Can Subtyping Depressive Symptoms Predict Antidepressant Response?

Many clinicians have a working assumption that subtyping patients is a critical process relevant to antidepressant treatment selection.

Since the introduction of imipramine in the 1950s as a treatment for depressive symptoms, there has been a desire to identify symptoms, dimensions (or factors) that identify groups of individuals more, or less likely, to respond, to an antidepressant. Many iterations of the Diagnostic and Statistical Manual (DSM) have included reference to several subtypes, including but not limited to, atypical and melancholic features. The DSM 5 (2013) introduced two new specifiers relevant to subtyping: anxiety distress as well as the mixed features specifier. The forgoing subtypes are in addition to the well-known subtype of psychotic depression.1

Major depressive disorder is a collection of disorders heterogeneous in phenomenology, pathophysiology, comorbidity, as well as treatment. Available evidence indicates that there is no singular neural, cellular, or molecular substrates that subserves all dimensional features of a depressive illness. Typologies, such as reactive versus endogenous depression, have been mentioned in the literature for decades and carry with them both pathogenetic and treatment implications.

Informally many clinicians have a working assumption that subtyping patients is a critical process relevant to antidepressant treatment selection, and more broadly, modality of treatments assigned. For example, the implication for characterizing endogenous versus reactive depression was that the latter, presumably in response to identifiable interpersonal triggers, would be best treated with a psychosocial intervention, while the former was more appropriately treated with a “somatic” intervention. Unfortunately, this rather simplistic notion has turned out not to be empirically supported.

Notwithstanding the historical, conceptual, and scientific emphasis given to subtyping major depressive episodes, the evidence supporting the robust predictive utility of a particular depressive subtype is mixed and rather, in most cases, unconvincing. What is convincing, though, is notwithstanding individuals with depressive symptoms complicated by psychotic features exhibit preferential response to the combination of a conventional antidepressant and an antipsychotic medication when compared to an antidepressant alone.

The percentage of individuals with clinically significant depressive symptoms as part of major depressive disorder who exhibit psychotic symptoms varies as a function of the health care setting with modal rates of approximately 20%. Melancholic and atypical depressions, as well as mixed melancholic and atypical symptoms, appear to be much more commonly encountered in clinical practice.Emphasis on parsing atypical depressive symptoms from other depressive subtypes was initially thought to be relevant, insofar as atypical depressive symptoms were thought to exert differential responses to monoamine reuptake inhibitors (MAO-I). Subsequent data, however, refuted earlier notions by demonstrating that atypical depressive symptoms could also robustly respond with a selective serotonin reuptake inhibitor (SSRI).

One of the largest studies ever to evaluate whether depressive subtypes are relevant from the perspective of predicting antidepressant response is a report from the International Study to Predict Optimized Treatment and Depression (iSPOT-D).2 The iSPOT-D is a large “practical trial” that enrolled adults 18–65 who met criteria for major depressive disorder. Individuals enrolled in the trial were randomly assigned to treatment with either escitalopram (mean dose 12mg/day), sertraline (mean dose 61mg/day) or extended-release venlafaxine (mean dose 83mg/day). Seventeen sites across five countries, including the United States, Europe, New Zealand and Australia were included.

Participants in the study were subtyped on the basis of meeting criteria for melancholic depression, atypical depression, anxious depression, mixed or no subtype. Melancholic depression was defined according to the MINI interview, as well as with a separate evaluation scale for measuring psychomotor retardation. Atypical depression was defined as mood reactivity, plus at least two items of hypersomnia, hyperphagia, leaden paralysis, and/or rejection sensitivity on the Columbia Atypical Depression Diagnostic Scale.