Where does the forgoing collection of observations lead us? Evidence is compelling that psychotic depression requires the combination of an antidepressant and antipsychotic therapy. With respect to atypical melancholic or combined atypical-melancholic depression, the evidence indicates that subtyping patients (at least the forgoing subtypes) appears to have minimal clinical relevance.

Clinicians, however, are still strongly encouraged to identify those anxious and distressed as adults with a major depressive disorder and anxiety distress specifier who are more likely to experience suicidality and unfavorable illness course. Non-pharmacological approaches combined with pharmacological therapy would seem prudent in most cases in anxious depression.


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Preliminary evidence exists that an atypical agent, i.e. lurasidone, is effective in mixed depression. Comparison efficacy and tolerability of lurasidone with an atypical antidepressant in mixed unipolar depression is a critical study to conduct. Emerging literature indicates that vortioxetine may have a greater effect on cognitive dimensions in major depressive disorder. However, it is not known whether pre-treatment cognitive deficits in adults with depression identify a subgroup preferentially responsive to any particular antidepressant.

In the interim, clinicians should be reminded the most robust predictive phenotype in treatment response with antidepressants is early symptomatic improvement, i.e., at week 2. While it is not likely that a single biomarker would be significantly predictive, the hope is that the future will include a biosignature to inform treatment responses to dimensions and domains in depression.

Roger McIntyre, MD, is head of the Mood Disorders Psychopharmacology Unit at the University Health Network, in Toronto, Canada. He is also a member of the Psychiatry Advisor editorial board.

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