Anxious depression was defined according to the definition employed in the STAR*D study, i.e., a HAM-D anxiety-somatization factor score ≥ 7. Results indicated that 25% of all participants (n=1008) did not meet criteria for any subtype. Of those who met criteria for at least one subtype, 52% met criteria for a single subtype, while 48% met criteria for multiple subtypes. Of those meeting criteria for one subtype, 15% met criteria for atypical depression, 13% for anxious depression and 11% for melancholic depression.

Treatment outcomes were defined on the basis of percentage of subjects who achieved symptom reduction and/or remission. Overall, the likelihood of symptomatic improvement and more specifically remission of symptoms (i.e. Quick Inventory of Depressive Symptomology–Self-Report QIDS-SR ≤ 5 at week 8) was not significantly different in any one subtype. Across all three antidepressants, the findings indicate that subtyping depression in this study was not relevant to predicting antidepressant outcomes.


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An often cited report from the STAR*D trial is that adults with major depressive disorder with prominent pre-treatment anxiety symptoms have lower response of remission rates with antidepressant therapy.3 It is hypothesized that perhaps with the high percentage of combined subtypes, the most common depressive presentation may have influenced results obtained in the STAR*D trial.With respect to atypical depressive symptoms, the findings of the iSPOT trial replicate and extend further published results from the STAR*D trial. The Combining Medications to Enhance Treatment Study (CO-Med) indicates that individuals with atypical symptoms do not exhibit differential treatment response outcomes when compared to individuals with other depressive subtypes.

Moreover the lack of any predictive utility of subtyping individuals on the basis of melancholic depression has been replicated by other investigations which have failed to identify clinically significant differences in response outcomes when individuals are subtyped on the basis of having melancholic features.4-7 A significant limitation on more recent studies, with respect to response outcomes in melancholic depression, is the relative lack of studies that have focused on efficacy outcomes utilizing tricyclic antidepressants (TCAs). Literature from the 1960s and 1970s indicated that melancholic depressions, often associated with greater total depression symptom severity, were differentially responsive to TCAs.

There remains a paucity of literature as to response outcomes of antidepressants with adults with major depressive disorder and mixed features. The relative absence is a consequence of the fact that mixed features as part of major depressive disorder has only first appeared in DSM 5. Identifying mixed features in bipolar disorder is relevant in so far as mixed mania has a very different illness trajectory and associated burden when compared to non-mixed mania. Disambiguating major depression disorder from bipolar disorder in adults presenting with a major depressive episode with mixed features can be very challenging with many individuals perhaps conceptualized along an affective spectrum between unipolar disorder and bipolar II disorder.

Notwithstanding the absence of controlled trial literature, a clinical impression has been that adults with major depressive disorder and prominent agitation may not respond as robustly and/or tolerate antidepressant therapy. Although agitated depression cannot be conceptualized as identical to mixed features, many aspects of agitated depression e.g. restlessness, irritability, over activity have symptom overlap with mixed features.8-10

The first and only study that has evaluated a treatment for mixed features as part of major depressive disorder was recently presented at the American Psychiatric Association Annual Meeting in Toronto in May in poster format. Adults with major depressive disorder (n=211) with two or three manic symptoms were randomly assigned to lurasidone (Latuda) 20 – 60mg/day (mean 38.2 mg/day) the primary efficacy measure was MADRS. Results indicated that the lurasidone-treated subjects had a significant improvement in depressive symptoms relevant to placebo at the endpoint (i.e. week 6), and at each time point beginning at week 1. The overall effect size was 0.8 denoting a high effect size with an NNT of 4 for remission. Overall tolerability was commensurate with what has been observed in other populations.