Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy. J Affect Disord

Department of Psychiatry and International Mood Center, University of California, La Jolla, CA, USA.
Journal of Affective Disorders (Impact Factor: 3.38). 04/2005; 85(3):245-58. DOI: 10.1016/j.jad.2004.12.004
Source: PubMed


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.

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    • "Individual factors encompass previous suicide attempts, mental disorders, alcohol or drug abuse, hopelessness, lack of social support, history of trauma or abuse, acute emotional stress, chronic physical illnesses, family history of suicide. The facts that we know to date show mental disorders to be the most significant predictors of suicidal behaviour (Nock et al., 2009; Akiskal et al. 2005) and the majority of authors regard suicidal behaviour as a symptom of psychiatric disorders. The greatest risk has been detected in patients with depressive and/or bipolar disorders (Balazs et al., 2006). "

    Journal of Affective Disorders 09/2015; · 3.38 Impact Factor
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    • "Notwithstanding the efficacy of antidepressant treatment for FM among individuals with MDD (Goldenberg et al., 2004), initiating treatment with antidepressants in patients with comorbid BD to mitigate FM without the concomitant use of mood stabilizing agents might increase the risk of inducing mania, psychotic episodes, and/or rapid cycling (Henry et al., 2001; Preda et al., 2001; El-Mallakh and Karippot, 2002; Goldberg and Truman, 2003; Yildiz and Sachs, 2003). Moreover, induction of the foregoing states has been reported to increase risk of suicide, particularly with SNRI use (Ghaemi et al., 2003; Post et al., 2003; Akiskal et al., 2005; Balazs et al., 2006). For example, duloxetine (SNRI) is approved by the Food and Drug Administration (FDA) for the treatment of FM that may represent a hazard to a subset of individuals with undiagnosed comorbid BD (Hauser et al., 2009; Peritogiannis et al., 2009; Mustafa et al., 2010). "
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    ABSTRACT: Background: Fibromyalgia (FM) is a chronic disorder with high morbidity and significant health service utilization costs. Few studies have reported on the phenotypic overlap of FM and bipolar disorder (BD). The aim of this review is to qualitatively and quantitatively summarize the results and clinical implications of the extant literature on the co-occurrence of FM and BD. Methods: A systematic search of PubMed/Medline, Cochrane, PsycINFO, CINAHL and Embase was conducted to search for relevant articles. Articles were included if incidence and/or prevalence of BD was determined in the FM sample. Results of prevalence were pooled from all studies. Pooled odds ratio (OR) was calculated based on case-control studies using standard meta-analytic methods. Results: A total of nine studies were included. The pooled rate of BD comorbidity in samples of FM patients was 21% (n=678); however, results varied greatly as a function of study methodology. Case-controlled studies revealed a pooled OR of 7.55 of BD co-morbidity in samples of FM patients [95% Confidence Interval (CI)=3.9-14.62, FM n=268, controls n=413] with low heterogeneity (I(2)=0%). Limitations: The current study was limited by the low number of available studies and heterogeneity of study methods and results. Conclusions: These data strongly suggest an association between BD and FM. Future studies employing a validated diagnostic screen are needed in order to more accurately determine the prevalence of BD in FM. An adequate psychiatric assessment is recommended in FM patients with suspected symptoms consistent with BD prior to administration of antidepressants in the treatment of FM.
    Journal of Affective Disorders 09/2015; 188:134-142. DOI:10.1016/j.jad.2015.08.030 · 3.38 Impact Factor
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    • "The relationship between psychomotor agitation and BPD has been controversial. Previous reports demonstrated that psychomotor agitation was more common in BPD (Abrams and Taylor, 1974; Akiskal et al., 2005; Maj et al., 2003); however, additional reports demonstrated relationship in unipolar MDD (Katz et al., 1982; Spitzer et al., 1978). Although most of these previous findings used crosssectional data in contrast to the present study, the Zurich Study was a large, prospective project focusing on the relationship between psychomotor agitation and bipolarity (Angst et al., 2009). "
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    ABSTRACT: Background The relationship between psychomotor agitation in unipolar depression and mood-switching from depression to manic, hypomanic and mixed states has been controversial. We investigated the future risk of initial mood-switching as a function of psychomotor agitation in unipolar depression. Methods We identified 189 participants diagnosed with major depressive disorder (MDD). We divided all patients with MDD into two categories (1) agitated patients (n=74), and (2) non-agitated patients (n=115). These groups were prospectively followed and compared by time to mood-switching. Kaplan–Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazard ratio estimates for a multivariate model were conducted to examine the risk of mood-switching by psychomotor agitation. Results During follow-up, mood-switching occurred in 20.3% of the agitated patients and 7.0% of the non-agitated patients. In the Kaplan–Meier survival estimates for time to incidence of mood-switching with agitated or non-agitated patients, the cumulative probability of developing mood-switching for agitated patients was higher than those for non-agitated patients (log-rank test: χ2=7.148, df=1, p=0.008). Survival analysis was also performed using Cox proportional hazards regression within a multivariate model. The agitation remained significantly associated with incidence of mood-switching (HR=2.98, 95% CI: 1.18–7.51). Limitations We did not make a clear distinction between antidepressant-induced mood-switching and spontaneous switching. Conclusions The main finding demonstrated that MDD patients with agitation were nearly threefold as likely to experience mood-switching, suggesting that psychomotor agitation in MDD may be related to an indicator of bipolarity.
    Journal of Affective Disorders 01/2015; 170:185–189. DOI:10.1016/j.jad.2014.09.001 · 3.38 Impact Factor
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