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: 3.71). 04/2005; 85(3):245-58. DOI: 10.1016/j.jad.2004.12.004
Source: PubMed

ABSTRACT 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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    • "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 · 3.71 Impact Factor
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    • "This interest has been stimulated by the observation that clinicians often initially underdiagnose bipolarity in patients in favour of a diagnosis of depression [8] [12] [19] [21]. Some studies have focused on agitated depression within mixed mood episodes [1] [5]. Among the different symptom dimensions that have been described in psychosis, the manic dimension appears to be the best discriminator between schizophrenia and affective psychosis [6]. "
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    ABSTRACT: To examine the predictive diagnostic value of affective symptomatology in a first-episode psychosis (FEP) sample with 5years' follow-up. Affective dimensions (depressive, manic, activation, dysphoric) were measured at baseline and 5years in 112 FEP patients based on a factor structure analysis using the Young Mania Rating Scale and Hamilton Depression Rating Scale. Patients were classified as having a diagnosis of bipolar disorder at baseline (BDi), bipolar disorder at 5years (BDf), or "other psychosis". The ability of affective dimensions to discriminate between these diagnostic groups and to predict a bipolar disorder diagnosis was analysed. Manic dimension score was higher in BDi vs. BDf, and both groups had higher manic and activation scores vs. "other psychosis". Activation dimension predicted a bipolar diagnosis at 5years (odds ratio=1.383; 95% confidence interval, 1.205-1.587; P=0.000), and showed high levels of sensitivity (86.2%), specificity (71.7%), positive (57.8%) and negative predictive value (90.5%). Absence of the manic dimension and presence of the depressive dimension were both significant predictors of an early misdiagnosis. The activation dimension is a diagnostic predictor for bipolar disorder in FEP. The manic dimension contributes to a bipolar diagnosis and its absence can lead to early misdiagnosis.
    European Psychiatry 09/2013; 29(7). DOI:10.1016/j.eurpsy.2013.07.005 · 3.21 Impact Factor
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    • "The high number of previous episode, the multiple comorbidity and the frequent history of suicide attempts suggests a possible destabilizing role of previous treatment with antidepressants (Akiskal and Mallya, 1987; Koukopoulos, 1999; McElroy et al., 2006). The emergence of mixed features in an initially non-mixed episode can be induced pharmacologically and has been associated with increased suicidality (Akiskal et al., 2005; Goldberg et al., 2009; Zimmermann et al., 2009). The P-MM subtype is characterized by the lowest number of previous episode and comorbid disorders. "
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    ABSTRACT: The aim of the present study was to identify different clinical subtypes in severe, treatment resistant bipolar mixed state (MS). The sample comprised 202 Bipolar I patients currently in MS referred for an Electro-convulsive Therapy (ECT) trial and evaluated in the first week of hospitalization and one week after the ECT course. Principal component factor analysis (PCA) followed by Varimax rotation was performed on 21 non-overlapping items selected from Hamilton rating-scale for depression (HAMD) and from Young mania rating-scale (YMRS) at baseline evaluation. Cluster subtypes derived from the factor scores were compared in clinical variables and final HAMD, YMRS, Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI) scores. The principal-component analysis extracted 6 interpretable factors explaining 55.9% of the total variance. Cluster analysis identified four groups, including respectively 63 (31.2%) subjects with Agitated-Irritable Mixed-Depression, 59 (29.2%) with Psychotic Mixed-Mania, 17 (8.5%) with Anxious-Irritable-Psychotic Mixed-Mania, and 63 (31.2%) with Retarded-Psychotic Mixed-Depression. The four clusters were statistically distinct and did not show significant overlap in the main symptomatological presentation. Cluster subtypes reported differences in number of past mood episodes, duration of the current episode, suicide attempts, lifetime comorbidity with panic and eating disorders, baseline and final rating-scale scores and rate of remission after ECT trial. Our study indicates that, at least in severe treatment resistant MS, multiple depressive and manic subtypes can be observed with substantial differences in terms of clinical presentation, course, associated comorbidities and treatment response.
    Journal of Affective Disorders 09/2013; 151(3). DOI:10.1016/j.jad.2013.08.037 · 3.71 Impact Factor
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