder. Finally, for many patients, the relationship between mood symptoms and personality variables may be mediated through complex, cascade-like mechanisms. For instance, patients with BPD may lead a chaotic and self-defeating lifestyle that results in alienation from social support, which, in turn, leads to loneliness and isolation—and ultimately to depression.
The intricate relationship between personality and depression defies easy understanding. Nevertheless, in the following section, we break down the issue into a number of general categories and highlight the implications for the evaluation and treatment of TRD.