Agitated "unipolar" depression re-conceptualized as a depressive mixed state: Implications for the antidepressant-suicide controversy

ArticleinJournal of Affective Disorders 85(3):245-58 · April 2005with51 Reads
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.
    • "Overall, our clinical features did not determine a clear profile of patients experiencing AWSI. While the trend toward a higher rate of agitation at diagnosis among cases could support the hypothesis of mixed states, mistaken for MDEs and wrongly treated by antidepressants (Akiskal et al., 2005), the lower rate of first episodes in cases as well as the trend toward a higher number of depressive episodes in their history and a longer cumulative duration of depressive episodes contradict this argument and defend the hypothesis of severe multi-treated patients, who might have developed lower sensitivity to antidepressants. Besides, this last hypothesis is reinforced by the fact that adjustment on the " agitation " item does not alter the statistical association between AWSI and the rs1439050 SNP. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Antidepressant-worsening suicidal ideation is a rare but serious phenomenon. This study aimed to test for association between antidepressant-worsening suicidal ideation and polymorphisms of BDNF/NTRK2 neurotrophin pathway genes, known to be involved in depression and suicide. Methods: This was a case-control study comparing patients with antidepressant-worsening suicidal ideation to patients without. Patients were collected from the GENESE cohort (3771 depressed tianeptine-treated outpatients). Antidepressant-worsening suicidal ideation was defined by an increase of at least 2 points on the Montgomery-Åsberg Depression Rating Scale-item10 during treatment. Controls were matched for age, sex, and baseline Montgomery-Åsberg Depression Rating Scale-item10 score. Thirteen single nucleotide polymorphisms covering 5 BDNF/NTRK2 pathway genes were genotyped. Results: A total 78 cases and 312 controls were included. Two NTRK2 single nucleotide polymorphisms were associated to antidepressant-worsening suicidal ideation: rs1439050 (P=.01) and rs1867283 (P=.04). Association with rs1439050 remained significant after adjustment for potentially confounding factors, including previous suicide attempts (P<.01). Conclusions: This naturalistic prospective study is consistent with previous studies on highlighting the potential role of the neurotrophin pathway, and especially of NTRK2, in antidepressant-worsening suicidal ideation.
    Article · Jul 2016
    • "It may be that agitation is a correlate of suicidal ideation; indeed, both psychomotor agitation and suicidal thoughts comprise two of the nine symptom criteria for a diagnosis of major depressive disorder (American Psychiatric Association, 2013 ). In concordance with this viewpoint, symptoms of agitation coinciding with depressive episodes are associated with more severe suicidal ideation (Akiskal et al., 2005 ). However, agitation may also be associated specifically with suicidal behavior, particularly in those who possess a capability to enact lethal self-harm (Ribeiro et al., 2015a; Ribeiro, Yen, Joiner, & Siegler, 2015b ). "
    [Show abstract] [Hide abstract] ABSTRACT: Agitation has been implicated as an acute risk factor for suicidal behavior, yet the literature to date has not been consolidated to better understand this relationship. We conducted a meta-analysis of the association between agitation and suicidal behavior to synthesize the existing literature (k=13 studies) and point out future directions for research. Results indicated that the association between agitation and suicidal behavior is moderate (Hedge's g=0.40, p=0.007, 95% CI [0.08, 0.72]). Follow-up meta-regressions revealed that age, gender, and year of publication were not significant moderators of the magnitude of this relationship. However, there was evidence of publication bias, as shown by a funnel plot and Egger's test. These findings suggest the importance of future research that examines the nature of the association between agitation and suicidal behavior longitudinally and with novel research designs, as implications for clinical practice and suicide risk assessment may be substantial.
    Full-text · Article · Jun 2016
    • "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). "
    [Show abstract] [Hide abstract] 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
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