hyperactivity disorder (ADHD) symptoms and suicidality in children: The mediating role of depression, irritability and anxiety symptoms

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Attention-deficit/hyperactivity disorder (ADHD) symptoms and suicidality in children: The mediating role of depression, irritability and anxiety symptoms. Tomer Levy , Sefi Kronenberg , Jennifer Crosbie , Russell James Schachar PII: DOI: Reference:

S0165-0327(19)30728-1 https://doi.org/10.1016/j.jad.2020.01.022 JAD 11471

To appear in:

Journal of Affective Disorders

Received date: Revised date: Accepted date:

28 March 2019 22 November 2019 5 January 2020

Please cite this article as: Tomer Levy , Sefi Kronenberg , Jennifer Crosbie , Russell James Schachar , Attention-deficit/hyperactivity disorder (ADHD) symptoms and suicidality in children: The mediating role of depression, irritability and anxiety symptoms., Journal of Affective Disorders (2020), doi: https://doi.org/10.1016/j.jad.2020.01.022

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Highlights 

ADHD has been associated with increased suicidality risk in children.

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Comorbid symptoms frequently found in ADHD may mediate this association.

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Our results confirmed the association between ADHD symptoms and suicidality.

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Yet, this association was mediated by depression, irritability and anxiety symptoms.

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Measuring depression, irritability and anxiety may facilitate suicide assessment in ADHD.

Attention-deficit/hyperactivity disorder (ADHD) symptoms and suicidality in children: The mediating role of depression, irritability and anxiety symptoms.

Authors‟ names and affiliations: Tomer Levy1, 2 ; Sefi Kronenberg1, 2 ; Jennifer Crosbie1, 2 ; Russell James Schachar1, 2.

1.

Department of Psychiatry, The Hospital for Sick Children, Toronto, ON, Canada.

2.

Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Corresponding author contact information: Tomer Levy MD, Department of Psychiatry, The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada; Phone: 416-813-6854; Fax: 416-813-6565; Email: [email protected]

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BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with increased suicidality risk. Yet, potential mechanisms transmitting the effect of ADHD to suicidality remain unclear. We investigated whether depression, irritability and anxiety symptoms mediate between ADHD symptoms and suicidality. METHODS: ADHD, depression, irritability and anxiety symptoms as well as suicidality (composited of suicidal ideation, attempts or self-harm) were measured in an outpatient clinic for ADHD (N = 1,516, 6-17 years old, 61.1% diagnosed with ADHD) using parent and teacher questionnaires. Multiple mediator models adjusted for age, sex and psychosocial adversities were constructed separately for parent- and teacher-report. RESULTS: Parents reported higher rates of suicidality than did teachers (12.1% and 3.8%, p < .001). Suicidality was associated with parent (OR = 1.10, 95%CI: 1.07-1.14) and teacher (OR = 1.08, 95%CI: 1.03-1.15) reported ADHD symptoms. The association between ADHD symptoms and suicidality was mediated by both parent- and teacher-reported depression (39.1% and 45.3% of total effect, respectively) and irritability symptoms (36.8% and 38.4% of total effect, respectively). Anxiety symptoms mediated between ADHD and suicidality for parent- but not teacher-report (19.0% of total effect). No direct effect of ADHD symptoms was found once depression, irritability and anxiety were controlled. LIMITATIONS: The cross-sectional design limits the ability to determine causal order between mediators and outcome. CONCLUSIONS: Our results confirmed the association between ADHD symptoms and suicidality. However, this association was indirect and fully mediated by symptoms of depression, irritability and anxiety. Assessing these symptoms may enable an estimate of suicidality and help managing suicidal risk in ADHD.

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Keywords: Suicide; Attention-deficit/hyperactivity disorder; Irritability; Depression; Anxiety.

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; PAI, Psychosocial Adversity Index; OCHS-R, The Ontario Child Health Survey Scales-Revised; CBCL, Child Behavior Checklist; P-ADHD, parent-report of ADHD symptoms; T-ADHD, teacher-report of ADHD symptoms; P-Sui, parent-report of suicidality; T-Sui, teacher-report of suicidality; P-Dep, parent-report of depression symptoms; T-Dep, teacher-report of depression symptoms; P-Irr, parent-report of irritability symptoms; T-Irr, teacher-report of irritability symptoms; P-Anx, parent-report of anxiety symptoms; T-Anx, teacher-report of anxiety symptoms.

1. Introduction Attention-deficit/hyperactivity

disorder

(ADHD)

is

characterized

by

inattention, restlessness and impulsivity that is age-inappropriate and impairing. It is one of the most common psychiatric disorders in children and adolescents and affects approximately 5-12% of children and adolescents worldwide. ADHD is a major public health problem because it is associated with a broad range of negative outcomes over the patients‟ lifetime (Quintero et al., 2018). One of these negative outcomes is suicidal ideation and behavior (i.e., suicidality) (Balazs and Kereszteny, 2017). The association between ADHD and suicidality has been demonstrated in both population and clinical-based studies of children and adolescents, with a greater risk evident among those diagnosed with a ADHD combined presentation (i.e., with both inattention and hyperactivity/impulsivity symptoms) (Balazs and Kereszteny, 2017; Hurtig et al., 2012; Mayes et al., 2015). Early suicidality is associated with a range of

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long-term negative outcomes, such as high need for general medical services and school services and not just suicidal death risk (Nock et al., 2013). Most of the evidence bearing on the question of suicidal risk is derived from studies in adolescents and young adults, leaving unanswered the question as to what are the precipitating factors of suicidality in preadolescent children (Bridge et al., 2015). Two-thirds of children and adolescents who suffer from ADHD present with symptoms related to at least one comorbid psychiatric disorder (Faraone et al., 2015). These symptoms could play a role in the association between ADHD and suicidality (Balazs and Kereszteny, 2017). Symptoms of depression, considered to be a primary risk factor for suicidality in youth (Barzilay and Apter, 2014), are more frequent in children and adolescents with ADHD (Angold et al., 1999). Moreover, longitudinal as well as cross-sectional data indicates that symptoms of depression likely serve as a mediator linking ADHD and suicidality (Balazs et al., 2014; Chen et al., 2019; Cho et al., 2008; Manor et al., 2010). Although depression symptoms are strongly linked with suicidality risk in youth, studies have suggested many other factors that could contribute to increased suicidality (Turecki and Brent, 2016). Moreover, studies investigating the role of depression symptoms in the association between ADHD and suicidality indicated that depression symptoms only partially mediate ADHD-suicidality association, implying that additional factors may contribute to this association (Chen et al., 2019; Cho et al., 2008). Studies have demonstrated a strong association between ADHD and irritability (Shaw et al., 2014). Irritability reflects proneness to anger and a propensity for behavioral outbursts (Brotman et al., 2017). It exists on a continuum from developmentally normal to extreme and sometimes aggressive, it may be stable across development, and it is associated with negative psychological and functional outcomes (Copeland et al., 2015; Stringaris et al., 2009). There

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is emerging evidence for an association between irritability and suicidality across different age groups (Holtmann et al., 2011; Orri et al., 2018a, 2018b; Pickles et al., 2010). Some data suggest that symptoms of irritability in children with ADHD predict poorer outcome including, increased rates of depression, anxiety and aggression in later adulthood (Eyre et al., 2017; Shaw et al., 2014). Yet, no study has examined if irritability mediates the association between ADHD and suicidality. Anxiety symptoms are often comorbid with ADHD symptoms (Schatz and Rostain, 2006; Tannock, 2009), and in addition, has been shown to predict suicidality in children and adolescents (O‟Neil Rodriguez and Kendall, 2014). In addition, few studies have suggested that symptoms of specific-anxiety (i.e., separation anxiety, specific phobia and social phobia) (Balazs et al., 2014), or depression and anxiety symptoms combined (Chen et al., 2019), may mediate the association between ADHD and suicidality. In summary, children with ADHD show increased risk for suicidal ideation and behavior. Identifying intermediary variables that mediate between ADHD symptoms and suicidality may further the understanding of underlying mechanisms and guide clinical practice. The purpose of the current study was to determine if depression, anxiety and irritability symptoms mediate the association between ADHD symptoms and suicidality using one integrative model. We estimated the effect of ADHD symptoms on suicidality when the mediators were not included in the model (i.e., the total effect), the relative effect of ADHD symptoms on suicidality when the mediators were included in the model (i.e., the direct effect), and the association transmitted from ADHD symptoms through mediating symptoms of depression, irritability and anxiety to suicidality (i.e., indirect effects) (Little, 2013). 2. Methods 2.1 Setting

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Participants were children referred to an outpatient clinic for children with ADHD, in a large, urban, children‟s hospital in Toronto, Ontario, Canada. Parents and teachers of each participant were the informants for this study. Each participant was assessed by a child and adolescent psychiatrist or a child psychologist using a semi-structured clinical interview. Informed consent was obtained from the parents, and assent from the participants. All procedures were approved by the Institutional Research Ethics Board. 2.2 Study Population Participants were 1,516 children 6-17 years of age (M = 9.00, SD = 2.19, with 96.2% below the age of 14), 74% males and 26% females. Clinical diagnosis was based on DSM-IVTR or DSM-5 criteria. Children with diagnosis of intellectual disability, psychosis, bipolar disorder or autism were excluded. Of the sample, 61.1% were diagnosed with ADHD of whom 50.2% were diagnosed with at least one other disorder. Among those who did not meet criteria for ADHD, 29.9% were diagnosed with a psychiatric disorder other than ADHD, while the other participants presented with symptoms that were below the threshold for any diagnosis (Table 1). Of the sample, 22.2% were taking a stimulant medication at the time of the assessment. 2.3 Measures Under the supervision of a clinical psychologist, the Wechsler Intelligence Scale for Children-IV was administered to assess intellectual functioning (Wechsler, 2004). The mean Full-Scale IQ scores of the sample was 101.1 (SD = 13.49, n = 1451). The Family and Household Form from the Ontario Child Health Survey was used to collect information about psychosocial and environmental risk factors (Boyle et al., 1996). A Psychosocial Adversity Index (PAI) was created by summing the following risk factors: single parent household, parental education below college or other community or technical

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training, financial problems and domestic violence. Each factor contributed 1 point. The PAI scores of the sample ranged 0-4 (M = 0.77, SD = 0.87), with 47.2% of the sample scoring 0. The Ontario Child Health Survey Scales-Revised (OCHS-R) screen for broad range of psychopathology symptoms (Boyle et al., 1993). The parent-version and the teacher-version included 104 and 83 items, respectively, rated from 0 (not true) to 2 (very true or often true) about the participant in the past 6 months. OCHS-R was originally adapted from the Child Behavior Checklist (CBCL) of the Achenbach System of Empirically Based Assessment. All composite measures used in our study, not including the irritability measure, were calculated based on previous studies (Boyle et al., 1993). We created a parent- and a teacher-reported composite ADHD symptoms measure (PADHD and T-ADHD, respectively), summing the scores of 6 items of inattention and 8 items of hyperactivity or impulsivity from the OCHS-R (Boyle et al., 1993). Twelve out of the 14 items corresponded with DSM-5 ADHD „A‟ criteria. The internal consistency of both PADHD and T-ADHD was excellent (Cronbach‟s αs = 0.90 and 0. 93, respectively). The correlation between P-ADHD and T-ADHD was rs = .36, p < .001. We created a parent- and a teacher-reported composite suicidality measure (P-Sui and T-Sui, respectively) by adding two items from the OCHS-R, “talks about killing self” and “deliberately harms self or attempts suicide”. This measure of suicidality was used in previous studies that utilized the OCHS-R (Joffe et al., 2014, 1988) and in studies that utilized identical items from the CBCL (Haltigan et al., 2018a). A score of 1 or 2 (on a 3point scale) on at least one of these two items was coded as positive for suicidality. We created a parent- and a teacher-reported composite depression symptoms measure (P-Dep and T-Dep, respectively), summing the scores of 15 and 11 items, from the OCHS-R, which corresponded with 8 and 5, respectively, out of 9 DSM-5 major depressive disorder „A‟ criteria (Boyle et al., 1993). Items measuring appetite, weight and sleep were not

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included in the teacher-version. The two items designated to measure suicidality were not included as they reflect the outcome. The item “Can‟t sit still, restless or hyperactive” was excluded as it loaded with the ADHD symptoms measure (item to total scale correlation: rs ≥ .72, p < .001). The internal consistency of P-Dep and T-Dep was acceptable (Cronbach‟s α = 0.78 for both scales). The correlation between P-Dep and T-Dep was rs = .26, p < .001. We created a parent and a teacher-reported composite irritability symptoms measure (P-Irr and T-Irr, respectively), summing the scores of 5 items from the OCHS-R. The items included in this scale were: “Cranky”, “Angry and resentful”, “Temper tantrum or hot temper”, “Explosive and unpredictable behavior” and “Easily annoyed by others”. The internal consistency of P-Irr and T-Irr was good (Cronbach‟s αs = 0.86 and 0.88, respectively). The correlation between P-Irr and T-Irr was rs = .33, p < .001. We created a parent and a teacher-reported composite anxiety symptoms measure (PAnx and T-Anx, respectively), summing the scores of 7 items in P-Anx and 6 available items in T-Anx from the OCHS-R (Boyle et al., 1993). The internal consistency of P-Anx and TAnx was acceptable (Cronbach‟s αs = 0.75 and 0.74, respectively). The correlation between P-Anx and T-Anx was rs = .25, p < .0001. 2.4 Data Analysis Correlations between non-normally distributed variables were measured using Spearman‟s Rho and Kendall's tau tests. All tests were two-tailed. An α-level of .05 was considered significant for all analyses. Age, sex and PAI were included as covariates in all regression analyses unless noted otherwise. A multiple mediator model was employed, and the total (i.e., the sum of the direct and the indirect effects), direct (i.e., the effect after controlling for the mediators) and indirect effects (i.e., the effect via the mediators) were computed (Mackinnon and Dwyer, 1993). Two separate mediation models were constructed for parent and teacher reported data. Binomial and ordinal logistic regression were used to 9

predict the outcomes. Bootstrapping was conducted using 1,000 bootstrap samples. A 95% bias-corrected and accelerated bootstrap confidence interval (95% CI) was used. In order to estimate what proportion of the total effect was mediated by each of the mediation pathways, each regression coefficient (B) was multiplied by the SD of the predictor variable in the equation and then divided by the SD of the outcome variable, as described by Mackinnon et al. (1993) (Mackinnon and Dwyer, 1993). In addition, the presence of two-way interaction was examined to determine if there was a combined mediation and moderation effects (Muller et al., 2005). Given the non-experimental, cross-sectional design, the hypothesized causal order between the mediators and the outcome measure cannot be fully determined (Fiedler et al., 2011). Nonetheless, in order to evaluate if the hypothesized pathway of ADHD- mediator symptom variables- suicidality (i.e., X - M- Y) potentially reflects a more plausible flow of the effects, a reverse analysis was conducted by transposing each of the mediators with the outcome measure (i.e., X- Y -M), and comparing the significance and the magnitude of the indirect effects of the hypothesized pathways with those obtained from the reverse pathways (Lemmer and Gollwitzer, 2017). 3. Results 3.1 Agreement between parent and teacher reports of suicidality The correlation between the parent (P-Sui) and the teacher (T-Sui) reports of suicidality was low although significant (rτb = .16, p < .001). The rates of suicidality reported by parents were significantly higher than those reported by teachers (12.1% versus 3.8%, respectively; exact McNemar‟s significance of p < .001; Cohen‟s K = .13, p < .001). 3.2 Demographic, social and cognitive correlates of suicidality Age, sex and the Full-Scale IQ were not associated with P-Sui or T-Sui. Recent stimulant medication treatment was not associated with P-Sui or T-Sui when controlling for the ADHD symptoms as reported by parents or teachers. 10

PAI was associated with P-Sui and T-Sui (OR = 1.61, 95% CI: 1.37-1.90, OR = 1.33, 95% CI: 1.00-1.76, respectively, both models with p < .001). 3.3 ADHD symptoms and suicidality The association between ADHD symptoms and suicidality, reflecting the total effect in the multiple mediator model, was significant using both parent-report (B = 0.10, OR = 1.10, 95% CI: 1.07-1.14, p = .001) and teacher-report (B = 0.08, OR = 1.08, 95% CI: 1.031.15, p = .002. See Table 2 for a summary of multiple mediator models). Parent-reported hyperactivity/impulsivity (OR = 1.08, 95% CI: 1.02-1.15, p = .014) and inattention symptoms (OR = 1.14, 95% CI: 1.05-1.25, p = .003) were both associated with increased suicidality (Nagelkerke R2 = .11, χ25 = 85.46, p < .001). Whereas, teacherreported hyperactivity/impulsivity (OR = 1.16, 95% CI: 1.06-1.38, p = .001) but not inattention symptoms (OR = 0.96, 95% CI: 0.08-1.10, p = .57) were associated with suicidality (Nagelkerke R2 = .07, χ25 = 25.92, p < .001). 3.4 Depression, anxiety and irritability symptoms in mediating between ADHD symptoms and suicidality First, the associations between parent- and the teacher-reports of ADHD symptoms and each of the hypothesized mediators was examined separately. P-ADHD and T-ADHD were associated with P-Dep and T-Dep, respectively, P-Anx and T-Anx, respectively, and PIrr and T-Irr, respectively. Coefficients and model fits were all significant with p < .001 (summarized in Table 2). Second, parent- and the teacher-reports of ADHD, depression, anxiety and irritability symptoms were examined in a multiple regression model to predict suicidality. P-Dep (OR = 1.19, 95% CI: 1.11-1.30, p = .001), P-Anx (OR = 1.11, 95% CI:1.04-1.19, p = .003) and P-Irr

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(OR = 1.17, 95% CI: 1.08-1.28, p = .001) each predicted P-SI. No two-way interaction was found between P-ADHD, P-Dep, P-Anx and P-Irr in predicting P-Sui. T-Dep (OR = 1.31, 95% CI: 1.17-1.48, p = .001), T-Irr (OR = 1.18, 95% CI: 1.051.35, p = .001) but not T-Anx (OR = 1.02, 95% CI: 0.92-1.13, p = .64) predicted T-SI. In addition, a negative interaction was found between T-ADHD and T-Irr in predicting T-Sui (OR = 0.98, 95% CI: 0.72-0.10, p = .02; Nagelkerke R2 = .17; χ28 = 69.7; p < .001). The proportion of the total effect accounted for by the indirect effect was calculated for each of the pathways in the multiple mediator model (Figure 1). The parent- and teacherreported models indicated that depression symptoms mediated 39.1% and 45.3%, respectively, of the total effect, and that irritability symptoms mediated 36.8% and 38.4%, respectively, of the total effect of ADHD symptoms on suicidality. Anxiety mediated 19.0% of the total effect using the parent-report model, but no mediation was observed using the teacher-report model. 3.5 Direct association between ADHD symptoms and suicidality Once depression, anxiety and irritability symptoms were controlled, P-ADHD (OR = 1.01, 95% CI: 0.98-1.05, p = .43) and T-ADHD (OR = 1.01, 95% CI: 0.95-1.08, p = .79) no longer predicted P-Sui and T- Sui, indicating the absence of direct effect of ADHD symptoms on suicidality. 3.6 Depression, anxiety and irritability symptoms in mediating between ADHD symptoms and suicidality in participants with ADHD Examining the association between ADHD symptoms and suicidality within the subgroup of participants clinically diagnosed with ADHD (n = 927), P-ADHD (OR = 1.10, 95% CI: 1.05-1.06, p < .001; χ24 = 43.53, p < .001) and T-ADHD (OR = 1.12, 95% CI: 1.041.20, p = .003; χ24 = 17.37, p = .002) were associated with P-Sui and T-Sui, respectively.

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P-ADHD and T-ADHD were associated with P-Dep (OR = 1.18, 95% CI: 1.15-1.20) and T-Dep (OR = 1.10, 95% CI: 1.08-1.12), P-Anx (OR = 1.13, 95% CI: 1.11-1.16) and TAnx (OR = 1.07, 95% CI: 1.05-1.09) and P-Irr (OR = 1.17, 95% CI: 1.14-1.19) and T-Irr (OR = 1.17, 95% CI: 1.14-1.20), respectively (all model fits were at a significance level of p < .001). P-Dep (OR = 1.24, 95% CI: 1.13-1.37, p < .001), P-Anx (OR = 1.13, 95% CI:1.04-1.23, p = .006) and P-Irr (OR = 1.17, 95% CI: 1.06-1.27, p = .002) each predicted P-Sui (χ27 = 127.97, p < .001). T-Dep (OR = 1.35, 95% CI: 1.12-1.63, p = .001) but not T-Anx (OR = 1.03, 95% CI: 0.89-1.20, p = .71) and T-Irr (OR = 1.12, 95% CI: 0.97-1.30, p = .12) predicted T-Sui (χ27 = 41.29, p < .001). Once depression, anxiety and irritability symptoms were controlled, PADHD (p = .98) and T-ADHD (p = .15) were no longer associated with P-Sui and T- Sui, respectively. 3.7 The causal order between the mediators and the outcome measure In order to examine if the hypothesized pathways were more compatible with the data compared to the reverse, indirect effects of the reverse pathways were calculated for the full sample. The indirect effects of all parent- and teacher-reported reverse pathways did not exceed 8.3% of the total effects, and as such were considerably lower compared to the indirect effects of the hypothesized pathways described above. 4. Discussion The study confirmed the association between ADHD symptoms and suicidality found in previous studies (Balazs and Kereszteny, 2017), and sought to determine the role of comorbid depression, anxiety and irritability symptoms in potentially mediating this association. Both parent- and teacher-report models indicated that depression (39.1% and 45.3% of total effect, respectively) and irritability symptoms (36.8% and 38.4% of total effect, respectively) partially mediated the relationship between ADHD symptoms and

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suicidality. The parent- but not teacher-report of anxiety symptoms (19.0% of total effect) partially mediated the relationship between ADHD symptoms and suicidality. Examining these pathways in the subgroup of participants clinically diagnosed with ADHD, both parent- and teacher-reported models indicated a significant association between ADHD symptoms and suicidality. This association was indirect and mediated by comorbid symptoms. However, in participants diagnosed with ADHD the teacher-reported irritability symptoms were not found to mediate between the ADHD symptoms and suicidality. One of the most prominent characteristic of ADHD is its high rates of comorbidity (Faraone et al., 2015). These comorbidities may serve as risk factors for suicidality and underpin the elevation of suicidality rather than ADHD symptoms per se (Balazs et al., 2014). One other hypothesis explains the association between ADHD and suicidality by the effect of impulsivity, inferring a direct effect of ADHD symptoms on suicidality (Balazs and Kereszteny, 2017). Impulsivity, is a core symptom of ADHD, and was shown to predict suicidality (Balazs and Kereszteny, 2017) and the transition from suicidal ideation to behavior (Oquendo and Mann, 2000). Our results suggested that when comorbid symptoms are not included in the model, both parent-reported inattention and hyperactivity/impulsivity symptoms were associated with increased suicidality. Moreover, after controlling for the effects of depression, anxiety and irritability symptoms, ADHD symptoms were no longer associated with suicidality, suggesting that this relationship was indirect and a function of these common comorbidities. The association between ADHD and depression has been confirmed by previous studies (Angold et al., 1999). Given the earlier age of onset of ADHD compared to depression, and the increased rates of depression in subjects with ADHD from childhood to young adulthood, it is more likely that ADHD increases the risk for concurrent and later

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depression than the other way around (i.e., depression  ADHD) (Chronis-Tuscano et al., 2010; Knouse et al., 2013; McQuade et al., 2011). Alternatively, this association could be a function of shared genetic risk that confers susceptibility to both disorders (Anttila et al., 2018). In any case, depression appear to signal a risk for suicidal ideation or behavior in the ADHD population (Cho et al., 2008; Manor et al., 2010). The current study is the first to suggest that irritability mediates the risk for suicidality that is associated with ADHD symptoms. Findings from community-based, cross-sectional and longitudinal studies have indicated that irritability might serve as a risk factor for suicidality in children (Holtmann et al., 2011). This association was demonstrated even when controlling for the effects of depressive and anxiety symptoms (Orri et al., 2018b, 2018a; Pickles et al., 2010). However, to our best knowledge, our study is the first to suggest that the association between irritability symptoms and suicidality is already evident in such a young age group. Although in the current investigation we examined the relationships between ADHD, depression, anxiety and irritability symptoms as predictors of suicidality, studies have suggested that adding a broader dimension of general psychopathology to previously used dimensions, or a dysregulation factor that cuts across internalizing, externalizing dimensions better predicted suicidality in adolescence (Haltigan et al., 2018b). Nevertheless, there is much debate about the value of categorical models of psychopathology versus dimensional ones (Krueger et al., 2018), and categorical constructs of depression, anxiety and irritability symptoms are still commonly utilized in psychiatry thus may better inform clinical practice. Strengths of this study include the large and well-characterized clinic sample of children and the use of standard measures and of multiple informants. Nonetheless, there were several limitations that should be considered when interpreting our findings. Based on previous empirical findings we had strong theoretical reasons to assume that depression,

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anxiety and irritability symptoms mediate associations between ADHD and suicidality. However, our results cannot be taken as evidence that these are causal mediators of the ADHD-suicidality effect. Moreover, a measured mediator may be a confound of a true mediator that is unknown and as such not included in this study, thus mimicking it (Fiedler et al., 2011). For example, one factor that could derive the ADHD-irritability-suicidality association is aggression, which was not measured in the current study. In addition, the study sample was not enriched with children diagnosed with conduct disorder. Previous research indicated that substance could mediate the link between ADHD and suicidality (James et al., 2004). Given that the great majority of our sample (96.2%) was below 14, substance use was less relevant in the current study. Nevertheless, this could not be examined as there was no available data regarding substance use. Although not a panacea to this problem, reverse testing provides a practical check of the presumed causal flow of effects and may offer increased causal inference (Lemmer and Gollwitzer, 2017).

The indirect effects in the reverse pathways (i.e., M-X-Y) were

considerably lower compared to their hypothesized counterparts, not exceeding 8.3% of the total effect. This reverse testing supported the hypothesis that depression, irritability and anxiety mediate the association of ADHD and suicidality, rather than ADHD mediating the relationship of depression, irritability and anxiety and suicidality. Future studies, using for example a cohort design, may adjudicate the hypothesized pathways in the current investigation. We examined if irritability symptoms were a mediator between ADHD symptoms and suicidality in a sample of children enriched with symptoms of ADHD. However, there are alternative pathways involving irritability that were not examined in the current study. For example, irritability symptoms could possibly also mediate between symptoms of depression or anxiety and suicidality. The correlation between

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the parent- and the teacher-report of suicidality was low, with significantly higher rates of suicidality reported by parents compared to teachers (12.1% and 3.8% of the sample, respectively). This observation converges with a body of evidence showing differences in rates of suicidality by the source of report (Zalsman et al., 2016). One plausible explanation for the low cross-informant reliability may be related to children‟s tendency to disclose these symptoms more often to their parents compared to their teachers (Ferdinand et al., 2007). In addition, studies have demonstrated that parents report lower rates of suicidality than the youth‟s self-report (Brahmbhatt and Grupp-Phelan, 2019). These findings suggest that parent and teacher reports might miss suicidality that could have been depicted with self-reports, and as a result underestimate the ADHD-suicidality association and the effects mediated by internalizing symptoms of depression and anxiety. This study used a composite index of suicidality, derived from two items measuring suicidal ideation, suicidal attempts and self-harm, as in previous studies using OCHS‟s and CBCL questionnaires (Haltigan et al., 2018b; Joffe et al., 2014). Combining these items into one measure of suicidality limits the possibility of separating suicidal ideation and suicidal behavior when translating these findings into the clinical practice, e.g., of risk assessment. In the current study, ADHD symptoms were measured on a continuum in participants with (61.1%) and without (38.9%) clinical diagnosis of ADHD. To our knowledge, this is the first study to use OCHS-R to measure irritability. The measure used for irritability in the current study accords with the current literature of irritability construct (Brotman et al., 2017), and a composite measure of irritability extracted from the CBCL (Aebi et al., 2013). Nevertheless, the internal consistency and predictive validity of the irritability measure indicated by the current results should be further evaluated. We created a psychosocial adversity index to control for the effect of the psychosocial factors in predicting suicidality. PAI was positively associated with suicidality as reported by

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parents and teachers and was included in the multiple mediator model. Nevertheless, counting the number of different adversities does not allow the estimation of the relative contribution of each of the adversities. Moreover, data regarding other important psychosocial adversities was not available. 5. Conclusion Children with ADHD symptoms were found at elevated risk for suicidal ideation or behavior. The results of our study indicated that it is critical to assess risk profiles among those with ADHD in order to reduce and manage that risk. Children with ADHD symptoms who exhibit depression, irritable or anxious symptoms are those who are at elevated risk for suicidality. These comorbid traits need to be considered when estimating and managing the risk for suicidality that is associated with ADHD.

Competing interests All authors declare no conflict of interests. Contributors TL, RJS and Sk conceived of the study. TL and RJS managed the analysis. All authors contributed to data interpretation and article preparation. All authors approved the final manuscript. Funding This paper reports on an independent study which was funded by the Department of Psychiatry at the Hospital for Sick Children. Acknowledgements The authors would like to express their sincere appreciation to Dr. John D. Haltigan for his advices regarding the data analysis and the constructive criticism of the manuscript.

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Authors Statement

Dr. Levy, Dr. Kronenberg and Dr. Schachar designed the study. Dr. Levy and Dr. Schachar wrote the protocol and managed the analyses. Dr. Levy, Dr. Schachar and Dr. Crosbie wrote the first draft of the manuscript. Dr. Crosbie and Dr. Kronenberg wrote the following iterations of the draft. All authors contributed to and have approved the final manuscript.

Tomer Levy MD, Research-Clinical Fellow in Child and Adolescent Psychiatry Department of Psychiatry The Hospital for Sick Children University of Toronto [email protected]

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Tables and Figures: Table 1 Sociodemographic and Clinical Characteristics of the Sample (N = 1516). Age, M (SD) 9.00 (2.19) Sex, n (%) 1122(74%) Full Scale IQ, M (SD) 101.1 (13.49) Psychosocial Adversity Index, M (SD) 0.77 (.87) Stimulant medication, n (%) 336 (22.2%) Clinical Diagnoses, n (%) ADHD 927 (61.1%) Major depression or dysthymia 72 (4.7%) Generalized anxiety disorder 173 (11.4%) Oppositional defiant disorder 250 (16.5%) Conduct disorder 79 (5.2%) Specific anxiety disorders 118 (7.8%) Obsessive compulsive disorder 11 (.7%) Tic disorders 52 (3.4%) Specific learning disorder 133 (8.8%) Sleep disorder 28 (1.8%) Note: ADHD: Attention-deficit/hyperactivity disorder. Generalized anxiety disorder also included Anxiety disorder unspecified. Specific anxiety disorder included separation anxiety disorder, social anxiety disorder, specific phobia and panic disorder.

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Table 2 Total and Direct Effects of ADHD, Depression, Irritability and Anxiety Symptoms on Suicidality Based on the Parent-Report and the Teacher-Report. Parent-Report (n = 1461)

Teacher-Report (n = 1423)

Sociodemographic Correlates of Suicidality B

SE

p

Wald

Age

-.068

.05

.13

-2.2

-.164

Sex

.400

.22

.06

3.4

-.007

PAI

.277

.10

.004

8.5

.077

B

SE

ADHD –suicidality

.099

95% CI

B

SE

p

Wald

.017

-.119

.08

.11

-2.48

-.281

.010

.871

.309

.41

.43

.022

-.405

1.46

.475

.125

.15

.39

.76

-.181

.392

p

Wald

<.001

11.80

ADHD Associations with Suicidality (Total Effect) p Wald 95% CI B SE

.02

<.001

43.6

.068

.131

.079

Nagelkerke R2 = .11, χ24 = 84.61, p < .001

B ADHD- Depression

.181

SE .01

.001

481.0

.166

.198

Nagelkerke R = .33; χ = 5245.5; df = 4; p < .001

.126

.01

2

<.001

270.9

.108

.145

Nagelkerke R2 = .20; χ2 = 320.5; df = 4; p < .001

ADHD- Irritability

.155

.01

<.001

377.4

.139

.173

.132

.01

<.001

.127

Wald 333.7

95% CI .116

.147

Nagelkerke R = .24; χ = 384.11; df = 4; p < .001 2

.072

.01

2

<.001

112.2

.058

.085

Nagelkerke R2 = .08; χ2 = 124.1; df = 4; p < .001

.155

Nagelkerke R = .27, χ 4 = 451.8, p < .001 2

95% CI .034

Nagelkerke R2 = .06, χ24 = 22.07, p < .001

ADHD Associations with Depression, Anxiety and Irritability p Wald 95% CI B SE p 2

ADHD- Anxiety

.02

95% CI

.01

<.001

Nagelkerke R = .29, χ

2

2

374.9 2 4

.139

.173

= 480.0, p < .001

ADHD, Depression, Anxiety and Irritability Associations with Suicidality (Direct Effects) B SE p Wald 95% CI B SE p Wald 95% CI ADHD

.014

.02

.43

0.6

-.021

.050

.009

.03

.79

.00

-.052

.073

Depression

.176

.04

.001

19.6

.101

.260

.273

.06

.001

24.10

.158

.393

Anxiety

.104

.04

.003

8.2

.037

.174

.024

.05

.61

0.12

-.078

.122

Irritability

.159

.04

.001

17.7

.081

.245

.166

.06

.001

7.61

.053

.297

Nagelkerke R = .24, χ 7 = 193.0, p < .001 2

2

Nagelkerke R = .16, χ 7 = 64.8, p < .001 2

2

Note: B: Unstandardized coefficient; SE: Standard error; PAI: Psychosocial Adversity Index; ADHD: Attention-deficit/hyperactivity disorder. All associations in the mediation model are adjusted for age, sex and PAI. Number of bootstraps = 1000. 95% CI are bias corrected and accelerated. The sociodemographic correlates associations with suicidality are derived from the model that examined direct effects.

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Figure 1

Legend: Note: ADHD- Attention-deficit/hyperactivity disorder. Age, sex and Psychosocial Adversity Index are included in the model as covariates but not represented in the figure. Figures above arrows represent unstandardized regression coefficients. Percent of the total effect were estimated after standardization using standard error of predictor divided by standard error of outcome.

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