Agitated "unipolar" depression re-conceptualized as a depressive mixed state: Implications for the antidepressant-suicide controversy
The nosologic status of agitated depression is unresolved. Are they unipolar (UP) or bipolar (BP)? Are they mixed states? Even more controversial is the notion that antidepressants might play some role in the suicidality of such patients (Akiskal and Mallya, 1987) [Akiskal, H.S., Mallya, G., 1987. Criteria for the "soft" bipolar spectrum: treatment implications. Psychopharmacol Bull. 23, 68-73]. After excluding all patients with history of hypomanic episodes occurring outside the frame of a major depressive episode (MDE), even those with a shorter duration of hypomanic symptoms than stipulated in DSM-IV, the remaining consecutive 254 unipolar major depressive disorder (MDD) private adult (> 21 years old) outpatients were interviewed (off psychoactive drugs for 2 weeks) with the Structured Clinical Interview for DSM-IV (SCID-CV), the Hypomania Interview Guide (HIGH-C), and the Family History Screen. Intra-MDE hypomanic symptoms were systematically assessed, with > or = 3 such symptoms required for a diagnosis of depressive mixed state (DMX). Agitated depression was defined as an MDE with HIGH-C psychomotor agitation score > or = 2. Logistic regression was used to study associations and control for confounding variables. In this strictly defined unipolar sample, agitated depression was present in 19.7%. Compared with its non-agitated counterpart, it had significantly fewer recurrences, less chronicity, higher rate of family history for bipolar disorder, and DMX; and, among the intra-depressive non-euphoric hypomanic symptoms (in decreasing order of frequency), distractibility, racing/crowded thoughts, irritable mood, talkativeness, and risky behavior. The most striking finding was the robust association between agitated depression and DMX (OR = 36.9). Furthermore, patients with psychomotor agitation had significantly higher rate of weight loss and suicidal ideation. Of DMX symptoms, we found an association between suicidal ideation, psychomotor activation, and racing thoughts. Agitated depression was tested by forward stepwise logistic regression versus all variables significantly different in the pairwise comparisons, yielding DMX, talkativeness, and suicidal ideation as the independent significant positive predictors. No suicidal ideation scale was used. Agitated depression emerges as a distinct affective syndrome with weight loss, pressure of speech, racing thoughts and suicidal ideation. Psychomotor activation and racing thoughts during MDD independently predicted suicidal ideation. In this "unipolar" MDD sample, agitated depression had a strong clustering of intra-episode non-euphoric hypomanic symptoms (i.e. DMX) which, coupled with its association with bipolar family history, support its link with the bipolar spectrum. Agitated depression is therefore best regarded as "pseudo-unipolar." These findings overall accord with classical German concepts of agitated depression as a mixed state. Given that these patients are typically activated along the lines of risk-taking behavior, Kraepelin's rubric of "excited (mixed) depression" appears to us the preferred terminology over "agitated depression". The data reported herein, placed in the setting of the literature reviewed in the discussion suggest that the reports of increased risk of suicidal ideation and/or behavior in some depressed patients treated by antidepressant monotherapy or combinations thereof might be attributed to baseline psychomotor activation/agitation as part of an unrecognized bipolar mixed state. Whether antidepressants induce de novo suicidality in MDD cannot be answered without adequately powered prospective double-blind studies, unlikely to be conducted because of ethical constraints. Nonetheless, we submit that agitated, activated, or otherwise excited depressions (which we consider as depressive mixed states) overlap considerably with the so-called antidepressant "activation syndrome." Furthermore, the rare occurrence of suicidality on antidepressants should not obscure the fact that the advent of the new antidepressants is associated with worldwide decline in suicide rates. We finally wish to point out that our formal nosology (i.e. DSM-IV and ICD-10), in its failure to recognize the bipolar nature of depressive mixed states, thereby fails to shield pseudo-unipolar patients from antidepressant monotherapy, which is inappropriate for such patients.