Sultans of Swing: A Reappraisal of the Intertwined Association Between Affective Lability and Mood Reactivity in a Post Hoc Analysis of the BRIDGE-II-MIX Study

Sultans of Swing:

A Reappraisal of the Intertwined Association Between Affective Lability and Mood Reactivity in a Post Hoc Analysis of the BRIDGE-II-MIX Study

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ABSTRACT

Objective: This post hoc analysis of the BRIDGE-II-MIX study is aimed at evaluating affective lability (AL) as a possible clinical feature of mixed depression and assessing the relationship with atypical depressive features, particularly mood reactivity (MR).

Methods: In the BRIDGE-II-MIX multicenter, cross-sectional study, 2,811 individuals suffering from a major depressive episode (MDE; DSM-IV-TR criteria), in the context of bipolar I or II disorder (BD-I, BD-II, respectively) or major depressive disorder, were enrolled between June 2009 and July 2010. Patients with (MDE-AL, n = 694) and without (MDE-noAL, n = 1,883) AL and with (MDE-MR, n = 1,035) or without (MDE-noMR, n = 1,542) MR were compared through χ2 test or Student t test. Stepwise backward logistic regression models, respectively testing AL and MR as the dependent variable, were performed to differentiate the 2 clinical constructs.

Results: AL was positively associated with BD-I (P < .001) and BD-II (P < .001), with DSM-5 mixed (DSM-5-MXS) (P < .001) and atypical (DSM-5-AD) features (P < .001) and negatively associated with MDD (P < .001). In the logistic regression models, MR was the variable most significantly associated with AL and vice versa (P < .001 for both). AL was positively associated with severity of mania and DSM-5-MXS and negatively correlated with severity of depression, while MR was better predicted by atypical symptoms such as hyperphagia, hypersomnia, and leaden paralysis and correlated with both comorbid anxiety disorders and DSM-5-MXS.

Conclusions: Mixed and atypical depression may lie on the same continuum. MR and AL could represent the underlying matrix, bridging the gap between mixed and atypical depression.

J Clin Psychiatry 2019;80(2):17m12082

To cite: Verdolini N, Menculini G, Perugi G, et al. Sultans of swing: a reappraisal of the intertwined association between affective lability and mood reactivity in a post hoc analysis of the BRIDGE-II-MIX study. J Clin Psychiatry. 2019;80(2):17m12082.

To share: https://doi.org/10.4088/JCP.17m12082

aBipolar Disorder Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain

bFIDMAG Germanes Hospital× ries Research Foundation, Barcelona, Catalonia, Spain

cCIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Barcelona, Spain

dDivision of Psychiatry, Clinical Psychology and Rehabilitation, Department of Medicine, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy

eDepartment of Experimental and Clinic Medicine, Section of Psychiatry, University of Pisa, Pisa, Italy

fCHU Clermont-Ferrand, Department of Psychiatry, University of Auvergne, Clermont-Ferrand, France

gFondation FondaMental, H×´pital Albert Chenevier, P×´le de Psychiatrie, Créteil, France

hDepartment of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland

iAP HM, Psychiatric Pole, Marseille, France

jDepartment of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas

kDepartment for Therapy of Mental Disorders, Moscow Research Institute of Psychiatry, Moscow, Russia

lCentre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom

mPsychiatry B, The Chaim Sheba Medical Center, Ramat-Gan, Israel

*Corresponding author: Eduard Vieta, MD, PhD, Bipolar Disorders Unit, Institute of Neuroscience, IDIBAPS CIBERSAM Hospital Cl×­nic de Barcelona, Calle Villarroel, 170, 12-0, 08036 Barcelona, Spain (EVIETA@clinic.cat).

Affective lability (AL) is defined as the predisposition to rapidly reversible and marked shifts in affective states that are extremely sensitive to environmental events with intense behavioral responses.1 According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), these abrupt switches are characterized by a few hours’ duration and can represent a response to both pleasant and unpleasant events.2,3

Affective lability has been used as a synonym of mood lability and emotional lability in consideration of the fluctuation between different mood states (eg, anger, depression, anxiety, elation/hypomania, disgruntled mood) and difficulties in controlling the consequences of these oscillations.4-7 Classically, AL was considered a trait feature of borderline personality disorder (BPD)3 and attention-deficit/hyperactivity disorder (ADHD).8,9 Nonetheless, AL has been considered a state symptom in mood disorders (mainly bipolar II disorder; BD-II) and in a percentage of patients with anxiety disorders and posttraumatic stress disorder (PTSD).6,7,10-12

The psychopathological construct of AL has been interpreted as a form of ultrarapid cycling.13 In bipolar disorder, it was related to clinical features such as age at onset, Axis I comorbidities, and number of previous episodes.11,14 It was also linked to impulse dyscontrol and suicidal behavior in BPD patients.4 AL assumed a central role as a trait-like clinical feature in mixed episodes, especially in those with depressive polarity.15-17 Moreover, it represented 1 of the 3 most frequent state features in mixed depression, together with agitation and irritability.18

Despite this crossover, AL was excluded from the DSM-5 "with mixed features" specifier, possibly leaving many cases of mixed depression undiagnosed and subsequently inadequately treated.19,20 On the contrary, in the DSM-5, mood reactivity (MR) represents a core criterion for depressive "atypical features" and is defined as a change of mood, but restrictively in response to positive stimuli.3 Traditionally, atypical depression was associated with an affective temperamental dysregulation21,22 as part of a common diathesis between depression, BD-II, and BPD.23,24 The evidence that patients with depressive mixed states often display atypical features received wide support.19,25-28

Many experimental studies evaluated AL by means of a number of different assessment tools, with modest clinical agreement.7,29 AL has been investigated in samples of patients with bipolar disorder and major depressive disorder (MDD) with major flaws in the study methodology, ie, not providing a clinical evaluation of comorbid BPD30 and avoiding a differentiation between the clinical components of AL related to BPD and those associated with the specific affective disorders.14 Finally, it has been poorly studied as a state clinical feature in large samples of patients in course of a major depressive episode (MDE). Indeed, several studies5,10,11,14,30,31 focused on the evaluation of this clinical symptom during euthymic periods, with a poor understanding of the framing of AL as a trait or a symptom.8

As a consequence, this post hoc analysis of the Bipolar Disorders: Improving Diagnosis, Guidance and Education (BRIDGE)-II-MIX study19 was aimed at investigating the psychopathological role of AL in a sample of unipolar and bipolar depressed patients (excluding comorbidity with BPD) as a possible mixed symptom and a clinical correlate of atypical features in depression.

METHODS

Sample and Assessment

The general methodology of the BRIDGE-II-MIX study has been described in previous reports.19,32-36 Briefly, the BRIDGE-II-MIX study was a multicenter, international, cross-sectional, diagnostic investigation conducted between June 2009 and July 2010 in 239 centers in 3 different continents. Hospital-based or community psychiatrists consecutively enrolled 10-20 eligible adult patients who were consulting them for a major depressive episode, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)37 criteria.

Reasons for nonparticipation were precoded (refusal to participate, patient unable to complete the questionnaire, other).

Reasons for exclusion were represented by acute nonpsychiatric conditions or emergency events.

The full analysis population included 2,811 patients who gave their written informed consent to attend the investigation and provided complete data.

The study was conducted according to the Declaration of Helsinki (Hong Kong Amendment; http://www.wma.net). The Good Epidemiology Practice and the International Epidemiologic Association European Federation (http://ieaweb.org) Good Epidemiologic Practice (GEP)-IEA guidelines were followed for proper conduct of epidemiologic research, as were pertinent national legal and regulatory requirements. The protocol was authorized in each country by national and local ethics committees.

Data Collection

Information about sociodemographic variables, inpatient or outpatient status, history of psychiatric symptoms, and previous psychiatric hospitalizations were collected. Features of the MDE, bipolar symptoms, known risk factors for bipolar disorder, previous response to antidepressants, psychiatric comorbidity, and current treatment were also gathered. Functional status was determined with the Global Assessment Scale (GAS),38 and illness severity was assessed using the Clinical Global Impressions scale for use in bipolar illness (CGI-BP).39

clinical points

  • Although affective lability has been widely studied as a trait-like clinical symptom of affective disorders, its role as a mixed-state feature in depression still remains unclear.
  • Affective lability represents a mixed feature that could help in targeting a tailored treatment strategy as it is positively correlated with the severity of mania, negatively correlated with the severity of depression, and strongly associated with mood reactivity and atypical depression.

The primary objective of the BRIDGE-II-MIX study was to establish the frequency of depressive mixed states. After the publication of DSM-5, the frequency of depressive mixed states was retrospectively defined as (1) the proportion of patients fulfilling the DSM-5 criteria for MDE with mixed features (DSM-5-MXS)3 or (2) research-based diagnostic criteria for depressive mixed states (RBDC-MXS). RBDC-MXS are defined by the presence of MDE plus 3 of the following 14 hypomanic symptoms for at least 1 week: irritable mood, emotional/mood lability, distractibility, psychomotor agitation, impulsivity, verbal or physical aggression, racing thoughts, more talkative/pressure to keep talking, hyperactivity, increased energy, risky behavior, grandiosity, elation, and hypersexuality.

The aim of the present post hoc analysis of the BRIDGE-II-MIX study was to investigate the psychopathological construct of AL in unipolar and bipolar depression and its clinical correlates, assessing specific features of depressed patients with (MDE-AL) or without (MDE-noAL) affective lability. An operational clinical definition has been adopted, delineating AL as a state feature represented by marked and rapid shifts between different affective states in response to positive or negative environmental stimuli and with subsequent influences on behavior. In adapting a definition of AL to the BRIDGE-II-MIX study, the steering committee of the BRIDGE-II-MIX study decided to combine different previous classifications of AL1,2,4,40 but not to consider it a trait symptom. In fact, AL was considered as a state feature of mixed depression, as highlighted in the Koukopoulos diagnostic criteria for mixed depression.18,41

The clinical implications of the association between AL and atypical features in depression, particularly MR, were also investigated. AL has been distinguished from MR, defined according to DSM-5 as a variation of mood in depressed patients following only positive stimuli.3

The presence of mixed features was defined according to the DSM-5 "with mixed features" specifier (DSM-5-MXS).

Patients diagnosed with BPD (n = 187) were excluded from the analysis in order not to bias the possible correlation between AL and mixed depression due to the trait-like characteristic of AL in BPD.3,4,42 For the same reason,7 patients presenting with ADHD comorbidity (n = 61) were excluded. The final total sample of the post hoc analysis was composed of 2,577 patients.

Statistical Analysis

Groups were compared using the χ2 or the Student t test according to the types of variables. The bivariate analysis involved many tests of statistical significance, raising the problem of type I error. A Bonferroni-corrected threshold for statistical significance (P .003) was then used.

A stepwise backward logistic regression model was used to identify the association between AL and 14 significant variables (DSM-5-MXS, BD-II diagnosis, MDD diagnosis, depression "with atypical features" according to DSM-5 [DSM-5-AD], severity of mania, severity of depression, age at first depressive episode, number of previous affective episodes, comorbid anxiety disorder, hyperphagia, hypersomnia, mood reactivity, treatment with mood stabilizers, and treatment with antipsychotics). Bipolar I disorder (BD-I) was excluded from the model because it violated the assumption of multicollinearity. Subsequently, a stepwise logistic regression model was performed to differentiate AL from MR, testing the correlations between MR and the same clinical variables included in the previous model, plus leaden paralysis. DSM-5-AD diagnosis was excluded from the model because it violated the assumption of multicollinearity. Finally, 2 further stepwise logistic regression models were performed to assess the associations between AL or MR and the 14 RBDC-MXS hypomanic symptoms.

The stepwise modeling procedure started with the full model and consisted of eliminating, for each step, the least statistically significant variable from the model and recomputing the revised model, until all remaining variables were at P < .1. Odds ratios (OR) with 95% confidence intervals were assessed for observed associations. All tolerance values in the regression analyses were > 0.2 and all variance inflation factors were < 2.0, expressing that multicollinearity was not a source of bias in the regression models. Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS for Windows, version 23.0, IBM Corp, Armonk, New York). All P values were 2-tailed, and statistical significance was set at P < .05.

RESULTS

Diagnostic and Clinical Correlates of Affective Lability

Of 2,577 patients with MDE, 694 (26.9%) presented with AL (MDE-AL group). The presence of AL was positively associated with BD-I (OR = 2.1; 95% CI, 1.62-2.79) and BD-II (OR = 2.2; 95% CI, 1.58-3.04) and negatively associated with the diagnosis of MDD (OR = 0.4; 95% CI, 0.34-0.54). The high relative percentage of MDD diagnosis and the low relative percentages of BD-I and BD-II diagnoses in the MDE-AL group depended on the diagnostic distribution of MDD, BD-I, and BD-II in the total sample size (84.5%, 9.4% and 6.1%, respectively). In addition, the MDE-AL group, compared with the MDE-noAL group, was more frequently diagnosed with DSM-5-MXS (OR = 10.5; 95% CI, 7.10-15.49) and DSM-5-AD (OR = 2.7; 95% CI, 1.92-3.64) (Table 1; bivariate analyses of MR are shown in Table 2).

Table 1

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Table 2

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Patients in the MDE-AL group (vs MDE-noAL group) showed higher prevalence of atypical features such as hypersomnia (20.6% vs 14.6%, χ2 = 13.000), hyperphagia (18.2% vs 12.4%, χ2 = 13.375), and MR (65.6% vs 30.8%, χ2 = 253.509), but not leaden paralysis (27.8% vs 24.3%, χ2 = 3.184) (Table 1).

A total of 164 (6.4%) patients were diagnosed with DSM-5-AD. Of these, 103 (62.8%) patients also presented DSM-5-MXS.

Lifetime Psychiatric History and Severity of the Clinical Presentation of Patients in the MDE-AL Group

The MDE-AL group differed significantly from the MDE-noAL group regarding mean ± SD age at onset of first depressive episode (34.37 ± 12.368 vs 36.34 ± 12.634, t = 3.529, P < .001) and total number of previous mood episodes (5.17 ± 5.389 vs 4.36 ± 5.645, t = −3.303, P = .001) (Table 1).

Patients in the MDE-AL group presented higher severity of mania (1.69 ± 1.028 vs 1.13 ± 0.541, t = −13.052, P < .001) evaluated with the CGI-BP and a lower severity of depression (4.40 ± 0.951 vs 4.52 ± 0.947, t = 2.868, P = .004) compared with those in the MDE-noAL group (Table 1).

Clinical Variables Associated With Affective Lability and Mood Reactivity

After performing a stepwise backward multiple logistic regression modeling procedure (χ25 = 546.632, P < .001) using AL as the dependent variable, the model explained between 20.6% (Cox and Snell R2) and 30.3% (Nagelkerke R2) of the variance. Statistical significance persisted for the presence of mixed features according to DSM-5 (OR = 3.0; 95% CI, 2.43-3.77), severity of mania (OR = 2.0; 95% CI, 1.71-2.30), and MR (OR = 3.7; 95% CI, 2.98-4.57), which were positively associated with AL, and severity of depression (OR = 0.9; 95% CI, 0.77-0.97), which showed a negative correlation with AL. The variables most significantly associated with AL were MR and DSM-5-MXS (Figure 1 and Table 3).

Figure 1

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Table 3

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To test the differences between AL and MR, a second stepwise backward logistic regression was performed, using MR as the dependent variable. The model (χ27 = 317.795, P < .001) explained between 12.6% (Cox and Snell R2) and 17% (Nagelkerke R2) of the variance. Variables significantly associated with MR were the presence of mixed features according to DSM-5 (OR = 1.5; 95% CI, 1.21-1.76), AL (OR = 3.7; 95% CI, 3.01-4.57), leaden paralysis (OR = 1.6; 95% CI, 1.29-1.92), hyperphagia (OR = 1.4; 95% CI, 1.05-1.77), hypersomnia (OR = 1.3; 95% CI, 1.05-1.71), and comorbidity with anxiety disorders (OR = 1.5; 95% CI, 1.20-1.80). The strongest correlation with MR was presented by AL. All the variables were positively correlated (Figure 1 and Table 3).

The RBDC-MXS symptoms significantly associated with AL or MR are shown in Supplementary Table 1. Irritable mood, racing thoughts, more talkative/pressure to keep talking, distractibility, and impulsivity were directly significantly associated with both AL and MR. Elation was directly significantly associated with AL, while risky behavior was inversely associated with MR.

DISCUSSION

In this BRIDGE-II-MIX post hoc analysis, AL was a common clinical state feature, assessed in 1 of every 4 patients presenting with a MDE, similar to previous studies.43 AL was a clinical feature associated with BD-I and BD-II, as already reported in clinical5,11 and neuropathology studies.44 Despite being a common symptom in MDD, AL in the present sample was inversely correlated with unipolar depression when compared with bipolar disorder. This does not mean that AL represents a bipolar symptom, but that this symptom could act as a possible bridge between unipolar depression and BD,5 within the concept of a mood spectrum.45,46

More than half the patients reporting AL were diagnosed with a mixed features specifier, in line with literature.18 Traditionally, AL in a depressive mixed episode was considered as a risk factor of shifting between MDD and BD.23,47 Several findings from the present study seem to support that the presence of AL during a MDE was associated with mixicity. We detected a 3-fold increased association between AL and mixed features (Figure 1). AL was positively associated with severity of co-occurring hypomanic and manic symptoms during a MDE, while it was negatively associated with the severity of depression , as found in previous research.43 Patients in the MDE-AL group were more frequently treated with antipsychotic and mood stabilizers and less frequently treated with antidepressants than patients in the MDE-noAL group, in accordance with the recent guidelines on mixed depression.48,49

Another finding claiming the "mixed" identity of AL was the association with a more severe clinical condition, evaluated through indirect measures of psychopathology, such as a higher total number of previous mood episodes and an earlier age at first depressive episode. Indeed, AL was found to independently predict worse outcomes in BD.16,50-56

In terms of outcomes, AL hinders the modulation of mood oscillations with consequent behavioral responses. In the present study, AL correlated with dysregulated behaviors such as alcohol abuse, as in previous findings.14 A possible association with suicidal attempts was not reported in this study. Previous findings are conflicting, with some studies31,57 reporting that AL does not increase the risk of suicidal behavior and others30,58 underlining that the risk of suicidal ideation increases with the level of AL.

In the present study, MR was the variable most significantly associated with AL, and vice versa. The association did not violate the assumption of independence, thus it is unlikely to consider the 2 clinical features as 2 overlapping symptoms. Different factors predicted AL and MR. The construct of AL was positively associated to severity of mania, while MR was predicted by atypical symptoms such as hyperphagia, hypersomnia, and leaden paralysis. This last finding is not surprising in consideration of the diagnostic criteria of the new "atypical features specifier" for depression, namely MR plus 2 or more atypical symptoms.3 Furthermore, there were few differences in the RBDC-MXS symptoms that predicted AL or MR. Despite few common clinical symptoms associated with both AL and MR (irritable mood, racing thoughts, more talkative/pressure to keep talking, distractibility, and impulsivity), AL was positively associated with elation. On the contrary, the presence of risky behavior was negatively associated with MR.

Mixed depression was seen to correlate with atypical features. In a French national study,16 severe clinical profiles displayed by patients with mixed depression included the presence of atypical features, and MDE with atypical features was significantly correlated with more depressive mixed states in an Italian study.25 Almost 50% of patients with atypical depression presented more than 2 hypomanic symptoms.59 The presence of a depressive mixed state was found to be the strongest bipolar diagnostic validator predicting atypical depression.60 Finally, mixed depression overlapped with atypical depression.26 As a consequence, our findings underlined that the polythetic diagnostic criteria of the new "atypical features specifier" for depression might not be completely reliable and valid because they do not take into consideration the longitudinal course of depression, particularly the association with other clinical features such as bipolarity, mixed depression, and the co-occurrence of anxious symptoms, deemed crucial in the diagnosis of atypical depression.61 The different DSM definitions of atypical depression were based on the response to monoamine oxidase inhibitors and emerged by a pattern of linked symptoms followed by studies pursuing diagnostic validity with little research support.61 In particular, the mandatory criterion of reactive mood may not be completely discriminatory, as it was seen to be significantly associated to other atypical symptoms in BD-II but not in unipolar depression.25 As a consequence, a reformulation of atypical depression within a dimensional framework in the context of both unipolar and bipolar depression, including certain expressions of anxiety and considering the longitudinal association and stability of atypical symptoms, that represents real psychopathological symptoms and not only adaptive homeostatic responses should be pursued in future research.61

The notion of mood tone has been extended through a dimensional approach to the construct of emotional reactivity, considering not only the tone, but also the intensity and reactivity of mood.43 A cluster analysis revealed 2 types of depression characterized by hypo- or hyperreactivity. Hyporeactivity identified the inhibited typical depression with loss of pleasure, anhedonia, and emotional anesthesia. Emotional hyperreactivity distinguished depressive states with prominent affective symptoms, identifying mixed depression. Emotional hyperreactivity was not restricted to positive stimuli and might affect all emotions, causing emotional pain.25

In the hypothetical assumption of a continuum between mood symptoms, Akiskal and Benazzi60 disclosed that atypical depression could link unipolar depression and BD-II. Benazzi26 challenged the unipolar-bipolar dichotomy, indicating that mixed depression could bridge the gap between the 2 affective disorders, on the basis of the correlation between intradepressive hypomanic symptoms and depressive symptoms. In other studies,53,62 Benazzi showed that intradepressive hypomanic symptoms did not present a bimodal distribution, reinforcing the continuity between BD-II and MDD depressions. Unipolar MDD patients that converted to BD-II were robustly distinguished from those who remained unipolar on the basis of AL, with AL intruding into, and possibly being accentuated during, depressive episodes, leading to a braided mixed weaving of trait and state.23

As a consequence, the findings of this study suggest that mixed depression and atypical depression lie on the same continuum from unipolar melancholic depression to BD-I manic episodes. The underpinning matrix might be the emotional hyperreactivity experienced by the patient. The difference between the 2 types of depression was represented by the presence of swings due to negative actual or perceived stimuli within the construct of AL.43 Indeed, MR and AL are strongly associated in terms of reaction to positive stimuli but are differentiated by the response to negative stressors (see Figure 2).

Figure 2

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The main strengths of the BRIDGE-II-MIX study include the large sample size and the multicenter international nature of the design.

The first limitation is the widely varying rates of hospitalized patients across countries, which reflected locally driven policies. A second limitation is that the participating centers were not randomly selected, comprising psychiatrists selected because of their particular interest in bipolar spectrum disorders. Also, the definitions of AL and MR relied only on retrospectively coded criteria and selected variables already collected in the dataset, rather than ad hoc variables fetched using validated ratings, which might introduce a measurement bias, especially considering that the operational definitions of AL and MR adopted were clinical. Another limitation is that atypical depression was not an a priori-defined primary outcome. The evaluators did not assess the presence of long-standing interpersonal rejection sensitivity; consequently, the investigators established retrospectively a diagnosis of DSM-5-AD that could be underestimated due to the presence of only 3 of the 4 symptoms defining criterion B of the DSM-5.

For these reasons, additional analyses correlating AL with mixed and atypical features should be undertaken in longitudinal prospective studies, addressing potential confounders.

In conclusion, affective lability seems to represent a simple discriminatory criterion for identifying depressive states with mixed features and should be included in the rubric of mixed features of major depressive episode. The role of affective lability as a mixed symptom in mixed mania could be extrapolated, but the authors suggest conducting further research on this specific topic. The intertwined association between affective lability and mood reactivity might bridge the gap between mixed and atypical depression, in the construct of a unique continuum between mood states. A better understanding of the presence of mixed and atypical features is needed to advocate the therapeutic research on 2 neglected areas and tailoring specific focused treatment strategies.

Submitted: December 13, 2017; accepted August 13, 2018.

Published online: February 19, 2019.

Potential conflicts of interest: Dr Verdolini is funded by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III through a "R×­o Hortega" contract (CM17/00258) and reports no financial or other relationship relevant to the subject of this article. Dr Perugi has acted as consultant of Lundbeck, Angelini, FB-Health; has received grant/research support from Lundbeck and Angelini; and is on the speaker/advisory board of Sanofi-Aventis, Lundbeck, FB-Health, and Angelini and reports no financial or other relationship relevant to the subject of this article. Dr Murru has served as a consultant, adviser, or speaker for Adamed, AstraZeneca, Bristol-Myers Squibb, Janssen-Cilag, Lundbeck, Otsuka, and Sanofi-Aventis and reports no financial or other relationship relevant to the subject of this article. Dr Samalin has received grants, honoraria, or consulting fees from AstraZeneca, Bristol-Myers Squibb, Janssen-Cilag, Lundbeck, Otsuka, Sanofi-Aventis, and Takeda and reports no financial or other relationship relevant to the subject of this article. Dr Azorin has received research support and has acted as a consultant or served on a speaker’s bureau for Janssen, Lundbeck, Otsuka, Roche, Servier, and Takeda and reports no financial or other relationship relevant to the subject of this article. Dr Bowden has received grant support from Sunovion and the National Institute of Mental Health (NIMH), has consulted for Takeda, and reports no financial or other relationship relevant to the subject of this article. Dr Mosolov has received research grants from and has been involved in clinical trials for Servier, Eli Lilly, Lundbeck, AstraZeneca, Janssen-Cilag, Sanofi-Aventis, Geodon Richter, Stada, and Amgen; has been a speaker for Sanofi-Aventis, AstraZeneca, Bristol Myers Squibb, Janssen-Cilag, Pfizer, Novartis, GlaxoSmithKline, and Servier; was an advisory board member for Medavante; and reports no financial or other relationship relevant to the subject of this article. Dr Young is honorary consultant for South London and Maudsley (National Health Service United Kingdom); has given paid lectures and served on advisory boards for the following companies with drugs used in affective and related disorders: AstraZeneca, Eli Lilly, Janssen, Lunbeck, Sunovion, Servier, Livanova, and Janssen but does not share holdings in pharmaceutical companies; is Lead Investigator for Embolden Study (AstraZeneca), BCI Neuroplasticity Study, and Aripiprazole Mania Study; did investigator-initiated studies from AstraZeneca, Eli Lilly, Lundbeck, and Wyeth; has received grant funding (past and present) from NIMH, Canadian Institutes of Health Research, National Alliance for Research on Schizophrenia and Depression (USA); Stanley Medical Research Institute (USA); Medical Research Council (UK); Wellcome Trust (UK); Royal College of Physicians Edinburgh (UK); British Medical Association (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); Michael Smith Foundation for Health Research (Canada); National Institute for Health Research (UK), and Janssen (UK); and reports no financial or other relationship relevant to the subject of this article. Dr Popovic has served as a speaker, medical writer, or has participated in advisory boards for Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen-Cilag, Ferrer, and Forum and reports no financial or other relationship relevant to the subject of this article. Dr Vieta has received research support from, or served as consultant, adviser or speaker for, AB-Biotics, Actavis, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, Telefónica, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the Seventh European Framework Programme (ENBREC), and the Stanley Medical Research Institute and reports no financial or other relationship relevant to the subject of this article. Dr Pacchiarotti has received CME-related honoraria or consulting fees from Adamed, Janssen-Cilag, and Lundbeck and reports no financial or other relationship relevant to the subject of this article. Drs Menculini, Angst, and Barbuti declare no conflict of interest and report no financial or other relationship relevant to the subject of this article.

Funding/support: Sponsored by Sanofi-Aventis. All investigators recruited received fees from the sponsor in recognition of their participation in the study on a per-patient basis. The Instituto de Salud Carlos III (ISCIII) supported this work through a "R×­o Hortega" contract (CM17/00258) to N.V.

Role of the sponsor: Sanofi-Aventis was involved in the study design, conduct, monitoring and preparation of the final database, but had no influence on the final data analysis of this report. The Instituto de Salud Carlos III was not involved in the study design, conduct, monitoring, preparation of the final database or on the final data analysis of this report.

Acknowledgments: The authors express thanks for the support of the Spanish Ministry of Economy and Competitiveness integrated into the Plan Nacional de I + D + I and cofinanced by the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER); the ISCIII, which supported this work through a "R×­o Hortega" contract (CM17/00258 to N.V.); the CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental); the Secretaria d’ Universitats i Recerca del Departament d’ Economia i Coneixement (2017 SGR 1365); and the CERCA Programme/Generalitat de Catalunya.

Supplementary material: Available at PSYCHIATRIST.COM.

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Editor’s Note: We encourage authors to submit papers for consideration as a part of our Early Career Psychiatrists section. Please contact Erika F. H. Saunders, MD, at esaunders@psychiatrist.com.

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