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

Università di Pisa, Pisa, Tuscany, Italy
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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    • "Recently, these findings have been extended to similar relationships in the children and adolescents with MDD. Akiskal and colleagues (Akiskal et al., 2005) have suggested that approximately 20% of depressed patients may present with an agitated unipolar depression that shares some features of a depressive mixed state with distractibility, racing thoughts, an irritable mood, talkativeness, risky behavior and increased suicidality. Impulsivity appears to discriminate depressed subjects without a history of suicide attempts from those with a positive personal history (Perroud et al., 2011). "
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    ABSTRACT: Cognitive dysfunction may be a core feature of major depressive disorder (MDD) including affective processing bias, abnormal response to negative feedback, changes in decision making, and increased impulsivity. Accordingly, a translational medicine paradigm predicts clinical action of novel antidepressants by examining drug-induced changes in affective processing bias. With some exceptions, these concepts have not been systematically applied to preclinical models to test new chemical entities. The purpose of this review is to examine whether an empirically-derived behavioral screen for antidepressant drugs may screen for compounds, at least in part, by modulating an impulsive biasing of responding and altered decision-making. The differential-reinforcement-of low rate 72-s (DRL 72-s) schedule is an operant schedule with a documented fidelity for discriminating antidepressant drugs from non-antidepressant drugs. However, a theoretical basis for this empirical relationship has been lacking. Therefore, this review will discuss whether response bias towards impulsive behavior may be a critical screening characteristic of DRL behavior requiring long inter-response times to obtain rewards. This review will compare and contrast DRL behavior with the 5-choice serial reaction time test (5-CSRTT), a test specifically designed for assessing motoric impulsivity, with respect to psychopharmacological testing and the neural basis of distributed macrocircuits underlying these tasks. This comparison suggests that the existing empirical basis for the DRL 72-s schedule as a pharmacological screen for antidepressant drugs is complemented by a novel hypothesis that altering impulsive response bias for rodents trained on this operant schedule is a previously unrecognized theoretical cornerstone for this screening paradigm.
    Full-text · Article · Dec 2015 · Journal of Pharmacology and Experimental Therapeutics
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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). "

    Full-text · Article · Sep 2015 · Journal of Affective Disorders
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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.
    Full-text · Article · Sep 2015 · Journal of Affective Disorders
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