Xavier Benarous

Johanne Renaud

Jean Jacques Breton

David Cohen

Réal Labelle

MD, FRCPC Jean-Marc Guilé
email: guile.jean-marc@chu-amiens.fr

; Jean

Jacques Breton

Are youths with disruptive mood dysregulation disorder different from youths with major depressive disorder or persistent depressive disorder?

Keywords: disruptive mood dysregulation disorder, major depressive disorder, persistent depressive disorder, suicidal behavior, adolescent, retrospective chart review

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Over the last two decades, the diagnosis and treatment of children presenting with severe and chronic irritability has become a challenge within the context of the pediatric bipolar controversy [START_REF] Masi | Child behavior checklist dysregulation profile in children with disruptive behavior disorders: A longitudinal study[END_REF][START_REF] Roy | Disruptive Mood Dysregulation Disorder: A New Diagnostic Approach to Chronic Irritability in Youth[END_REF][START_REF] Consoli | Manic-like symptoms in youths: Diagnosis issues and controversies[END_REF][START_REF] Tourian | Treatment Options for the Cardinal Symptoms of Disruptive Mood Dysregulation Disorder[END_REF] . On the basis of studies of youths with severe mood dysregulation (SMD), a clinical presentation characterized by persisting irritability and recurrent temper outbursts, the disruptive mood dysregulation disorder (DMDD) was included as a new diagnostic entity in the depressive disorders (DD) section of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [START_REF]Diagnostic and Statistical Manual of Mental Disorders[END_REF] . The DMDD is characterized by persistent irritable mood and, severe (i.e. out of proportion in intensity or duration) and frequent (i.e. three or more times per week) temper outbursts.

The discriminant validity of DMDD and its inclusion among DD have been, and still are, controversial issues [START_REF] Roy | Disruptive Mood Dysregulation Disorder: A New Diagnostic Approach to Chronic Irritability in Youth[END_REF][START_REF] Stringaris | Practitioner Review: Definition, recognition, and treatment challenges of irritability in young people[END_REF] . The inclusion of DMDD in the DD section of the DSM-5 was supported by longitudinal studies showing that chronic irritability in childhood led to internalizing disorders in adolescence and early adulthood, in particular anxiety and depressive disorders [START_REF] Brotman | Prevalence, clinical correlates, and longitudinal course of severe mood dysregulation in children[END_REF][START_REF] Stringaris | Adult outcomes of youth irritability: a 20-year prospective community-based study[END_REF][START_REF] Stringaris | Pediatric bipolar disorder versus severe mood dysregulation: risk for manic episodes on follow-up[END_REF][START_REF] Leibenluft | Severe Mood Dysregulation, Irritability, and the Diagnostic Boundaries of Bipolar Disorder in Youths[END_REF][START_REF] Vidal-Ribas | The Status of Irritability in Psychiatry: A Conceptual and Quantitative Review[END_REF] . The relationship between childhood irritability and depression in adolescence was also supported by genetic and family studies [START_REF]Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis[END_REF][START_REF] Propper | Disruptive mood dysregulation disorder in offspring of parents with depression and bipolar disorder[END_REF][START_REF] Krieger | Dimensions of oppositionality in a Brazilian community sample: testing the DSM-5 proposal and etiological links[END_REF][START_REF] Wiggins | Identifying Clinically Significant Irritability in Early Childhood[END_REF][START_REF] Brotman | Parental diagnoses in youth with narrow phenotype bipolar disorder or severe mood dysregulation[END_REF][START_REF] Stringaris | Adolescent irritability: phenotypic associations and genetic links with depressed mood[END_REF][START_REF] Savage | A genetically informed study of the longitudinal relation between irritability and anxious/depressed symptoms[END_REF] .

The delimitation of DMDD from other psychiatric disorders, and, in particular mood disorders, is an essential step towards the establishment of its diagnostic validity [START_REF] Robins | Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia[END_REF] . To date, the literature has mainly focused on the distinction between DMDD (and the research clinical entity of SMD) and bipolar disorder (BD) [START_REF] Stringaris | Pediatric bipolar disorder versus severe mood dysregulation: risk for manic episodes on follow-up[END_REF] . In contrast, the validity of DMDD has not been questioned against DD, i.e., major depressive disorder (MDD) and persistent depressive disorder (PDD). PDD differs from MDD with respect to the severity and duration of depressive symptoms. PDD is a chronic DD whereas MDD is regarded as mostly, but not exclusively, episodic. Cumulative findings showed that the chronic versus episodic course of mood symptoms is a key clinical feature with distinctive clinical correlates [START_REF] Masi | The Clinical Phenotypes of Juvenile Bipolar Disorder:Toward a Validation of the Episodic-Chronic-Distinction[END_REF] and outcome in adulthood [START_REF] Leibenluft | Chronic versus episodic irritability in youth: a community-based, longitudinal study of clinical and diagnostic associations[END_REF] . DMDD differs from DD, both PDD and MDD, with respect to the presence of temper outbursts and the nature of mood symptoms. Findings from the prospective population-based Great Smoky Mountains Study [START_REF] Stringaris | Irritable mood as a symptom of depression in youth: prevalence, developmental, and clinical correlates in the Great Smoky Mountains Study[END_REF] showed that depressed mood was the most common cardinal mood symptom in youth meeting criteria for DD. On the contrary, irritable mood alone was rare (5.7%). Given that no study has questioned DMDD against MDD or PDD, the differences between MDD, PDD and DMDD (in terms of clinical correlates, natural course, and vulnerability factors) have yet to be characterized. The present study aimed to address these issues.

The first objective of the present study was to determine the frequency of DMDD (compared to MDD and PDD) in a clinical outpatient sample. The frequency of DMDD is expected to be similar to the values reported in outpatient samples (22-31%) [START_REF] Margulies | Will disruptive mood dysregulation disorder reduce false diagnosis of bipolar disorder in children?[END_REF][START_REF] Axelson | Examining the proposed disruptive mood dysregulation disorder diagnosis in children in the Longitudinal Assessment of Manic Symptoms study[END_REF][START_REF] Freeman | Disruptive Mood Dysregulation Disorder in a Community Mental Health Clinic: Prevalence, Comorbidity and Correlates[END_REF][START_REF] Tufan | Sociodemographic and Clinical Features of Disruptive Mood Dysregulation Disorder: A Chart Review[END_REF] . The extent of overlap between DMDD, MDD and PDD would help to document the validity of the diagnosis of DMDD. Indeed, if DMDD is a distinct, valid clinical entity, its overlap with MDD and/or PDD should be moderate -or at least no larger than for the two other disorders. The study's second objective was to compare the clinical characteristics of youths with DMDD, MDD and PDD. We hypothesized that the comorbidity rate would be higher for DMDD than for the two other disorders. This would be in line with previous studies showing a high rate of comorbidity in children and adolescents with DMDD compared to other psychiatric disorders [START_REF] Margulies | Will disruptive mood dysregulation disorder reduce false diagnosis of bipolar disorder in children?[END_REF][START_REF] Axelson | Examining the proposed disruptive mood dysregulation disorder diagnosis in children in the Longitudinal Assessment of Manic Symptoms study[END_REF][START_REF] Freeman | Disruptive Mood Dysregulation Disorder in a Community Mental Health Clinic: Prevalence, Comorbidity and Correlates[END_REF][START_REF] Tufan | Sociodemographic and Clinical Features of Disruptive Mood Dysregulation Disorder: A Chart Review[END_REF][START_REF] Dougherty | DSM-5 disruptive mood dysregulation disorder: correlates and predictors in young children[END_REF][START_REF] Axelson | Taking disruptive mood dysregulation disorder out for a test drive[END_REF][START_REF] Stringaris | Disruptive Mood: Irritability in Children and Adolescent[END_REF][START_REF] Copeland | Prevalence, comorbidity, and correlates of DSM-5 proposed disruptive mood dysregulation disorder[END_REF] . This would also be consistent with the assumption that irritability, the core symptom in DMDD, is located at the interface between internalizing disorders and externalizing disorders [START_REF] Stringaris | Disruptive Mood: Irritability in Children and Adolescent[END_REF] . The study's third objective was to compare the impairments respectively associated with DMDD, MDD and PDD. We expected that youths with DMDD would present a range of peer-relationship difficulties that went beyond aggressive behavior. Several dysfunctions in social information processing have been reported in youths with chronic irritability; this exposes them to a greater risk of experiencing repeated interpersonal difficulties [START_REF] Leibenluft | Severe Mood Dysregulation, Irritability, and the Diagnostic Boundaries of Bipolar Disorder in Youths[END_REF][START_REF] Vidal-Ribas | The Status of Irritability in Psychiatry: A Conceptual and Quantitative Review[END_REF][START_REF] Vidal-Ribas | Deficits in emotion recognition are associated with depressive symptoms in youth with disruptive mood dysregulation disorder[END_REF] . Based on preliminary findings, we would also expect school functioning to be more impaired in youths with DMDD than in youths with MDD or PDD [START_REF] Dougherty | DSM-5 disruptive mood dysregulation disorder: correlates and predictors in young children[END_REF][START_REF] Copeland | Prevalence, comorbidity, and correlates of DSM-5 proposed disruptive mood dysregulation disorder[END_REF] .

Lastly, the study's fourth objective was to compare the vulnerability factors profile for mood disorders in youths with DMDD, MDD and PDD. The focus was placed on vulnerability factors consistently associated with DD in children and adolescents, i.e., a firstdegree family history of depression, a history of adverse life events and an impaired developmental history [START_REF] Thapar | Depression in adolescence[END_REF] .

METHODS

Participants

Data were retrospectively reviewed after their extraction from the medical records of youths referred to the two mood disorder outpatient clinics in Montreal (Canada) between November 2006 and December 2010. The recruitment sites for French-speaking and Englishspeaking youths were respectively the Rivière des Prairies Hospital (RPH) and the Douglas Mental Health University Institute (DMHU). The main inclusion criteria were age between 7 and 17, and admission to one of the two outpatient clinics following a standardized diagnostic evaluation by a multidisciplinary team (including a child psychiatrist). A total of 163 consecutive participants were assessed (114 at RPH and 49 at DMHU) during the study period. The study population comprised 65 males (40%) and 98 females (60%), and the mean ± standard deviation (range) age was 13.4 ± 0.3 (7-17).

Setting and study design

Clinical and sociodemographic data were gathered using a chart review instrument that had previously been validated in a retrospective study of adolescent outpatients with DD [START_REF] Breton | Clinical characteristics of depressed youths in child psychiatry[END_REF][START_REF] Guile | Familial and Clinical Correlates in Depressed Adolescents with Borderline Personality Disorder Traits[END_REF][START_REF] Leboeuf | Exploratory Study of the Clinical Characteristics of Adolescent Girls with a History of Physical or Sexual Abuse Consulting in a Mood Disorder Clinic[END_REF] .

The instrument recorded all the clinical data noted by healthcare professionals (clinicians, social workers and nurses) in the patient's medical file. All information pertaining to a participant's identity was removed. The inter-rater agreement (κ = 0.80) had previously been measured at each site, using a sample of ten charts. Data on sociodemographic characteristics, family and personal medical histories, DSM diagnoses, symptoms, and treatment were extracted using the instrument. In the medical records, the psychiatric diagnoses had been defined according to the DSM-IV-TR criteria and categories. In the current analysis, the psychiatric diagnoses were presented with respect to the DSM-5 criteria and categories. At both recruitment sites, the routine diagnostic work-up encompassed several standardized evaluations including the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS-PL) [START_REF] Kaufman | Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data[END_REF] and the Children-Global Assessment Scale (C-GAS) [START_REF] Shaffer | A children's global assessment scale (CGAS)[END_REF] . In accordance with the ethics regulatory framework enforced in the province of Québec (Canada), access to medical files was authorized by the Director of Professional Services at each of the two investigating centers.

Measurements

Psychiatric diagnoses

The K-SADS-PL was completed as part of each patient's routine clinical assessment at DMHU and RPH. The parents were the informants in the present study. The K-SADS-PL' internal validity (inter-rater reliability: 93-100%; test-retest reliability: 0.74-0.90) and external validity are excellent. Clinical data relative to psychiatric diagnoses were extracted using the chart review instrument. Apart from the removal of the bereavement exclusion criteria, the diagnostic criteria for MDD in DSM-5 (notably the presence of symptoms for at least two weeks) are the same as those in DSM-IV-TR. The diagnosis of PDD was introduced in the DSM-5 as a consolidation of the previously defined DSM-IV-TR category of dysthymia and the chronic subtype of MDD. All participants meeting criteria for dysthymia have been identified as PDD. None of the study participants met the criteria for chronic subtype of MDD.

With respect to the DMDD diagnosis, symptoms reported in the patient's medical file were compared with the DSM-5 criteria for DMDD. Data were abstracted using an additional chart review instrument based on the criteria for temper dysregulation disorder with dysphoria -a research entity developed by the DSM-5 Task Force prior to the publication of the final criteria for DMDD [START_REF] Leibenluft | Severe Mood Dysregulation, Irritability, and the Diagnostic Boundaries of Bipolar Disorder in Youths[END_REF][START_REF]Justification for temper dysregulation disorder with dysphoria[END_REF] . Each criterion was scored as present, absent or unknown. The diagnostic algorithm is provided in the Supplementary Material, and follows the international guidelines (Table S1) [START_REF]Justification for temper dysregulation disorder with dysphoria[END_REF] . In particular, DMDD was endorsed only if the patient met the criteria for duration, cross-domain impairment, and age of onset, with the exclusion criteria rule for bipolar disorder. The psychometric properties of this diagnostic instrument for DMDD have previously been explored in another sample of 12-to 15-year-old outpatients (n=192; Cronbach's α for internal validity: 0.90; κ for test-retest reliability: 0.87) [START_REF] Boudjerida | Disruptive Mood Dysregulation Disorder Scale in Adolescence[END_REF] .

Suicidal behavior and substance use

Suicidal behavior was documented by rating a set of four items: "prior suicidal ideation", "a single prior suicide attempt", "multiple prior suicide attempts", and "prior self-aggressive behavior". The Columbia-Suicide Severity Rating Scale (C-SSRS) [START_REF] Posner | Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants[END_REF] was completed for the study participants at the DMHU clinic. The C-SSRS assesses various forms of suicidal behaviors (active suicidal ideation, interrupted suicide attempts, and aborted suicide attempts), and non-suicidal self-injuries.

Substance use was documented using a set of five items: "prior use of a substance", "regular alcohol use", "regular alcohol use before the age of 12", "regular tobacco use", and "regular tobacco use before the age of 12". In the study sample from DMHU, the DEP-ADO questionnaire [START_REF] Germain | DEP-ADO Grille de dépistage de consommation problématique d'alcool et de drogues chez les adolescents et les adolescentes[END_REF] was additionally used to document substance use in the previous 12 months. The screening question was "During the last twelve months, how often have you [has X] used one of the following substances: alcohol, cannabis, cocaine, inhalant/solvent, stimulant, hallucinogen, or heroin"; examples and trivial names were provided for each substance.

Functional impairment

The level of global functioning was evaluated using the Children-Global Assessment Scale (C-GAS) [START_REF] Shaffer | A children's global assessment scale (CGAS)[END_REF] on the basis of the multidisciplinary evaluation at the first medical visit.

Peer-relationship problems were assessed by the clinician using an eight-item checklist used in chart reviews for the assessment of social functioning in youths with DD [START_REF] Breton | Clinical characteristics of depressed youths in child psychiatry[END_REF][START_REF] Guile | Familial and Clinical Correlates in Depressed Adolescents with Borderline Personality Disorder Traits[END_REF][START_REF] Leboeuf | Exploratory Study of the Clinical Characteristics of Adolescent Girls with a History of Physical or Sexual Abuse Consulting in a Mood Disorder Clinic[END_REF] . The instrument whose reliability has been previously assessed [START_REF] Breton | Clinical characteristics of depressed youths in child psychiatry[END_REF] , regroups the following items: physical and aggressive behaviors, stealing goods from other youths, passive and active social withdrawal, feeling of being rejected by other youths, victim of physical or verbal aggression.

School impairments were assessed using the school reports annexed to the medical file with regard to the following domains: prior grade repetition, reported learning difficulties, repeated unjustified school absence.

Vulnerability factors

A modified version of the Family History Screen [START_REF] Weissman | Brief screening for family psychiatric history: the family history screen[END_REF] was used to retrospectively collect information on the psychiatric history of the participants' first-and second-degree relatives. This included the history of paternal and maternal depression, which is the most wellrecognized risk factor for children and adolescent depression [START_REF] Thapar | Depression in adolescence[END_REF] . Adverse childhood experiences (ACE) were assessed using all available data, with respect to a set of ten items from the Adverse Childhood Experience Questionnaire [START_REF] Anda | Building a framework for global surveillance of the public health implications of adverse childhood experiences[END_REF] A major ACE was defined as an episode of physical and/or sexual and/or emotional abuse and/or a severe form of emotional and/or physical neglect [START_REF] Anda | Building a framework for global surveillance of the public health implications of adverse childhood experiences[END_REF] . Data from administrative sources (e.g. a history of placement in foster care) were also collected following the method used in previous chart-review studies for pediatric mood disorders [START_REF] Garno | Impact of childhood abuse on the clinical course of bipolar disorder[END_REF][START_REF] Benarous | Adverse Childhood Experiences Among Inpatient Youths with Severe and Early-Onset Psychiatric Disorders: Prevalence and Clinical Correlates[END_REF] . The developmental history was explored regarding four domains: a history of complicated pregnancy, a history of delayed psychomotor development, the presence of an associated neurological disorder, and a history of head trauma.

Statistical analyses

Considering the small sample size and the non-Gaussian data distribution, nonparametric Kruskal-Wallis tests were used to compare three groups: (i) youths with DMDD (and, in some cases, a concomitant DD), (ii) youths with MDD only (i.e., without DMDD and/or PDD), and (iii) youths with PDD only (i.e., without DMDD and/or MDD). First, we aimed at increasing the homogeneity of the control groups and thus raise the study's statistical power. Second, in order to increase external validity, we wanted to form the largest possible and most representative clinical sample of youths with DMDD. In order to facilitate the interpretation of our findings with respect to the previous studies [START_REF] Margulies | Will disruptive mood dysregulation disorder reduce false diagnosis of bipolar disorder in children?[END_REF][START_REF] Axelson | Examining the proposed disruptive mood dysregulation disorder diagnosis in children in the Longitudinal Assessment of Manic Symptoms study[END_REF][START_REF] Freeman | Disruptive Mood Dysregulation Disorder in a Community Mental Health Clinic: Prevalence, Comorbidity and Correlates[END_REF][START_REF] Tufan | Sociodemographic and Clinical Features of Disruptive Mood Dysregulation Disorder: A Chart Review[END_REF] , we compared the DMDD group with the rest of the sample ("non-DMDD youths") (studies detailed in Table S2). The groups were compared using Pearson's chi-squared test or Fisher's exact test for categorical variables (e.g., DSM-5 diagnoses), and Student's test or a Mann-Whitney test for continuous variables (e.g., age). Similar analyses were performed for the study's third and fourth objectives. The results were not corrected for multiple comparisons; we considered that in the context of an exploratory analysis, the type II error outweighed the type I error. All statistical analyses were performed with STATASE software (version 12). The threshold for statistical significance was set to p < .05. All analyses were replicated with (i) a more homogeneous DMDD group (i.e., after the exclusion of youths with associated MDD and/or PDD), and (ii) a DMDD group without associated Attention Deficit with/out Hyperactivity Disorder (ADHD) (Table S3).

RESULTS

Objective 1. Frequency of DMDD and overlap with MDD and/or PDD

Thirty-six youths (22%) met the criteria for DMDD (Table 1). The frequencies of MDD and PDD were respectively 36% and 25%. The two sites did not differ significantly (p = .191) with regard to the frequency of DMDD. Thirty-six percent of the youths with DMDD were also diagnosed with a DD (MDD n=7, PDD n=6), but none met the diagnostic criteria for all three disorders (Figure 1).

[Insert Table 1 about here] [Insert Figure 1 about here]

Objective 2. Clinical characteristics of youths with DMDD, MDD and PDD

Youths with DMDD were an average of 3.3 years younger than those with MDD and 2.5 years younger than those with PDD. The proportion of boys was significantly higher in the DMDD group than in the other two groups.

[Insert Table 2 about here] The comorbidity profiles of youths with DMDD and youths with other DD are summarized in Table 2. All the youths with DMDD had at least one other comorbid DSM-5 diagnosis. The number of comorbidities was significantly higher among youths with DMDD than among youths with MDD or PDD. Compared with youths with PDD or MDD, youths with DMDD were more likely to have concurrent trauma-and stressor-related disorders (odds ratio (OR)=2.5, p=.004), ADHD (OR=3.9, p<.001) or disruptive, impulse-control and conduct disorders (DICCD) (OR=3.0, p=.006). The frequency of anxiety disorders was highest in the PDD group and lowest in the MDD group. The DMDD, MDD or PDD groups did not differ significantly with regard to the frequency of substance use (see figure 3), learning disorders or other psychiatric disorders.

[Insert Figure 2 about here] [Insert Figure 3 about here] The proportion of youths with suicidal ideation was significantly lower for the youths with DMDD than for youths with MDD or PDD (Figure 2). However, the frequencies of suicide attempts, multiple suicide attempts, and non-suicidal self-injuries were similar in the three groups. After examining the C-SSRS data for the 14 youths with DMDD from the DMHU site, we found that 8 participants had made a suicide attempt (hanging in one case, wristcutting in three cases, and another method in four cases). Six of the 8 suicide attempts were impulsive. Only one participant had made multiple suicide attempts.

3.3.Objective 3. Impairments associated with DMDD, MDD and/or PDD

The C-GAS score, as measured during the first medical visit, did not statistically differ between the three groups (Table 3). However, youths with DMDD reported more learning difficulties and a more frequent history of grade repetition, relative to youths with MDD or PDD. Peer relationships were significantly more impaired in youths with DMDD compared to youths with MDD or PDD. Youths with DMDD were 3-4 times more likely to display physically or verbally aggressive behavior; they were also more likely to have been victims of verbal and physical aggression.

[Insert Table 3 about here]

Objective 4. Vulnerability factors associated with DMDD, MDD and/or PDD

Exposure to parental mental illness was more frequent in youths with MDD than in youths with DMDD or PDD (Table 4). However, no statistically significant difference was found between the three groups with regard to the family history of psychiatric diagnoses, including depression and substance use.

[Insert Table 4 about here] The proportion of major ACE and the frequency of foster care placement did not differ between the DMDD, MDD and PDD groups.

Youths with DMDD were significantly more likely to have a history of complicated pregnancy than youths with MDD or PDD, but the association was no longer statistically significant after youths with DMDD and ADHD were excluded from the analysis (Table S3).

No difference was observed regarding the psychomotor development and the association with a neurological disorder.

DISCUSSION

4.1.Interpretation

Regarding the study's first objective, the frequency of DMDD observed (22%) was slightly lower than that reported for two other outpatient studies using retrospective diagnoses (see Table S2) [START_REF] Axelson | Examining the proposed disruptive mood dysregulation disorder diagnosis in children in the Longitudinal Assessment of Manic Symptoms study[END_REF][START_REF] Freeman | Disruptive Mood Dysregulation Disorder in a Community Mental Health Clinic: Prevalence, Comorbidity and Correlates[END_REF] . Twenty-six to 31% of the 706 children aged 6-12 years in the Longitudinal Assessment of Manic Symptoms study met the criteria for DMDD [START_REF] Axelson | Examining the proposed disruptive mood dysregulation disorder diagnosis in children in the Longitudinal Assessment of Manic Symptoms study[END_REF] . Among the 597 children and adolescents (ages 6-18) treated at a community mental health center in the US, 31% were diagnosed with DMDD [START_REF] Freeman | Disruptive Mood Dysregulation Disorder in a Community Mental Health Clinic: Prevalence, Comorbidity and Correlates[END_REF] . The frequencies observed in child psychiatry facilities clearly contrast with the relatively low prevalence estimate of 1% in the general population [START_REF] Stringaris | Practitioner Review: Definition, recognition, and treatment challenges of irritability in young people[END_REF] . The disparity in the reported frequencies may result from disparities in countries' prevalence rates, sampling bias, and more likely, differences in the diagnostic procedures, our study being uniquely based on the DMDD algorithm of the DSM-5.

The degree of overlap between DMDD and DD was substantial (36%), but comparable to the overlap observed with each other group: 30% with PDD and 22% with MDD.

Regarding our second objective, youths with DMDD were younger and more likely to be male than youths with either PDD or MDD. This higher proportion of males among youths with DMDD has been consistently reported in previous studies [START_REF] Margulies | Will disruptive mood dysregulation disorder reduce false diagnosis of bipolar disorder in children?[END_REF][START_REF] Axelson | Examining the proposed disruptive mood dysregulation disorder diagnosis in children in the Longitudinal Assessment of Manic Symptoms study[END_REF][START_REF] Freeman | Disruptive Mood Dysregulation Disorder in a Community Mental Health Clinic: Prevalence, Comorbidity and Correlates[END_REF][START_REF] Tufan | Sociodemographic and Clinical Features of Disruptive Mood Dysregulation Disorder: A Chart Review[END_REF][START_REF] Dougherty | DSM-5 disruptive mood dysregulation disorder: correlates and predictors in young children[END_REF][START_REF] Axelson | Taking disruptive mood dysregulation disorder out for a test drive[END_REF][START_REF] Stringaris | Disruptive Mood: Irritability in Children and Adolescent[END_REF][START_REF] Copeland | Prevalence, comorbidity, and correlates of DSM-5 proposed disruptive mood dysregulation disorder[END_REF][START_REF] Copeland | Adult diagnostic and functional outcomes of DSM-5 disruptive mood dysregulation disorder[END_REF] . The higher comorbidity, observed in our sample, with externalizing disorders associated with a predominantly male sex ratio [START_REF] Breton | Quebec child mental health survey: prevalence of DSM-III-R mental health disorders[END_REF] , could have contribute to this finding. Of note, the sex ratio observed with DMDD differs from the more balanced sex ratio reported in depressed prepubertal children [START_REF] Angold | Effects of age and pubertal status on depression in a large clinical sample[END_REF] . The high comorbidity rate among youths with DMDD reported in the present study is in line with all the prior studies, in which other psychiatric disorders were observed in between 60% and 92% of outpatients with DMDD [START_REF] Margulies | Will disruptive mood dysregulation disorder reduce false diagnosis of bipolar disorder in children?[END_REF][START_REF] Axelson | Examining the proposed disruptive mood dysregulation disorder diagnosis in children in the Longitudinal Assessment of Manic Symptoms study[END_REF][START_REF] Freeman | Disruptive Mood Dysregulation Disorder in a Community Mental Health Clinic: Prevalence, Comorbidity and Correlates[END_REF][START_REF] Tufan | Sociodemographic and Clinical Features of Disruptive Mood Dysregulation Disorder: A Chart Review[END_REF][START_REF] Dougherty | DSM-5 disruptive mood dysregulation disorder: correlates and predictors in young children[END_REF][START_REF] Axelson | Taking disruptive mood dysregulation disorder out for a test drive[END_REF][START_REF] Stringaris | Disruptive Mood: Irritability in Children and Adolescent[END_REF][START_REF] Copeland | Prevalence, comorbidity, and correlates of DSM-5 proposed disruptive mood dysregulation disorder[END_REF] . In our sample, ADHD and DICCD were the most frequently associated diagnoses in youths with DMDD. Most interestingly, youths with DMDD were 2.5 times more likely to have an associated traumaand stressor-related disorder, compared to youths without DMDD. To our knowledge this is the first study reporting a positive association between DMDD and trauma-related disorders (Table S2). Albeit preliminary, this finding brings additional support to the postulated relationship between the exposure to chronic stress/repeated trauma and chronic mood dysregulation [START_REF] Dvir | Childhood maltreatment, emotional dysregulation, and psychiatric comorbidities[END_REF] .

In the present study, youths with DMDD presented with a lower frequency of suicidal ideation than the other two groups. In keeping with the relationship between suicidal behavior and the DMDD core symptom of irritability, and as previously discussed [START_REF] Benarous | Suicidal behaviors and irritability in children and adolescents: a systematic review of the nature and mechanisms of the association[END_REF] , suicide attempts might result from the intermixture of covert suicidal ideation and a temporary increase in irritability caused by intercurrent triggering stressors. This model described in literature [START_REF] Benarous | Suicidal behaviors and irritability in children and adolescents: a systematic review of the nature and mechanisms of the association[END_REF][START_REF] Stringaris | Probing the Irritability-Suicidality Nexus[END_REF][START_REF] Orri | Association of Childhood Irritability and Depressive/Anxious Mood Profiles With Adolescent Suicidal Ideation and AttemptsAssociation of Childhood Irritability and Depressive/Anxious Mood Profiles With Adolescent SuicidalityAssociation of Childhood Irritability and Depressive/Anxious Mood Profiles With Adolescent Suicidality[END_REF] is further supported by our data as youths with DMDD mostly reported suicidal attempts as unplanned and impulsive.

With respect to the study's third objective, unlike prior studies [START_REF] Dougherty | DSM-5 disruptive mood dysregulation disorder: correlates and predictors in young children[END_REF][START_REF] Copeland | Prevalence, comorbidity, and correlates of DSM-5 proposed disruptive mood dysregulation disorder[END_REF] , no significant difference was observed between the three groups relative to the measure of global functioning (C-GAS score). However, several other findings mitigated this overall absence of association. First, youths with DMDD presented more school difficulties (leaning difficulties and a more frequent history of grade repetition) and peer-relationship problems compared to youths with MDD or PDD. The poor levels of school achievement of youths with DMDD was in line with previous community studies [START_REF] Dougherty | DSM-5 disruptive mood dysregulation disorder: correlates and predictors in young children[END_REF][START_REF] Copeland | Prevalence, comorbidity, and correlates of DSM-5 proposed disruptive mood dysregulation disorder[END_REF] . Copeland et al. (2013) reported that the frequency of recent school suspension was higher among youths with DMDD than among psychiatric case-controls [START_REF] Copeland | Prevalence, comorbidity, and correlates of DSM-5 proposed disruptive mood dysregulation disorder[END_REF] . Dougherty et al. (2014) [START_REF] Dougherty | DSM-5 disruptive mood dysregulation disorder: correlates and predictors in young children[END_REF] in turn, noted that youths with DMDD were more likely than their counterparts to require remedial education. Further studies are needed to determine whether the association between DMDD and learning difficulties can be explained by the presence of perinatal risk factors and other developmental difficulties. Our data support this hypothesis because the relationship was no longer statistically significant after youths with ADHD had been excluded from the analysis (Table S3).

Second, the positive association between DMDD and aggressive behavior might be seen as somewhat inevitable, since aggressive reactions can be seen as a consequence of irritability. However, youths with DMDD were more likely to be victims of aggressive behavior by peers than youths without DMDD; this finding is in line with earlier reports on youths displaying reactive aggression [START_REF] Geoffroy | Childhood trajectories of peer victimization and prediction of mental health outcomes in midadolescence: a longitudinal population-based study[END_REF] . Only longitudinal studies might be able to determine the interplay between victimization by peers, reactive aggression, and mood symptoms in chronically irritable youths. Among youths with chronic irritability, it has been noted neurocognitive impairments (e.g. emotional recognition difficulties), which were involved in the daily expression of social skills [START_REF] Vidal-Ribas | Deficits in emotion recognition are associated with depressive symptoms in youth with disruptive mood dysregulation disorder[END_REF][START_REF] Stoddard | Aberrant amygdala intrinsic functional connectivity distinguishes youths with bipolar disorder from those with severe mood dysregulation[END_REF] . They would be worth studying to better understand peer-relationship difficulties in youths with DMDD, in comparison to MDD and PDD.

With respect to the last objective relative to vulnerability factors, no statistically significant difference was found between the three groups with regard to the family history of psychiatric diagnoses. This meant that the well-documented vulnerability factor for childhood depression, i.e., the history of parental depression, was observed at a similar rate among the three groups. The association between a history of complicated pregnancy and DMDD is probably partly mediated by the presence of developmental cognitive impairments, since the association was no longer significant after the exclusion of youths with DMDD and ADHD (Table S3).

On should remain cautious with regard to these preliminary findings. First, reporting no differences does not mean that the role of the vulnerability factor is comparable across the three groups. Second, information on the vulnerability factors resulted from a cross-sectional study design rather than a prospective longitudinal study. We can only conclude that on a small sample of help-seeking outpatients, no significant difference was observed with respect to the youth's profile of environmental vulnerability factors associated with mood disorders between DMDD, MDD, and PDD.

4.2.Strength and limitations

The results of this study should be interpreted in the context of its limitations. Firstly, the study suffered from retrospective bias and a small number of patients in the study groupsdespite the four-year recruitment period. The study's statistical power was reduced by the substantial number of variables, and the small sample size also precluded the use of multivariate analysis. It will be important to confirm that the observed differences between the DMDD, MDD and PDD groups do not reflect sociodemographic features. Secondly, the evaluation of psychosocial risk factors (such as ACE) may be prone to recall bias. To limit the potential bias, we measured the data's validity against official records (i.e. administrative data from child protection agencies). Thirdly, the lack of a control group without psychiatric disorders makes it more difficult to interpret intergroup differences between groups. To facilitate comparisons with previous studies, we compared DMDD and non-DMDD subsets.

Fourthly, the study sample comprised outpatients consulting at specialist mood disorders clinics in a large urban area. This might account for the high observed prevalence of mood disorders and the relative paucity of other conditions for which there are specific care pathways (e.g. severe developmental disorders). Our results could only be generalized to other clinics with similar patient profiles.

The study also had a number of strengths: (i) the use of a well-validated, DSM-5-based instrument for the clinical diagnosis of DMDD, (ii) our comparison of mood disorder groups addresses important issues in how DMDD can be discriminated from pre-existing DD diagnoses in clinical practice, and (iii) some environmental risk factors (such as the developmental history and ACE) have never been investigated in DMDD.

4.3.Clinical and research implications

In this study, we aimed at documenting the common and distinctive features of DMDD, MDD, and PDD. As mentioned in the introduction, there is still an ongoing debate about the best diagnostic approach for youths with chronic irritability, i.e. whether adding a new specifier for youths with oppositional defiant disorder (ODD) or subtyping DD with a new diagnostic entity as proposed with the DSM-5 [START_REF] Roy | Disruptive Mood Dysregulation Disorder: A New Diagnostic Approach to Chronic Irritability in Youth[END_REF][START_REF] Stringaris | Practitioner Review: Definition, recognition, and treatment challenges of irritability in young people[END_REF] . Therefore, following Occam's razor principle, it is mandatory to compare DMDD with preexisting DD diagnostic categories, i.e. MDD and PDD, to ensure that the new clinical entity is not a more fashionable label for youths with chronic depression, i.e. PDD. In keeping with the aforementioned debate, this study has several implications. First, DMDD could be discriminated from MDD and PDD. Of the 36 youths with DMDD, only six met the criteria for PDD. This is in line with the assumption that youths with chronic irritability do not fit prior DD diagnostic categories, and therefore deserve a more specific DD diagnostic category. In contrast, the high comorbidity rate consistently reported for DMDD 23- 26 ., may dismiss the claim for specificity. However, in this study and all the prior studies, the DSM-5 non-dual diagnosis criterium for ODD was not applied, resulting in an overestimation of the comorbidity rate of DMDD with externalizing disorders. In addition, youths with DMDD presented a more mixed clinical presentation with mood and developmental disturbances components (i.e., younger age, predominantly male sex ratio, history of complicated pregnancy, persisting peer-relationship and school difficulties) compared to youths with MDD and/or PDD. This clinical presentation with an admixture of mood and developmental disturbances was only partially mediated by the association with ADHD (Table S3). Therefore, youths presenting with DMDD should be carefully assessed for neurodevelopmental disorders.

Second, from a research standpoint, the aforementioned neurocognitive characteristics could be seen as promising mediators between childhood irritability and later depression [START_REF] Vidal-Ribas | Deficits in emotion recognition are associated with depressive symptoms in youth with disruptive mood dysregulation disorder[END_REF] .

The relation between chronic irritability in childhood and, depression in adolescence and adulthood has been well demonstrated, in particular on the basis of longitudinal studies [START_REF] Brotman | Prevalence, clinical correlates, and longitudinal course of severe mood dysregulation in children[END_REF][START_REF] Stringaris | Adult outcomes of youth irritability: a 20-year prospective community-based study[END_REF][START_REF] Stringaris | Pediatric bipolar disorder versus severe mood dysregulation: risk for manic episodes on follow-up[END_REF][START_REF] Leibenluft | Severe Mood Dysregulation, Irritability, and the Diagnostic Boundaries of Bipolar Disorder in Youths[END_REF][START_REF] Vidal-Ribas | The Status of Irritability in Psychiatry: A Conceptual and Quantitative Review[END_REF] , [START_REF] Whelan | Developmental continuity of oppositional defiant disorder subdimensions at ages 8, 10, and 13 years and their distinct psychiatric outcomes at age 16 years[END_REF] .

In a meta-analysis, Vidal-Ribas et al. (2016) reported a positive and independent relation between chronic irritability in childhood on the one hand and on the other hand, depression in adolescence and adulthood (OR=1.80) [START_REF] Vidal-Ribas | The Status of Irritability in Psychiatry: A Conceptual and Quantitative Review[END_REF] . Consequently, search for common pathophysiological underpinnings is under way. Families studies unveiled an association between childhood irritability and a history of parental depression [START_REF] Propper | Disruptive mood dysregulation disorder in offspring of parents with depression and bipolar disorder[END_REF][START_REF] Krieger | Dimensions of oppositionality in a Brazilian community sample: testing the DSM-5 proposal and etiological links[END_REF][START_REF] Wiggins | Identifying Clinically Significant Irritability in Early Childhood[END_REF][START_REF] Brotman | Parental diagnoses in youth with narrow phenotype bipolar disorder or severe mood dysregulation[END_REF] , in coherence with our findings. Moreover, two twin-studies suggested that the association between irritability and depression might be, in part, genetically mediated [START_REF] Stringaris | Adolescent irritability: phenotypic associations and genetic links with depressed mood[END_REF][START_REF] Savage | A genetically informed study of the longitudinal relation between irritability and anxious/depressed symptoms[END_REF] . Another study showed that irritability partly mediated the link between maternal depression and depression in adolescents [START_REF] Whelan | Pathways from maternal depressive symptoms to adolescent depressive symptoms: the unique contribution of irritability symptoms[END_REF] . Future research would help better disentangling the interplay between risk factors for depression, irritability, and depressive disorders in adolescence and adulthood, and clarifying transition pathways from one disorder to the other. Third, our study has several evaluation and therapeutics implications. With respect to our findings, clinicians caring for youths with DMDD should better recognize clinical dimensions generally associated with internalized symptoms, in particular suicidal behaviors, the presence of adverse life events, and the presence of trauma-related symptoms. Second, some therapeutic interventions for DMDD have been justified by the association with depression [START_REF] Benarous | Evidence-based treatments for youths with severely dysregulated mood: a qualitative systematic review of trials for SMD and DMDD[END_REF] . As depression and irritability might share common pathophysiological mechanisms [START_REF] Stringaris | Adolescent irritability: phenotypic associations and genetic links with depressed mood[END_REF][START_REF] Savage | A genetically informed study of the longitudinal relation between irritability and anxious/depressed symptoms[END_REF][START_REF] Vidal-Ribas | Deficits in emotion recognition are associated with depressive symptoms in youth with disruptive mood dysregulation disorder[END_REF] , effective treatment for the former could be useful for the later. So far, only one randomized controlled trial showed that a positive effect of 8 weeks of citalopram, a selective serotonin reuptake inhibitor (SSRI), in youths with SMD + ADHD previously treated by methylphenidate [START_REF] Towbin | A Double-Blind Randomized Placebo-Controlled Trial of Citalopram Adjunctive to Stimulant Medication in Youth With Chronic Severe Irritability[END_REF] .

In conclusion, we identified DMDD as a distinct entity from MDD and/or PDD in this clinical sample of outpatient youths. While we found some clinical features more specifically

Figure 1 .

 1 Figure 1. Overlap between Disruptive Mood Dysregulation Disorder, Major Depressive Disorder and Persistent Depressive Disorder

Figure 2 .Figure 3 .

 23 Figure 2. Suicidal behaviors among youth with DMDD, MDD without DMDD/PDD, and PDD without DMDD/MDD

Table 1 .

 1 Frequency of psychiatric disorders among recruitment sites Note. RPH= Mood Disorders Clinic at the Rivière-des-Prairies Hospital; DMHU= Program of DD Pediatric section of the Douglas Mental Health University Institute; MDD= major depressive disorder; PDD= persistent depressive disorder; DMDD= disruptive mood dysregulation disorder; ADHD= attention deficit hyperactivity disorder; BD= bipolar disorder type 1 and type 2; DICCD= disruptive, impulse-control and conduct disorders a The category "Traumaand Stressor-Related Disorders" encompasses adjustment disorder, acute stress disorder and post-traumatic stress disorder b The category "Other psychiatric disorders" encompasses sleep disorder, tics and Tourette syndrome, obsessive compulsive disorder, eating disorder

	RPH	DMHU	Total
	(n=114)	(n=49)	(N=163)

ACKNOWLEDGMENTS

The authors would like to thank Christophe Huynh Ph.D. for his help with data collection, Cosmin Lancu (psychiatry resident) for his assistance in studying the reliability of the chart review instrument's DMDD module, and Hughes Pellerin MSc for assistance with statistical analysis. Professor Guilé pursue his contribution during his time as invited researcher at the Center for Research and Intervention on Suicide, Ethical Issues and End-of-life practices (CRISE), Montreal, Canada. Therefore, the corresponding author would like to thank Pr Choukroun, Dean of Faculty of Medicine (Amiens) and Pr Mishara, Director of CRISE (Montreal).

associated with DMDD (association with the externalized disorders and trauma-related disorder, the severity of peer-relationship and school difficulties), the vulnerability factors studied were broadly comparable across disorders. Further studies are needed to confirm this findings and determine on which extend DMDD youths differ from those with other types of mood disturbances.

FUNDING

The study was funded by the Quebec Network on Suicide, Mood Disorders and Related Disorders RQSHA (grant: ASClin #2).

DISCLOSURE

Dr. Benarous, Pr. Labelle, Pr. Guilé, Pr. Cohen, Dr. Renaud, and Dr. Breton report no biomedical financial interests or potential conflicts of interest. Highlights  22% of an outpatient child and adolescent population were diagnosed with DMDD  36% of the youths with DMDD were also diagnosed with either MDD or PDD.  Compared with youths with MDD or PDD, youths with DMDD were more likely to have a comorbid non-depressive psychiatric disorder  Relative to youths with either MDD or PDD, youths with DMDD presented with higher levels school and peer-relationship difficulties (verbal and physical aggressiveness, and peer victimization), and some degree of developmental impairment.