Childhood Psychiatric Disorders as Risk Factor for Subsequent Substance Abuse: A Meta-Analysis

Accepted Manuscript Childhood Psychiatric Disorders as Risk Factor for Subsequent Substance Abuse: A Meta-Analysis Annabeth P. Groenman, PhD, Tieme W.P. Janssen, PhD, Jaap Oosterlaan, PhD, Search Strategy, Data Extraction PII:

S0890-8567(17)30206-X

DOI:

10.1016/j.jaac.2017.05.004

Reference:

JAAC 1754

To appear in:

Journal of the American Academy of Child & Adolescent Psychiatry

Received Date: 24 January 2017 Revised Date:

11 April 2017

Accepted Date: 4 May 2017

Please cite this article as: Groenman AP, Janssen TWP, Oosterlaan J, Strategy S, Extraction D, Childhood Psychiatric Disorders as Risk Factor for Subsequent Substance Abuse: A MetaAnalysis, Journal of the American Academy of Child & Adolescent Psychiatry (2017), doi: 10.1016/ j.jaac.2017.05.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Childhood Psychiatric Disorders as Risk Factor for Subsequent Substance Abuse: A MetaAnalysis RH = Child Psychiatry and Later Substance Abuse

Supplemental material cited in this article is available online. Accepted May 5, 2017

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Annabeth P. Groenman, PhD, Tieme W.P. Janssen, PhD, Jaap Oosterlaan, PhD

Dr. Groenman is with Section of Clinical Neuropsychology, Faculty of Behavioral and

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Movement Sciences, Vrije Universiteit Amsterdam, the Netherlands and Accare, Center for Child and Adolescent Psychiatry, University Medical Center Groningen, the Netherlands.

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Dr. Janssen is with Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam. Dr. Oosterlaan is with Section of Clinical Neuropsychology, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam. Disclosure: Drs. Groenman, Janssen, and Oosterlaan report no biomedical financial interests

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or potential conflicts of interest.

Correspondence to Annabeth Groenman, PhD, Accare, Center for Child and Adolescent Psychiatry, University Medical Center Groningen, Hanzeplein 1, Groningen, the Netherlands;

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email: [email protected].

ACCEPTED MANUSCRIPT ABSTRACT Objective: Assess the prospective risk of developing substance-related disorders following childhood mental health disorders (i.e. attention-deficit/hyperactivity disorder [ADHD], oppositional defiant disorder/conduct disorder [ODD/CD], anxiety disorder, and depression)

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using meta-analysis.

Method: PubMed, Embase, and PsycInfo were searched for relevant longitudinal studies that described childhood (
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alcohol-, nicotine-, or drug- related disorders or substance use disorders published in peerreviewed journals in the English language between 1986 until May 2016. Two researchers

(MOOSE) guidelines were followed.

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conducted all review stages. Meta-analysis of Observational Studies in Epidemiology

Results: A total of 37 studies including over 762,187 participants were identified for quantitative analyses. These studies included 22,029 participants with ADHD, 434

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participants with ODD/CD, 1,433 participants with anxiety disorder, and 2.451 participants with depression. In total, 97 ESs were extracted for analyses. Meta-analysis showed a significantly increased risk for addiction in ADHD (n=23, OR=2.27,95%CI=1.98-3.67; i.e.

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OR alcohol=2.15,95%CI=1.56-2.97, OR drugs=1.52,95%CI=1.52-5.27, OR

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nicotine=2.52,95%CI=2.01-3.15, OR SUDs=2.61,95%CI=1.77-3.84), ODD/CD (n=8, OR=3.18,95%CI=1.97-5.80; i.e. OR alcohol=1.73,95%CI=1.51-2.00, OR drugs=4.24,95%CI=1.3.21.5.59, OR nicotine =4.22,95%CI=3.21-5.55, OR SUDs=4.86,95%CI=3.09-7.56) and depression (n=13, OR=2.03,95%CI=1.47-2.81; i.e. OR alcohol=1.10,95%CI=1.02-1.19, OR nicotine=2.56,95%CI=1.89-3.48, OR SUDs=2.20,95%CI=1.41-3.43), but not for anxiety disorders (n=15, OR=1.34,95%CI=.901.55, n.s.). Conclusion: We show that not only childhood ADHD increases the risk of developing

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ACCEPTED MANUSCRIPT substance-related disorders, but also childhood ODD/CD and depression. Anxiety disorders do not seem to increase the risk for future substance-related disorders, although findings are highly heterogeneous. These findings emphasize the need for early detection and intervention to prevent debilitating substance-related disorders in later life.

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Key words: Substance-related disorders, Mental disorders diagnosed in childhood. INTRODUCTION

Substance-related disorders result in high personal, societal, and economical costs1.

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For example, alcohol dependence globally accounts for 4% of mortality with associated

costs1, and chronic smoking is a major cause of premature death2. Adolescence and young

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adulthood are critical periods for the transition from recreational use to problematic use of substances and nicotine3. Mental health disorders in childhood and adolescence appear to be associated with increased levels of later substance-related disorders compared to typically developing youngsters4. Prevention of substance-related disorders should therefore target

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these vulnerable groups.

Previous meta-analyses have been helpful in revealing elevated risk for substance abuse in psychiatric disorders but are limited in explanatory power or scope. Limitations

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include (1) that most meta-analyses have not solely investigated prospective relationships5,

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limiting inferences about directionality, and (2) a lack of comparative meta-analyses that assess risk for substance abuse across different mental health disorders. Exceptions to the first limitation are two recent meta-analyses that focused on childhood attentiondeficit/hyperactivity disorder (ADHD) and the development of substance-related disorders prospectively, both showing an increased risk6,7. Only a handful of studies have compared childhood mental health disorders in their risk for developing substance abuse. Where one study found the highest risk for substance-related disorders in childhood externalizing disorders8, another found the highest risk in childhood internalizing disorders9, yet another

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ACCEPTED MANUSCRIPT found a relatively equal risk for childhood internalizing and externalizing disorders10. Although evidence-based early prevention interventions are available, they often do not reach those in greatest need11. By using equal methods, comparability of the risk assessment of substance-related disorders will increase. This will allow comparison between risk

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assessments of disorders, which in turn will facilitate more optimal allocation of the limited resources to those in greatest need. Furthermore, some studies find the highest risk for

substance-related disorder in those with childhood anxiety disorders compared to other

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disorders4, while another study found a decreased risk compared to controls in those with childhood anxiety disorders8.

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Several outstanding questions regarding substance abuse remain unanswered for specific childhood mental disorders. In ADHD, an ongoing discussion focuses on the role of comorbid oppositional defiant disorder/conduct disorder (ODD/CD). Some studies show that ADHD itself is a risk factor for substance-related disorders12-14, while others show that the

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risk for substance-related disorders is carried by comorbid ODD/CD15. Another issue is the role of gender in the association between depression and substance abuse. These factors could provide explanations for the inconsistent results across studies and disorders.

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To our knowledge, we are the first to conduct a meta-analysis encompassing multiple

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mental disorders that occur in childhood and the prospective risk of developing a substancerelated disorder. Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed (available on request). Separate meta-analyses were conducted for four childhood mental disorders occurring before the age of eighteen: ADHD, ODD/CD, anxiety disorder, and depression. For each of these disorders, we assessed the risk of addiction, alcohol-related disorders, drug-related disorders, nicotine-related disorders, and substance use disorder (SUD). We hypothesized we would find an increased risk of substance-related disorders in all childhood mental health disorders. With the current meta-

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ACCEPTED MANUSCRIPT analysis, we focused on longitudinal studies to improve causal inference, and the comparative design allowed us to compare risks among childhood disorders with the same methodology. Furthermore, using meta-regression, outstanding questions, such as the effect of comorbidity and gender, will be assessed.

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METHOD Study Selection

Authors A.G. and T.J. (both postdoctoral researchers) performed the selection of

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studies. The complete search-query is available in the supplement (available online). Studies published in peer-reviewed journals in the English language (i.e. no member of the review

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team was fluent in any relevant languages) between 1986 (i.e. the DSM-III-R) until the 20th of May 2016 were included. The inclusion of studies was based on study type, population, and outcome.

Study Type. Studies were selected that described longitudinal data, either prospective

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or retrospective, and included odds ratios (ORs) or information to calculate OR. Selected studies had to predict substance outcomes starting from the childhood psychiatric disorder. We considered studies that included community or clinical samples. We did not consider

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studies that included high-risk participants (i.e. children of parents with a psychiatric disorder

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or substance-related problems, or participants with prenatal exposure to substances), as we believe this would artificially inflate the risk of substance-related problems, clouding the generalizability of the results concerning mental health disorders. If multiple studies described the same sample, the study with the longest follow-up interval was selected to maximize the prospective power of the analyses. Population. Originally, the purpose of this meta-analysis was aimed at all childhood mental disorders. We found that there is a paucity of literature concerning other disorders than ADHD, ODD/CD, anxiety, or depression. Therefore, the present meta-analysis included

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ACCEPTED MANUSCRIPT studies in which individuals with ADHD, ODD/CD, anxiety, or depression diagnosed before the age of 18 were compared with control participants on the later risk of substance-related disorders. Oppositional defiant disorder and CD are taken together here. Diagnoses were required to be based on (i) DSM-III-R or more recent versions of the DSM or later diagnostic

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versions of nosological frameworks such as the International Classification of Diseases

(ICD), or (ii) scores above the clinical threshold on diagnostic questionnaires, or (iii) medical records. Control participants were participants without the disorder. Studies that included

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participants with comorbid disorders were not excluded.

Outcome. Studies were selected that included outcomes related to SUD, nicotine-

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related disorder, alcohol-related disorder, or drug-related disorder (see Table S1, available online). We included both DSM-defined outcomes (e.g. SUDs, alcohol use disorder) and heavy use, as heavy use is responsible for similar consequences (e.g. health, social) as dependence16. The outcome measures were grouped according to substance, which led to five

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outcome measures, namely: (i) SUDs (i.e. if a study did not specify which substance was examined and the general term SUDs was used), (ii) alcohol-related disorders, (iii) drugrelated disorders, (iv) nicotine-related disorders, (v) an aggregated measure of addiction. By

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using an aggregated measure of addiction, it was possible to include all studies of one

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disorder (e.g. ADHD) in meta-regression, increasing the statistical power. For studies with one outcome measure, this outcome was used as the aggregated measure of addiction. If there were multiple outcomes in a study, the aggregated measure of addiction was calculated using the method of Borenstein.17 Search Strategy A two-step approach to identifying relevant articles was used. First, PubMed, Embase, and PsycInfo were searched for relevant papers using a combination of the following search terms and their synonyms, as well as hierarchical family form (e.g. MeSH

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ACCEPTED MANUSCRIPT terms): childhood, ADHD, oppositional defiant disorder, conduct disorder, anxiety, depression, childhood mental disorders, longitudinal, substance use disorder, nicotine dependence. Second, literature lists of all selected studies were searched to identify possible

eligibility for inclusion in the meta-analysis (see Figure 1). Data Extraction

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missing articles. The abstracts and full-texts of the articles selected were screened to assess

Authors A.G. and T.J. extracted the following data from the selected studies: effect

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sizes (ORs) or information to calculate ORs, age at diagnosis at baseline, and age at followup, follow-up interval, percentage male, study design (prospective or retrospective), nature of

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sample (clinical or community), outcome(s), and for ADHD samples: percentage of cases comorbid with ODD/CD. Where possible, unadjusted ORs were extracted from the papers. In the case of any missing data, the authors were contacted by email to request these data. If authors did not reply, a reminder was sent after a month. A total response rate of 73% percent

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was reached. Two papers did neither report ORs nor information to calculate ORs. For one of these studies, the first authors could not be reached18, while for the other study, the authors were unable to provide additional information on outcome data for the missing outcomes19.

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For the latter, a previous follow-up of the same sample (i.e. 10-year follow-up instead of 16-

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year follow-up)20 was used to derive the outcomes missing at 16-year follow-up (i.e. alcohol dependence, drug dependence, and SUDs). The other missing data that could not be retrieved concerned information on sample size,10,21-23 and information necessary to perform metaregression (see Table 1). Study Quality Authors A.G. and T.J. independently rated the quality of the selected studies using the Newcastle-Ottowa Scale (NOS).24 Scores ranged between zero and nine, with higher ratings corresponding to higher study quality. Substantial agreement was found between the authors

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ACCEPTED MANUSCRIPT (kappa: .92). Inter-rater discrepancies were resolved by consensus. Statistical Analyses Meta-Analyses. Analyses were performed using Comprehensive Meta-Analysis 3.0, and SPSS 22.0. First, the four childhood mental disorders (i.e. ADHD, ODD/CD, anxiety

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disorder, depression) were analyzed separately for the aggregated addiction outcome (i.e. addiction), and second, for individual addictions (alcohol-related disorder, nicotine-related disorder, drug-related disorder, and SUD). When the data allowed (i.e. more than four ESs

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available for analyses), random effects models were used, because random effects models allow for variation in true effect sizes between populations.17 Fixed effects models were used

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when the number of ES was limited, because random effects models use Tau2 to weigh studies, and Tau2 becomes less reliable when there are less than four ESs available.17 Second, we checked whether there were significant differences between childhood mental health disorders in the risk for addiction. Unfortunately, some studies investigating risk for

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substance-related disorders in more than one childhood mental health disorder used partially overlapping control groups. These studies were removed from the analyses comparing the childhood mental health disorders on their risk for substance-related disorders.

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Meta-Regression. If significant heterogeneity was detected in the aggregated ES, as

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measured with I2, meta-regression was performed to assess the effect of age at baseline and follow-up, follow-up interval, gender, sample type (clinical or community samples), study design (prospective or retrospective), study quality, DSM-related outcomes (heavy use or DSM-defined), clinical diagnosis (clinical, questionnaire, or structured interview-based), cannabis or other illicit drugs, and for ADHD samples, percentage of ODD and CD (percentages in Table S2, available online). Following the Cochrane handbook for systematic reviews25, meta-regression was only performed if more than 10 ES were available. Publication Bias. Publication bias was assessed using funnel plots, Egger’s test, and

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ACCEPTED MANUSCRIPT Rosenthal’s Fail-safe N. Publication bias was assessed when over 10 studies were published on a topic26. RESULTS Studies Included in the Meta-Analysis

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A total of 8,750 studies were identified (see also Figure 1), of which 6,439 remained after removal of duplicates. Titles of all studies were screened for eligibility, leaving a total of 296 studies that were screened for eligibility using both abstracts and full-texts. A total of

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37 studies including 762,187 participants were identified for quantitative analyses; for a summary, see Table 18-10,14,15,19-23,27-56 and Table S3, available online, for reasons of

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exclusion. These studies included 22,029 participants with ADHD, 434 participants with ODD/CD, 1,433 participants with anxiety disorder, and 2,451 participants with depression. Eighteen studies reported solely on ADHD, 1 study on ODD/CD, 8 studies on anxiety disorders, 7 on depression, and 5 studies on combinations of those. In total, 97 ESs were

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extracted for analyses. All studies, except one34, used a prospective longitudinal design. Studies concerning ADHD used a mix of clinical and community samples, but studies concerning ODD/CD, anxiety and depression, all used community samples. Follow-up times

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ranged between 1 and 35 years (M=10.16, SD=6.97). Age at baseline was between 5.00 and

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17.50 years (M=12.85, SD=3.34), age at follow-up was between 13.6 and 36.6 years (M=21.98, SD=6.45), and the percentage of male participants ranged between 0 and 100 percent (M=51.79 SD=25.28). Externalizing Disorders

Attention-Deficit/Hyperactivity Disorder. Analyses showed that there was an increased risk for later addiction in individuals with ADHD in childhood (see Table 2 and Figure 2). Significant heterogeneity was detected. Meta-regression showed significantly higher effect sizes in those studies including participants younger at baseline, and those with

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ACCEPTED MANUSCRIPT higher quality ratings. Moreover, studies including participants with a clinically established diagnosis show higher effect sizes compared to those studies including participants with questionnaire-based or structured interview-based diagnoses (see Table 3). Meta-regression revealed no other significant effects, including no effects of ODD/CD comorbidity.

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Heterogeneity was lowered by baseline age (I2=81.53%), follow-up age (I2=49.28%), quality score (I2=75.92%), and comorbid ODD/CD (I2=33.85%). No single study was responsible for the significant results.

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When looking at individual substance-related disorders in ADHD, it was found that individuals with ADHD are at increased risk for alcohol-related disorder (OR=2.15),

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nicotine-related disorder (OR=2.52), drug-related disorder (OR= 1.52), and any SUDs (OR=2.61; see Table 2 and Figure S1, available online). Significant heterogeneity was detected in alcohol-related disorder, nicotine-related disorder, and drug-related disorder. In alcohol-related disorders, higher effect sizes were found in studies including younger

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participants at baseline; heterogeneity was lowered in the model with gender (I2=77.91). Concerning nicotine-related disorder in ADHD, meta-regression revealed a significantly higher effect in clinical compared to community samples (also see Table 3). Heterogeneity

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was lowered in the model including DSM outcome (I2=33.93). Meta-regression concerning

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drug-related disorder in ADHD detected no significant causes of heterogeneity; quality score lowered heterogeneity. No difference was found in studies including cannabis disorder compared to other drug use disorders (Q=.00, p=.99, I2=96.42%). Although we hypothesized a significant effect of comorbid ODD/CD in participants with ADHD, we did not find support for this hypothesis in any comparison. Conduct Disorder. Analyses showed a significantly increased risk to develop addiction in individuals with childhood ODD/CD (see Table 2 and Figure 2). Significant heterogeneity was detected. However, not enough studies were available (n=8) to conduct

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ACCEPTED MANUSCRIPT meta-regression. Individuals with CD were at increased risk for developing alcohol-related disorder (OR=1.73), nicotine-related disorder (OR=4.22), drug-related disorder (OR=4.24), and any

studies available, meta-regression could not be performed. Internalizing Disorders

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SUDs (OR=4.86; see Figure S3, available online, and Table 2). Due to a limited number of

Anxiety Disorders. Analyses concerning anxiety disorders in childhood and later

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addiction revealed no significant results (see Table 2 and Figure 2). Significant heterogeneity was detected. Meta-regression did not reveal significant effects, but age at baseline and

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follow-up age lowered I2 (from 61.79% to 46.68%, 46.94%, respectively). Leave-one-out analyses did not reveal that removal of any studies would lead to a change in results. Concerning individual addictions, we found that individuals with childhood anxiety disorders were at increased risk for drug-related disorder (OR=1.60), but not alcohol-related

available online).

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disorder (OR=.85), nicotine-related disorder (OR=1.23), or SUDs (OR=1.22; see Figure S2,

Depression. A significant increase in addictions was found in those with childhood

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depression (see Table 2 and Figure 2). Significant heterogeneity was detected. Metaregression revealed no significant moderators, lowered heterogeneity was found in the

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models with baseline age (I2=67.34%), and DSM outcome (I2=74.93%). Leave-one-out analyses did not reveal that removal of any studies would lead to a change in results. Individuals with childhood depression were at increased risk of alcohol-related

disorders (OR=1.10), nicotine-related disorder (OR=2.56), and SUDs (OR=2.20). Not enough studies were available to look at drug-related disorder (see Figure S4, available online). Mental Disorders in Childhood

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ACCEPTED MANUSCRIPT A random effects model showed an increased risk for addiction in those with a childhood mental disorder (OR= 2.19, 95%CI=1.81-2.63). However, significant heterogeneity was found (Q[58]=1744.85, P<.001, I2=96.68%). There was a significant difference between the childhood mental disorders (Q[3]=8.89, p=.03) in the risk for

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substance-related disorders. Pairwise comparisons revealed a significantly lower risk in

anxiety disorders compared to both externalizing disorders ADHD (Q[1]=6.78, p=.009) and ODD/CD (Q[1]=6.06, p=.014). Depression did not differ from ADHD (Q[1]=1.55, p=.21) or

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ODD/CD (Q[1]=1.96, p=.16). Unfortunately, overlapping control groups did not allow for pairwise comparison between ADHD and ODD/CD, and between anxiety and depression.

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Meta-regression showed larger effect-sizes in those studies with a higher quality rating and baseline age (see Table 3). Meta-regression showed lower heterogeneity in models with follow-up age (I2=86.83%) and quality score (I2= 85.92%; also see Table 3). Leave-one-out analyses did not reveal that removal of any studies would lead to a change in results.

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Publication Bias

There was an indication for publication bias in the results concerning depression and addiction (Eggers’ test t=4.34, p=.002, fail safe N= 221). There was also an indication for

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publication bias in the results concerning ADHD and the aggregated measure of addiction

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(Eggers’ test t=3.78, p=.001, fail safe N=5,003) and nicotine-related disorders (Eggers’ test t=4.04, p=.002, fail safe N =2,502). Furthermore, bias was found in the results concerning any mental disorder and the aggregated measure of addiction (Eggers’ test t=4.34, p.001, fail safe N=4,387). Although Eggers test indicated publication bias, fail safe N was very high for all outcomes. For all other outcomes, there was no evidence for publication bias (also see Table 2). DISCUSSION We aimed to clarify prospective outcomes concerning substance-related disorders for

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ACCEPTED MANUSCRIPT childhood ADHD, ODD/CD, anxiety disorder, or depression. A total of 37 studies including over 762,187 participants were identified for meta-analysis. Substance-related disorders result in high personal, societal, and economical costs1, and prevention should be top priority. We found that individuals with childhood externalizing disorders (ADHD and ODD/CD)

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were at increased risk of later substance-related disorders. In childhood internalizing

disorders, we found childhood depression to be associated with an increased later risk of addiction, including SUD and nicotine. Concerning anxiety disorders, we only found an

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increased risk for drug-related disorders. Those with anxiety were at a lower risk for

addiction compared to externalizing disorders ADHD and ODD/CD, but depression did not

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differ from these externalizing disorders.

The self-medication hypothesis provides an attractive explanation for increased risks of substance-related disorders in mental health disorders57. This hypothesis states that individuals with mental health disorders start using substances to self-medicate symptoms of

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their illness. Although this hypothesis may in part explain the risk of substance-related disorders in mental health conditions, there are still some caveats to this hypothesis. For example, this hypothesis would imply that successfully treated participants would not

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develop substance-related disorders. In ADHD, a recent meta-analysis concurs with the selfmedication hypothesis, in that stimulant medications appears to have a protective effect on

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smoking behaviors,58 although another recent meta-analysis found no effect of stimulant medication on SUDs,59 showing inconclusive results. Furthermore, according to the selfmedication hypothesis, substance use should commence after the onset of the first symptoms of the mental health disorders. While we show that depression in childhood is associated with later substance-related disorders, previous studies in depression and anxiety have shown that substance-related disorders and depression are bi-directionally associated, showing that not only mental health disorders in childhood are a risk factor for substance-related disorder, but

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ACCEPTED MANUSCRIPT that this association works both ways.60-62 This would suggest shared liability between substance-related disorders and mental health disorders, which is supported by previous studies that have shown a shared genetic origin among common psychiatric disorders.63,64 Also, children of alcoholics are not only at increased risk of developing alcohol problems, but

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also other psychopathology, showing cross-disorder transfer65. Here we suggest that although self-medication plays a part in the co-occurrence of mental health disorders and substancerelated disorders, a shared liability between the disorders likewise plays a part.

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Although individuals with ADHD, ODD/CD, and depression in childhood were at increased risk of developing a variety of addictive disorders, individuals with anxiety

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disorders were only at increased risk of developing drug-related disorders. Also, anxiety disorders had a significantly lower risk for addiction compared to ADHD and ODD/CD. A possible explanation for our disorder-specific results is the heterogeneity within anxiety disorders. For example, social anxiety does not increase the risk of cannabis use disorders

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(OR=.8), while panic disorder increases the risk almost six times (OR=5.9).9 When looking at our own results (also see Figure S5, available online), it indeed appears that social anxiety does not increase the risk of addiction. The disorders included in anxiety disorders appear to

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have a differential risk for substance-related disorders.

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Several moderators affected the risk of developing substance-related disorders. First, the risk for nicotine addiction in ADHD was higher in clinical samples than in community samples. Possibly, clinical samples tend to include more severely affected participants. Second, we found a higher risk of addictions in persons with anxiety disorder and in any mental health disorder in childhood in those younger at baseline. Although we cannot conclude that age at onset of the disorder is the same as age at baseline, it does provide a plausible explanation. Those with a younger age of onset have more severe outcomes, including more frequent adult psychopathology and worse functional outcomes (e.g. lower

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ACCEPTED MANUSCRIPT socioeconomic status [SES])66. This indicates the need for early detection and intervention in order to prevent these escalating problems. Lastly, it was found that studies with a higher quality rating showed higher ORs, indicating the risk found in persons with a childhood mental health disorder is not the result of poor quality studies, but truly concerning. Although

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we could indicate some causes for the heterogeneity in effect sizes and found some

reductions in heterogeneity (also see Table 3), we unfortunately could not completely explain all heterogeneity. In concluding, our results indicate the need for early identification and

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intervention of mental health disorders in childhood, and more awareness for the risk of

substance-related disorders in later life in those seeking help for childhood mental health

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disorders.

It is often thought comorbidities increase the severity of outcomes of mental health disorders. Among researchers in the field of ADHD, there is an ongoing discussion whether comorbid ODD/CD actually explains the whole risk of substance-related disorders ADHD, or

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whether ADHD itself is a risk factor for substance-related disorders12-15. Using metaregression, we found no significant effect of the percentage of children with comorbid ODD/CD within studies on the development of addiction and nicotine-related disorders;

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however, it did reduce heterogeneity. From this finding, it may be concluded that the

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percentage of children with concomitant ODD/CD does only in part influence the severity of substance-related outcomes later in life for those who had childhood ADHD. However, a previous meta-analysis by Serra-Pinheiro et al.67 including only studies into ADHD that statistically adjusted for the impact of comorbid ODD/CD found no significant increase of illicit substance use, suggesting that ADHD-only does not increase the risk for substancerelated disorders. One possible explanation for these inconsistent results is that SerraPinheiro et al. included studies that were not only statistically adjusted for the impact of comorbid ODD/CD, but also a variety of other measures, such as age, gender, SES, parental

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ACCEPTED MANUSCRIPT substance use, and other comorbidities than ODD/CD, significantly reducing the ecological validity of their findings. The findings of the current study should be viewed in the light of some limitations. Amongst the studies on ADHD, we found a higher risk in those including a clinical sample

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than a community sample, but in ODD/CD, anxiety disorder, and depression, only

community samples were included. If clinical samples have more severe outcomes than community samples, one may hypothesize that clinical samples of ODD/CD, anxiety

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disorder, and depression might have a higher risk for substance-related disorders compared to community samples found in this meta-analysis. Another explanation is that gender is

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unequally divided among sample types (i.e. clinical samples have more males), and that males are more likely to suffer from substance-related disorders. Although our study does not have sufficient power to test this interaction directly, we did not find an effect of gender and also did not find a difference in gender among sample types (t=-1.88, p=.26). More studies

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into clinical samples are warranted to elucidate this issue. We were only able to assess the effects of comorbid ODD/CD in ADHD but did not have data to study the effects of other comorbidities in other disorders. It is often thought that participants suffering from comorbid

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conditions are more severely affected than participants suffering from a single disorder

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(e.g.,68). Studying the effects of other comorbid disorders in ODD/CD, anxiety disorder, and depression is of major importance to assess the long-term outcomes of these disorders. We only included papers that were published in English language peer-reviewed journals, leading to possible bias in our results. Furthermore, Eggers test indicated possible publication bias for four outcomes (i.e. for both ADHD and depression and all addiction disorders and the aggregated measure of addiction, and for ADHD and nicotine-related disorders). However, as the fail safe N was high, we are not concerned that inclusion of unpublished or other language results would have led to other results. The use of stringent criteria for selecting

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ACCEPTED MANUSCRIPT studies applied across disorders increases the comparability of the results. Our findings are of great clinical relevance. We show that not only childhood ADHD may increase the risk of developing substance-related disorders, but also childhood ODD/CD and depression. Childhood anxiety disorders do not seem to increase the risk for future

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substance-related disorders, although findings are highly heterogeneous. Future studies into the risk of substance-related disorders following childhood mental health disorder should take comorbidities into account and should focus on the heterogeneity within disorders. Our

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findings emphasize the need for early detection and intervention to prevent debilitating substance-related disorders in later life.

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Table 1. Summary of Included Studies

August et al. 2006

ADHD-only

ADHD: 27, control: 91

Babinski et al. 2011

ADHD

Benjet et al. 2016

a

Anxiety Disorder MDD

Age at followup

% Male

Type of Sample

Length followup

18.3

72.9

Community

9.4

9

ADHD: 34, Control: 24 Anxiety: 493, Control: 535 MDD: 107, Control: 921

19.9

0

Clinical

14.19

49.9

Community

14.19

49.9

Community

Study design

Prospective

Prospective

8 8

Prospective

SUD

7

100

Clinical

11

Prospective

Biederman et al. 2010

ADHD

ADHD: 96, Control: 91

22.1

0

Clinical

10.6

Prospective

Biederman et al. 2012

ADHD

Bittner et al. 2007

GAD

Brook et al. 2008

ADHD

Brook et al. 2010

ADHD

Brückl et al. 2007

Separation anxiety disorder

Anxiety: 109, Control: 938

30.6

30.6

CD

-

30.6

41

-

30.6

41

n: 1,653

17

50

Buckner et al. 2008 Cisler et al. 2011

Social anxiety disorder PTSD

TE D

21.2

AC C

36.6

Alcohol dependence, drug dependence, Substance dependence Alcohol dependence, drug dependence, nicotine dependence, SUD

6

6

100

Clinical

16.4

Prospective

Smoking dependence

6

55.6

Community

-

Prospective

Substance use disorder

6

17.55

Prospective

Smoking

6

22.5

Prospective

SUDs

7

46

EP

32

4 7

ADHD:112, Control: 105

19

6

SUD

ADHD

27.4

Alcohol use disorder, marijuana use disorder, regular tobacco use, other SUDs Binge drinking, daily smoking

Quality score

Prospective

Biederman et al. 2006

ADHD: 79, Control: 90 Anxiety: 23, Control: 883 ADHD: 58, Control: 531 ADHD: 58, Control: 392

Outcome

RI PT

n at follow-up

SC

Diagnosis

M AN U

Study

42.5

Community Community

Community

Community Community Community

14

Prospective

14

Prospective

14

Prospective

2.5

Prospective

Alcohol dependence, illegal drug abuse/dependence, nicotine dependence, any SUD Alcohol abuse, cannabis abuse Alcohol abuse, cannabis abuse Regular smoking

6

4 4 6

24

ACCEPTED MANUSCRIPT

GAD

Dalsgaard et al. 2014

n: 1,008

-

19-21

-

19-21

-

Depression

n: 1,008

19-21

-

ADHD

ADHD: 208, Community controls

31

88

ADHD

ADHD:128 Control: 1,036

18.15

49.7

CD

CD:241 Control:1,036

18.15

49.7

Anxiety disorder

Anxiety: 80, control: 736

30.45

41.2

ADHD

ADHD: 49, Control: 292

25

CD

CD: 49, Control: 291

25

48.7

17.6

43.6

15.5

50.2

15.5

ADHD CD Gau et al. 2007 Anxiety Depression

Community

5

12

Prospective

SUDs

5

Prospective

SUDs

5

Prospective

SUDs

5

Alcohol use disorder, SUDs

5

12 12 23

Community

Prospective

Alcohol abuse/dependence, Marijuana abuse/dependence, nicotine dependence Alcohol abuse/dependence, Marijuana abuse/dependence, nicotine dependence

Prospective

13.3

Prospective

17

Prospective

17

Prospective

2

Prospective

Frequent drunkenness

4

Community

3

Prospective

SUDs

7

50.2

Community

3

Prospective

SUDs

7

15.5

50.2

Community

3

Prospective

SUDs

7

15.5

50.2

Community

3

Prospective

SUDs

7

Community

Community

TE D 48.7

EP

Anxiety: 197, Control: 1,810 ADHD: 65, Control: 363 CD: 31, Control: 397 Anxiety: 86, Control: 342 Depression: 28, Control: 400

Community

SUDs

6.5

AC C

Social phobia

Community

Prospective

Prospective

Fergusson et al. 2007

Frojd et al. 2011

Community

12

6.5

Elkins et al. 2007

Essau et al. 2014

Community

RI PT

Copeland et al. 2009

n: 1,008

19-21

SC

ODD/CD

n: 1,008

M AN U

ADHD

Community

Community Community

Alcohol use disorder, SUD Alcohol abuse, Marijuana abuse, nicotine abuse, other illicit drug abuse Alcohol abuse, marijuana abuse, nicotine abuse, other illicit drug abuse

6

6

4 5

5

25

ACCEPTED MANUSCRIPT

Groenman et al. 2013

ADHD

Heron et al. 2013

CD

Johnson et al. 2000

Anxiety disorder

Kollins et al. 2005

ADHD

Lam et al. 2005

Depression

Lambert et al. 2005

ADHD

ADHD: 129, Control: 270

Marmorstein et al. 2010

Depressionmale Depressionfemale

Depression: 15, Control: 517 Depression: 61, Control: 572

Mcleod et al. 2016

Depression

Depression:123, Control: 614

Milberger et al. 1997a

ADHD

Milberger et al. 1997b

ADHD

Milberger et al. 1997c

ADHD

Molina and Pelham 2003

ADHD

Ottosen et al. 2016

30

42.3

16.4

68.1

16

68

22

49

23

49.5

13.6

48.8

26

78.1

25.1,

100

24.3

0

Community Clinical Community Community Community Community

1

Prospective

Smoking

4

13.4

Prospective

Alcohol use disorder

4

4.4

Prospective

Nicotine dependence, SUD

6

Prospective

High frequent drinkers

4

Prospective

Cigarette smoking

6

Retrospective

Regular smoking

5

.9

Prospective

Current smoking

6

28

Prospective

7

Prospective

7

Prospective

6 n.a.

Community Community Community

Alcohol dependence, Marijuana dependence, tobacco dependence Drug and alcohol dependence Drug and alcohol dependence Alcohol abuse/dependence, Illicit substance abuse/dependence Alcohol abuse/dependence, drug abuse/dependence

4

5 4

-

Community

35

Prospective

49

Clinical

4

Prospective

49.4

Clinical

4

Prospective

Smoking

7

15

100

Clinical

4

Prospective

Smoking

6

ADHD: 142, Control: 100

15.2

95.6

Clinical

5.3

Prospective

ADHDFemale

ADHD: 5,144 Control:344419

-b

0

Community

13.3

Prospective

ADHD-Male

ADHD: 14,501,

-b

100

Community

13.3

Prospective

EP

17.3 17.5

AC C

ADHD: 34, Control: 235 ADHD: 28, Control: 117 ADHD: 128, Control: 109

35

Community

RI PT

Anxiety disorder

50.6

SC

Gorka et al. 2014

15.3

M AN U

Depression

TE D

Depression:445, Control: 6,502 Anxiety: 80, Control: 737 ADHD: 511, Control: 220 CD: 873, Control: 2,714 Anxiety: 44, Control: 644 ADHD: 302, Control: 12,810 Depression: 413, Control: 1,269

Goodman et al. 2000

Alcohol use disorder, Marijuana use disorder, daily smoking Cannabis abuse, alcohol abuse, other illicit drug abuse Cannabis abuse, alcohol

7 7

5

9 9

26

ACCEPTED MANUSCRIPT

Control:349329

abuse, other illicit drug abuse 42.2

Sibley et al. 2014

ADHD

ADHD: 113, Control: 65

17.6

78.1

Sihvola et al. 2008

Depression

n: 1,545

17.5

51

Anxiety disorder

Anxiety: 44, Control: 91 Depression: 83, Control: 91 ADHD: 43 Controls: 1,267 CD: 76, Control: 805 Anxiety: 318, Control: 992 Depression: 91, Control: 1,219 Anxiety: 118, Control: 509 Depression: 167, Control: 460

21.5

57

22

58.6

21.93

51.18

21.93

51.18

21.93

51.18

21.93

51.18

Depression ADHD CD Wittchen et al. 2007

Anxiety Disorder Depression

Wolitzky-Taylor et al. 2012

Anxiety Disorder Depression

-b -b

Clinical Community Community Community

31.1 31.1

3.2

12.4 3.5

Prospective

Community Community Community Community

Community Community

Problematic alcohol use

Prospective

Prospective

Daily alcohol use, daily marijuana use, daily cigarette use Frequent alcohol use, daily smoking

5

4 6

11.5

Prospective

Substance use disorders

7

11.7

Prospective

SUDs

7

10

Prospective

Cannabis use disorder

5

10

Prospective

Cannabis use disorder

5

10

Prospective

Cannabis use disorder

5

10

Prospective

Cannabis use disorder

5

4

Prospective

SUDs

4

4

Prospective

SUDs

4

EP

Weissman et al. 1999

Community

RI PT

13.8

SC

Depression: 1,085, Control: 760

M AN U

Depression

TE D

Saraceno et al. 2012

AC C

Note: ADHD = attention-deficit/hyperactivity disorder; CD = conduct disorder; GAD = generalized anxiety disorder; MDD = major depressive disorder; ODD = oppositional defiant disorder; PTSD = posttraumatic stress disorder; SUD = substance use disorder. a Numbers for MDD are acquired through personal communication with the author. b Due to the design of the study, it is not possible to determine an accurate average age at follow-up.

27

ACCEPTED MANUSCRIPT

Table 2. Outcomes of Main Analyses

AC C

EP

TE D

M AN U

SC

RI PT

Heterogeneity Publication bias Type of Pooled ZpTau ppFailDisorder Outcome k 95% CI Q I2 t model OR value value 2 value value safe N ADHD Addiction Random 23 2.27 1.98-3.67 .27 <.001 0.44 371.90 <.001 94.08 3.78 .001 5003 - Alcohol Random 13 2.15 1.56-2.97 4.64 <.001 0.20 107.82 <.001 88.87 1.35 .20 1058 - Drugs Random 12 1.52 1.52-5.27 3.28 .001 1.04 339.16 <.001 96.76 4.04 .002 2502 - Nicotine Random 14 2.52 2.01-3.15 8.03 <.001 0.07 22.47 .05 42.14 0.93 .37 422 - SUD Random 8 1.77-3.84 4.87 <.001 0.13 12.57 .08 44.33 80 2.61 ODD/CD Addiction Random 9 1.97-5.80 4.41 <.001 0.59 108.09 <.001 92.60 229 3.38 - Alcohol Fixed 4 1.51-2.00 7.72 <.001 6.84 54.85 <.001 94.53 92 1.73 - Drugs Fixed 4 3.21-5.59 10.19 <.001 .10 6.12 .11 51.01 84 4.24 - Nicotine Fixed 3 3.21-5.55 10.27 <.001 .02 2.53 .28 21.00 68 4.22 - SUD Fixed 3 3.09-7.56 6.89 <.001 0.53 8.54 .01 76.57 34 4.86 Anxiety Addiction Random 14 1.15 .90-1.55 1.21 .27 0.55 34.02 .001 61.79 0.40 .69 1 - Alcohol Random 5 0.85 .64-1.13 -1.14 .26 0.02 4.69 .32 14.64 0 - Drugs Fixed 3 1.12-2.29 2.58 .01 0.10 2.97 .22 32.70 0 1.60 - Nicotine Fixed 3 1.23 .08-1.97 0.88 .38 0.04 2.479 .29 19.32 0 - SUD Random 8 1.22 .82-1.81 .96 .34 0.19 21.32 .003 67.16 0 Depression Addiction Random 13 2.03 1.47-2.81 4.26 <.001 0.23 61.91 <.001 80.62 4.39 .001 211 - Alcohol Fixed 3 1.02-1.19 2.39 .017 .032 -3.41 .18 41.32 1.10 - Drugs 2 - nicotine Fixed 3 1.89-3.48 5.98 <.001 0 0.59 .74 0 25 2.56 - SUD Random 7 1.41-3.43 3.52 .001 0.18 13.25 .039 54.71 40 2.20 Note. Bold figures indicate significant results. Presence of dashes indicates analyses were not performed due to a limited number of data points. ADHD = attention-deficit/hyperactivity disorder; CD = conduct disorder; ODD = oppositional defiant disorder; OR = odds ratio; SUD = substance use disorder.

28

ACCEPTED MANUSCRIPT

Table 3. Meta-Regression

Study design Sample type Quality score DSM-based outcome

a

-

Depression Addiction .70 .40 67.34** 77.62** .30 .59 81.66** .60 .44 .93 .33 82.14** .01 .90

SC

RI PT

Anxiety Addiction 2.58 .11 46.68 .89 .34 46.94* .00 .96 64.22* .49 .49 57.05* 1.39 .24 56.43* .44 .51

M AN U

Gender

Drug .00 1.00 96.98** .65 .42 97.12** .63 .73 95.76** 43.49 <.001 77.8**

TE D

Follow-up length

EP

Follow-up age

Q(1) p I2 Q(1) p I2 Q(1) p I2 Q(1) p I2 Q(1) p I2 Q(1) p I2 Q(1) p I2 Q(1) p

AC C

Baseline age

Addiction 17.78 <.001 81.53** .72 .40 49.28* .05 .82 93.83** .03 .86 94.81** .02 .88 93.6** .02 .90 91.79** 19.55 <.001 75.92** .51 .48

ADHD Alcohol Nicotine 6.74 .009 ** 87.07 .29 .39 .59 .53 42.81 42.15* .03 .00 .87 .98 ** 89.72 50.93* .98 .19 .32 .66 ** 77.91 44.47* .01 .91 46.47* 1.68 4.91 .43 .03 ** 88.37 26.49 3.79 .65 .052 .42 ** 84.91 40.17 a 2.92 .09

Any disorder Addiction 11.15 .001 93.13** .11 .74 86.83** .07 .79 96.85** .04 .84 97.22** .02 .89 96.73** 1 .32 96.73** 11.97 .001 85.92** .99 .32

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I2 Clinical diagnosesb

Q(2)

92.19** 27.66

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7.17

33.93 Alleen structured

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64.32**

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74.93** .07

93.26** 17.97

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p <.001c .03c <.001 .11 .80 <.001 2 ** ** ** * ** I 72.66 85.17 73.74 59.78 68.63 83.88** Q(1) .16 .58 Comorbid p .69 .45 ODD/CD 2 * I 33.85 53.99 Note. Bold figures indicate significant results. Presence of dashes indicates analyses were not performed due to a limited number of data points. ADHD = attention-deficit/hyperactivity disorder; CD = conduct disorder; ODD = oppositional defiant disorder. a Only studies included with a DSM-based outcome measure. b A comparison between clinical diagnosis, structured interview-based diagnosis or questionnaire-based diagnosis. c Those studies including participants with a clinical diagnosis show higher effect sized compared to those with structured interview based diagnosis or questionnaire based diagnosis. * significant at p<.05, ** significant at p<.001

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Figure 2. Forest plots for addiction following childhood mental health disorders: a) attentiondeficit/hyperactivity disorder (ADHD); b) anxiety; c) conduct disorder; d) depression. Note: SUDs = substance use disorder.

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Additional records identified through other sources (n=2)

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Records identified through database searching (n=8,750) PubMed: 4,578 PsycInfo: 1,631 Embase: 2,541

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Studies included in qualitative synthesis (n=39)

Studies included in quantitative synthesis (meta-analysis) (N=37)

Full-text articles excluded, with reasons (n = 257) Wrong predictor (n=125) Wrong outcome (n=30) Age at diagnoses >18 (n=24) Conference paper (n=22) Before DSM-III-R (n=19) Dissertation (n=11) Same cohort but reporting on earlier follow-up (n=10) Publication in language other than English (n=7) No longitudinal design (n=6) Did not contain right data (n=3)

Articles excluded because the right data could not be provided (n=2)

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Supplement 1: Search terms Table S1. Definitions Table S2. Oppositional Defiant Disorder (ODD)/Conduct Disorder (CD) Comorbidity in the Attention-Deficit/Hyperactivity Disorder Sample Table S3. Studies Excluded After Full-Text With Reasons Figures S1-4. Forest plots for addiction following childhood mental health disorders Post hoc Figure S5. Forest plot for addiction following anxiety disorders, per disorder References

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1. Search Terms PubMed ((((("Substance-Related Disorders"[Mesh] OR Alcohol*[tiab] OR Nicotin*[tiab] OR smoking[tiab] OR tobacco*[tiab] OR cigarette*[tiab] OR marijuana*[tiab] OR cannabis*[tiab] OR cocaine*[tiab] OR substance use*[tiab] OR substance abuse*[tiab] OR substance induce*[tiab] OR substance addict*[tiab] OR drug use*[tiab] OR drug abuse*[tiab] OR drug induce*[tiab] OR drug addict*[tiab] OR drugs use*[tiab] OR drugs abuse*[tiab] OR drugs induce*[tiab] OR drugs addict*[tiab] OR Alcohol*[ot] OR Nicotin*[ot] OR smoking[ot] OR tobacco*[ot] OR cigarette*[ot] OR marijuana*[ot] OR cannabis*[ot] OR cocaine*[ot] OR substance use*[ot] OR substance abuse*[ot] OR substance induce*[ot] OR substance addict*[ot] OR drug use*[ot] OR drug abuse*[ot] OR drug induce*[ot] OR drug addict*[ot] OR drugs use*[ot] OR drugs abuse*[ot] OR drugs induce*[ot] OR drugs addict*[ot]) AND ("Mental Disorders Diagnosed in Childhood"[MeSH] OR "Anxiety Disorders"[Mesh] OR "Impulse Control Disorders"[Mesh] OR neurodevelopmental[tiab] OR ADHD[tiab] OR ADD[tiab] OR attention deficit*[tiab] OR hyperactiv*[tiab] OR hyperkinetic*[tiab] OR minimal brain deficit*[tiab] OR minimal brain dysfunction*[tiab] OR anxiet*[tiab] OR affective disorder*[tiab] OR affective psychos*[tiab] OR mood disorder*[tiab] OR psychotic depressi*[tiab] OR bipolar disorder*[tiab] OR depressive disorder*[tiab] OR depression*[tiab] OR fobia*[tiab] OR phobia*[tiab] OR phobic*[tiab] OR obsessive compulsive[tiab] OR Anankastic Personalit*[tiab] OR Pervasive developmental disorder*[tiab] OR Asperger*[tiab] OR PDD NOS[tiab] OR autism*[tiab] OR autist*[tiab] OR Conduct disorder*[tiab] OR Oppositional defiant disorder*[tiab] OR CD[tiab] OR ODD[tiab] OR Disruptive Behavio*[tiab] OR oppositional behavio*[tiab] OR conduct problems[tiab] OR Impulse Control Disorder*[tiab] OR Reading Disorder*[tiab] OR Language disorder*[tiab] OR learning disabilit*[tiab] OR learning disorder*[tiab] OR Dyslexia[tiab] OR Word Blindness*[tiab] OR dyscalculia[tiab] OR childhood-onset-fluency disorder*[tiab] OR stuttering[tiab] OR speech sound disorder*[tiab] OR communication disorder*[tiab] OR Developmental Coordination Disorder*[tiab] OR Motor Skills Disorder*[tiab] OR childhood dyspraxia[tiab] OR developmental disorder of motor function*[tiab] OR clumsy child syndrome*[tiab] OR motor development disorder*[tiab] OR Stereotypic Movement Disorder*[tiab] OR Body Rocking[tiab] OR Body-Focused Repetitive Behavio*[tiab] OR Head Banging[tiab] OR trichotillomania[tiab] OR Tic Disorder*[tiab] OR Tourette syndrome*[tiab] OR Gilles de la Tourette*[tiab] OR Childhood-Onset Schizophren*[tiab] OR Childhood Schizophren*[tiab] OR Childhood-Onset psychos*[tiab] OR childhood dissociative disorder*[tiab] OR neurodevelopmental[ot] OR ADHD[ot] OR ADD[ot] OR attention deficit*[ot] OR hyperactiv*[ot] OR hyperkinetic*[ot] OR minimal brain deficit*[ot] OR minimal brain dysfunction*[ot] OR anxiet*[ot] OR affective disorder*[ot] OR affective psychos*[ot] OR mood disorder*[ot] OR psychotic depressi*[ot] OR bipolar disorder*[ot] OR depressive disorder*[ot] OR depression*[ot] OR fobia*[ot] OR phobia*[ot] OR phobic*[ot] OR obsessive compulsive[ot] OR Anankastic Personalit*[ot] OR Pervasive developmental disorder*[ot] OR Asperger*[ot] OR PDD NOS[ot] OR autism*[ot] OR autist*[ot] OR Conduct disorder*[ot] OR Oppositional defiant disorder*[ot] OR CD[ot] OR ODD[ot] OR Disruptive Behavio*[ot] OR oppositional behavio*[ot] OR conduct problems[ot] OR Impulse Control Disorder*[ot] OR Reading disorder*[ot] OR language disorder*[ot] OR Word Blindness*[ot] OR learning disabilit*[ot] OR learning disorder*[ot] OR Dyslexia[ot] OR dyscalculia[ot] OR stuttering[ot] OR speech sound disorder*[ot] OR communication disorder*[ot] OR Developmental Coordination Disorder*[ot] OR Motor Skills Disorder*[ot] OR childhood dyspraxia[ot] OR developmental disorder of motor function*[ot] OR clumsy child

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syndrome*[ot] OR motor development disorder*[ot] OR Stereotypic Movement Disorder*[ot] OR Body Rocking[ot] OR Body-Focused Repetitive Behavio*[ot] OR Head Banging[ot] OR trichotillomania[ot] OR Tic Disorder*[ot] OR Tourette syndrome*[ot] OR Gilles de la Tourette*[ot] OR Childhood-Onset Schizophren*[ot] OR Childhood Schizophren*[ot] OR Childhood-Onset psychos*[ot] OR childhood dissociative disorder*[ot])) AND (child*[tw] OR schoolchild*[tw] OR infan*[tw] OR adolescen*[tw] OR pediatri*[tw] OR paediatr*[tw] OR boy[tw] OR boys[tw] OR boyhood[tw] OR girl[tw] OR girls[tw] OR girlhood[tw] OR youth[tw] OR youths[tw] OR teen[tw] OR teens[tw] OR teenager*[tw] OR puberty[tw] OR preschool*[tw] OR toddler*[tw] OR juvenile*[tw])) AND ("Cohort Studies"[Mesh] OR cohort analys*[tw] OR cohort design*[tw] OR cohort evaluation*[tw] OR cohort research[tw] OR cohort stud*[tw] OR cohort survey*[tw] OR longitudinal analys*[tw] OR longitudinal design*[tw] OR longitudinal evaluation*[tw] OR longitudinal research[tw] OR longitudinal stud*[tw] OR longitudinal survey*[tw] OR follow up evaluation*[tw] OR followup evaluation*[tw] OR followup stud*[tw] OR follow up stud*[tw] OR followup survey*[tw] OR follow up survey*[tw] OR prospective analys*[tw] OR prospective design*[tw] OR prospective evaluation*[tw] OR prospective stud*[tw] OR prospective survey*[tw] OR retrospective analys*[tw] OR retrospective design*[tw] OR retrospective evaluation*[tw] OR retrospective research[tw] OR retrospective stud*[tw] OR retrospective survey*[tw])) NOT ("Animals"[Mesh] NOT "Humans"[Mesh])) NOT ("addresses"[Publication Type] OR "biography"[Publication Type] OR "comment"[Publication Type] OR "directory"[Publication Type] OR "editorial"[Publication Type] OR "festschrift"[Publication Type] OR "interview"[Publication Type] OR "lectures"[Publication Type] OR "legal cases"[Publication Type] OR "legislation"[Publication Type] OR "letter"[Publication Type] OR "news"[Publication Type] OR "newspaper article"[Publication Type] OR "patient education handout"[Publication Type] OR "popular works"[Publication Type] OR "congresses"[Publication Type] OR "consensus development conference"[Publication Type] OR "consensus development conference, nih"[Publication Type] OR "practice guideline"[Publication Type])

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Severe and problematic nicotine use.

Drug- related disorder

Severe and problematic drug use.

Substance use disorders

Severe and problematic alcohol or drug use. This measure is used when studies do not make the distinction between alcohol and drug related disorders, but only describe “

Alcohol abuse, alcohol use disorder, alcohol dependence, frequent drunkenness, high frequent drinkers, problematic alcohol use, daily alcohol use, frequent alcohol use. Regular tobacco use, daily smoking, nicotine dependence, smoking dependence, smoking, regular smoking, nicotine abuse, cigarette smoking, Tobacco dependence, daily cigarette use Marijuana use disorder, drug dependence, cannabis abuse, marijuana abuse/dependence, other illicit drug abuse, daily marijuana use, cannabis use disorder Substance use disorder, drug and alcohol dependence

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Terms used in individual studies All of the terms described below, combined into a single measure per study

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Alcohol-related disorder

Definition An aggregated measure of addiction. For studies with one outcome measure this outcome was used as an addiction. If there were multiple outcomes in a study, an aggregated measure was calculated (i.e. addiction) using the method of Borenstein. Severe and problematic alcohol consumption.

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Term Addiction

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Table S2: Oppositional Defiant Disorder (ODD)/Conduct Disorder (CD) Comorbidity in the Attention-Deficit/Hyperactivity Disorder Sample Study (lead author and % of participants with year of publication) ODD/CD August et al. 2006 0 Babinsky et al. 2011 52.94 Biederman et al. 2006b MV Biederman et al. 2010 9.38 Biederman et al. 2012 7 Brook et al. 2008 50 Brook et al. 2010 37.5 Copeland et al 2009 MV Dalsgaard et al. 2014 42.3 Elkins et al. 2007 46.1 Fergusson et al. 2007 MV Groenman et al. 2013 34.4 Lambert et al. 2005 MV Milberger et al. 1997a MV Milberger et al. 1997b MV Milberger et al. 1997c 21.89 Molina& Pelham 2003 74.3 Sibley et al. 2014 59.3 Wittchen et al. 2007 MV Note. MV = missing value.

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Before DSM-III-R

(57-75)

Age of the mental health disorder was not in childhood (i.e. participants were over 18 at time of diagnosis)

(76-99)

Did not provide right data

(100-103)

Conference paper

(104-125)

(8, 163-286)

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Table S3. Studies Excluded After Full-Text With Reasons Reason Study Study design was not (40-45) retrospective of prospective longitudinal

Same cohort as included studies (n=10)

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Figure S1. Forest plots for addiction following childhood attention-deficit/hyperactivity disorder. 1a. Alcohol-related disorders

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Figure S3. Forest plots for addiction following childhood conduct disorder. 3a. Alcohol-related disorders

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Figure S4. Forest plots for addiction following childhood depression 4a. Alcohol-related disorders

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Meta Analysis Group by specific preditcor

Subgroup within study Study name

Outcome

Anxiety Anxiety Anxiety Anxiety Anxiety Anxiety Anxiety Anxiety Anxiety Generalized anxiety disorder Generalized anxiety disorder Generalized anxiety disorder PTSD PTSD Seperation anxiety Seperation anxiety Social anxiety Social anxiety Social anxiety

Anxiety Anxiety Anxiety Anxiety Anxiety Anxiety Anxiety Anxiety

Gau et al. 2007 SUDs Wittchen et al. 2007 Cannabis Use Disorder Essau et al. 2014 Addiction Gorka et al. 2014 Alcohol Use Disorder Johnson et al. 2000 Smoking Weissman et al. 1999 SUDs Wolitzky-Taylor et al. 2012SUDs Benjet et al.2016 SUDs

Anxiety Anxiety

Bittner et al. 2007 Copeland et al. 2009

SUDs SUDs

Anxiety

Cisler et al. 2011

Regular Smoking

Anxiety

Bruckl et al. 2007

Addiction

Anxiety Anxiety

Buckner et al. 2008 Frojd et al. 2011

Addiction Frequent Drunkness

Statistics for each study

Odds ratio and 95% CI

0,638 1,876 0,801 0,679 0,880 2,487 1,980 1,353 1,159 2,100 3,100 2,411 1,900 1,900 0,936 0,936 0,696 0,517 0,564

0,260 1,566 1,256 2,803 0,615 1,043 0,330 1,396 0,362 2,137 1,107 5,588 1,072 3,657 1,013 1,806 0,992 1,354 0,610 7,224 0,586 16,404 0,894 6,505 0,931 3,876 0,931 3,876 0,495 1,769 0,495 1,769 0,206 2,353 0,238 1,124 0,293 1,085

0,326 0,002 0,099 0,292 0,777 0,027 0,029 0,041 0,064 0,239 0,183 0,082 0,078 0,078 0,838 0,838 0,560 0,096 0,086

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1. August GJ, Winters KC, Realmuto GM, Fahnhorst T, Botzet A, Lee S. Prospective study of adolescent drug use among community samples of ADHD and non-ADHD participants. Journal of the American Academy of Child and Adolescent Psychiatry. 2006;45:824-832. 2. Babinski DE, Pelham Jr WE, Molina BSG, Gnagy EM, Waschbusch DA, Yu J, MacLean MG, Wymbs BT, Sibley MH, Biswas A, Robb JA, Karch KM. Late adolescent and young adult outcomes of girls diagnosed with ADHD in childhood: An exploratory investigation. Journal of attention disorders. 2011;15:204-214. 3. Benjet C, Borges G, Méndez E, Albor Y, Casanova L, Orozco R, Curiel T, Fleiz C, MedinaMora ME. Eight-year incidence of psychiatric disorders and service use from adolescence to early adulthood: Longitudinal follow-up of the Mexican Adolescent Mental Health Survey. European Child & Adolescent Psychiatry. 2016;25:163-173. 4. Biederman J, Monuteaux MC, Mick E, Spencer T, Wilens TE, Silva JM, Snyder LE, Faraone SV. Young adult outcome of attention deficit hyperactivity disorder: a controlled 10-year follow-up study. Psychological medicine. 2006;36:167-179. 5. Biederman J, Petty CR, Monuteaux MC, Fried R, Byrne D, Mirto T, Spence T, Wilens TE, Faraone SV. Adult psychiatric outcomes of girls with attention deficit hyperactivity disorder: 11-year follow-up in a longitudinal case-control study. American Journal of Psychiatry. 2010;167:409-417. 6. Bittner A, Egger HL, Erkanli A, Jane Costello E, Foley DL, Angold A. What do childhood anxiety disorders predict? Journal of child psychology and psychiatry, and allied disciplines. 2007;48:1174-1183. 7. Brook JS, Duan T, Zhang C, Cohen PR, Brook DW. The association between attention deficit hyperactivity disorder in adolescence and smoking in adulthood. The American journal on addictions / American Academy of Psychiatrists in Alcoholism and Addictions. 2008;17:54-59. 8. Brook DW, Brook JS, Zhang C, Koppel J. Association between attentiondeficit/hyperactivity disorder in adolescence and substance use disorders in adulthood. Archives of pediatrics & adolescent medicine. 2010;164:930-934. 9. Bruckl TM, Wittchen HU, Hofler M, Pfister H, Schneider S, Lieb R. Childhood separation anxiety and the risk of subsequent psychopathology: Results from a community study. Psychotherapy and psychosomatics. 2007;76:47-56. 10. Buckner JD, Schmidt NB, Lang AR, Small JW, Schlauch RC, Lewinsohn PM. Specificity of social anxiety disorder as a risk factor for alcohol and cannabis dependence. Journal of psychiatric research. 2008;42:230-239. 11. Cisler JM, Amstadter AB, Begle AM, Resnick HS, Danielson CK, Saunders BE, Kilpatrick DG. A prospective examination of the relationships between PTSD, exposure to assaultive violence, and cigarette smoking among a national sample of adolescents. Addictive behaviors. 2011;36:994-1000. 12. Copeland WE, Shanahan L, Costello J, Angold A. Childhood and adolescent psychiatric disorders as predictors of young adult disorders. Archives of General Psychiatry. 2009;66:764-772. 13. Dalsgaard S, Mortensen PB, Frydenberg M, Thomsen PH. ADHD, stimulant treatment in childhood and subsequent substance abuse in adulthood - a naturalistic long-term follow-up study. Addictive behaviors. 2014;39:325-328. 14. Elkins IJ, McGue M, Iacono WG. Prospective effects of attention-deficit/hyperactivity disorder, conduct disorder, and sex on adolescent substance use and abuse. Arch Gen Psychiatry. 2007;64:1145-1152.

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15. Essau CA, Lewinsohn PM, Olaya B, Seeley JR. Anxiety disorders in adolescents and psychosocial outcomes at age 30. Journal of affective disorders. 2014;163:125-132. 16. Fergusson DM, Horwood LJ, Ridder EM. Conduct and attentional problems in childhood and adolescence and later substance use, abuse and dependence: Results of a 25-year longitudinal study. Drug and Alcohol Dependence. 2007;88:S14-S26. 17. Frojd S, Ranta K, Kaltiala-Heino R, Marttunen M. Associations of social phobia and general anxiety with alcohol and drug use in a community sample of adolescents. Alcohol and Alcoholism. 2011;46:192-199. 18. Gau SSF, Chong MY, Yang P, Yen CF, Liang KY, Cheng ATA. Psychiatric and psychosocial predictors of substance use disorders among adolescents: Longitudinal study. British Journal of Psychiatry. 2007;190:42-48. 19. Goodman E, Capitman J. Depressive symptoms and cigarette smoking among teens. Pediatrics. 2000;106:748-755. 20. Gorka SM, Shankman SA, Olino TM, Seeley JR, Kosty DB, Lewinsohn PM. Anxiety disorders and risk for alcohol use disorders: the moderating effect of parental support. Drug Alcohol Depend. 2014;140:191-197. 21. Groenman AP, Oosterlaan J, Rommelse N, Franke B, Roeyers H, Oades RD, Sergeant JA, Buitelaar JK, Faraone SV. Substance use disorders in adolescents with attention deficit hyperactivity disorder: a 4-year follow-up study. Addiction (Abingdon, England). 2013;108:1503-1511. 22. Heron J, Maughan B, Dick DM, Kendler KS, Lewis G, Macleod J, Munafò M, Hickman M. Conduct problem trajectories and alcohol use and misuse in mid to late adolescence. Drug and Alcohol Dependence. 2013;133:100-107. 23. Johnson JG, Cohen P, Pine DS, Klein DF, Kasen S, Brook JS. Association between cigarette smoking and anxiety disorders during adolescence and early adulthood. Jama. 2000;284:2348-2351. 24. Kollins SH, McClernon FJ, Fuemmeler BF. Association between smoking and attentiondeficit/hyperactivity disorder symptoms in a population-based sample of young adults. Archives of General Psychiatry. 2005;62:1142-1147. 25. Lam TH, Stewart SM, Ho SY, Lai MK, Mak KH, Chau KV, Rao U, Salili F. Depressive symptoms and smoking among Hong Kong Chinese adolescents. Addiction. 2005;100:10031011. 26. Lambert N. The contribution of childhood ADHD, conduct problems, and stimulant treatment to adolescent and adult tobacco and psychoactive substance abuse. Ethical Human Psychology and Psychiatry. 2005;7:197-221. 27. Marmorstein NR, Iacono WG, Malone SM. Longitudinal associations between depression and substance dependence from adolescence through early adulthood. Drug Alcohol Depend. 2010;107:154-160. 28. McLeod GFH, Horwood LJ, Fergusson DM. Adolescent depression, adult mental health and psychosocial outcomes at 30 and 35 years. Psychological medicine. 2016;46:1401-1412. 29. Milberger S, Biederman J, Faraone SV, Wilens T, Chu MP. Associations between ADHD and psychoactive substance use disorders. Findings from a longitudinal study of high-risk siblings of ADHD children. The American journal on addictions / American Academy of Psychiatrists in Alcoholism and Addictions. 1997;6:318-329. 30. Milberger S, Biederman J, Faraone SV, Chen L, Jones J. Further evidence of an association between attention-deficit/hyperactivity disorder and cigarette smoking. Findings

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from a high-risk sample of siblings. The American journal on addictions / American Academy of Psychiatrists in Alcoholism and Addictions. 1997;6:205-217. 31. Milberger S, Biederman J, Faraone SV, Chen L, Jones J. ADHD is associated with early initiation of cigarette smoking in children and adolescents. Journal of the American Academy of Child and Adolescent Psychiatry. 1997;36:37-44. 32. Molina BSG, Pelham Jr WE. Childhood predictors of adolescent substance use in a longitudinal study of children with ADHD. Journal of Abnormal Psychology. 2003;112:497507. 33. Ottosen C, Petersen L, Larsen JT, Dalsgaard S. Gender differences in associations between attention-deficit/hyperactivity disorder and substance use disorder. Journal of the American Academy of Child & Adolescent Psychiatry. 2016;55:227-234. 34. Saraceno L, Heron J, Munafo M, Craddock N, van den Bree MB. The relationship between childhood depressive symptoms and problem alcohol use in early adolescence: findings from a large longitudinal population-based study. Addiction. 2012;107:567-577. 35. Sibley MH, Pelham WE, Molina BSG, Coxe S, Kipp H, Gnagy EM, Meinzer M, Megan Ross J, Lahey BB. The role of early childhood ADHD and subsequent CD in the initiation and escalation of adolescent cigarette, alcohol, and marijuana use. Journal of Abnormal Psychology. 2014;123:362-374. 36. Sihvola E, Rose RJ, Dick DM, Pulkkinen L, Marttunen M, Kaprio J. Early-onset depressive disorders predict the use of addictive substances in adolescence: A prospective study of adolescent Finnish twins. Addiction. 2008;103:2045-2053. 37. Weissman MM, Wolk S, Wickramaratne P, Goldstein RB, Adams P, Greenwald S, Ryan ND, Dahl RE, Steinberg D. Children with prepubertal-onset major depressive disorder and anxiety grown up. Arch Gen Psychiatry. 1999;56:794-801. 38. Wittchen H-U, Fröhlich C, Behrendt S, Günther A, Rehm J, Zimmermann P, Lieb R, Perkonigg A. Cannabis use and cannabis use disorders and their relationship to mental disorders: A 10-year prospective-longitudinal community study in adolescents. Drug and Alcohol Dependence. 2007;88:S60-S70. 39. Wolitzky-Taylor K, Bobova L, Zinbarg RE, Mineka S, Craske MG. Longitudinal investigation of the impact of anxiety and mood disorders in adolescence on subsequent substance use disorder onset and vice versa. Addictive behaviors. 2012;37:982-985. 40. De Alwis D, Lynskey MT, Reiersen AM, Agrawal A. Attention-deficit/hyperactivity disorder subtypes and substance use and use disorders in NESARC. Addict Behav. 2014;39:1278-1285. 41. Hammerness P, Joshi G, Doyle R, Georgiopoulos A, Geller D, Spencer T, Petty CR, Faraone SV, Biederman J. Do stimulants reduce the risk for cigarette smoking in youth with attention-deficit hyperactivity disorder? A prospective, long-term, open-label study of extended-release methylphenidate. Journal of Pediatrics. 2013;162:22-27e22. 42. Hesselbrock V, Hesselbrock M, Chan G, Colleagues COGA. Deviance proneness as a model of alcoholism risk. Alcohol and Alcoholism. 2011;46:i5. 43. Knop J, Penick EC, Nickel EJ, Mortensen EL, Sullivan MA, Murtaza S, Jensen P, Manzardo AM, Gabrielli Jr WF. Childhood ADHD and conduct disorder as independent predictors of male alcohol dependence at age 40. Journal of Studies on Alcohol and Drugs. 2009;70:169177. 44. Orvaschel H, Lewinsohn PM, Seeley JR. Continuity of psychopathology in a community sample of adolescents. J Am Acad Child Adolesc Psychiatry. 1995;34:1525-1535.

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