New Formulations of Methylphenidate for the Treatment of ...



Pharmacotherapy of emotional dysregulation in adults with ADHD: a systematic review and meta-analysis

Francesca Lenzi 1, Samuele Cortese 2,3, Joseph Harris 2, Gabriele Masi *1

1 IRCCS Stella Maris, Scientific Institute of Child Neurology and Psychiatry, Viale del Tirreno 331, 56128 Calambrone, Italy

2 Department of Psychology, Centre for Innovation in Mental Health, University of Southampton, Highfield Campus, Clinical and Experimental Sciences (CNS and Psychiatry) and Solent NHS Trust, Southampton, SO17 1BJ UK

3 New York University Child Study Center, One Park Ave, 7th floor, New York City, New York, 10016, USA

Address correspondence to:

Gabriele Masi, M.D.

IRCCS Stella Maris

Viale del Tirreno 331, 56025 Calambrone, Pisa, Italy

Fax: +39 050 886 326

E-mail: gabriele.masi@fsm.unipi.it

ABSTRACT

Emotional dysregulation (ED) is a dysfunction in modifying an emotional state in an adaptive and goal oriented way, with excitability, ease anger, and mood lability. It is present in up to 70% of adults with ADHD, regardless of other comorbidities, and substantially worsens the psychosocial outcomes of the disorder. Besides fronto-parietal circuits mediating top-down control, brain regions involved in bottom-up processes (e.g., amygdala, orbitofrontal cortex, and ventral striatum) are implicated in ED. We performed a systematic review/meta-analysis of double-blind randomized controlled trials of ADHD medications to assess their effects on ED in adults with ADHD. We searched an extensive set of databases, international trials registries, and contacted study authors/drug companies for unpublished data. We retained 21 trials. We found small-to-moderate effects (methylphenidate: SMD=0.34, 95%CI=0.23-0.45; atomoxetine: SMD=0.24, 95%CI=0.15-0.34; lisdexamfetamine: SMD=0.50, 95%CI=0.21-0.8). We suggest that, whilst ADHD medications are effective on ADHD core symptoms, they may be less effective on bottom-up mechanisms underlying ED. Further research on novel pharmacological and non-pharmacological strategies for ED in adults with ADHD is warranted. PROSPERO: CRD42017068426.

Keywords: ADHD; emotional dysregulation; stimulants; methylphenidate; atomoxetine; amphetamines, lisdexamfetamine.

1. INTRODUCTION

Attention-Deficit/Hyperactivity Disorder (ADHD) is defined by a cluster of age-inappropriate, persistent and impairing symptoms of inattention and/or hyperactivity/impulsivity (American Psychiatric Association, 2013). With an estimated worldwide prevalence of about 5% in school-aged children, ADHD is one of the most commonly diagnosed neuropsychiatric disorders in children (Polanczyk, Willcutt, Salum, Kieling, & Rohde, 2014). Whilst in the past ADHD was considered to remit after adolescence, available evidence shows that impairing symptoms of ADHD persist in up to 65% of cases in adulthood (Faraone, Biederman, & Mick, 2006), with an estimated pooled prevalence around 2.5% (Simon, Czobor, Balint, Meszaros, & Bitter, 2009). ADHD is associated with a huge societal and financial burden, with average annual incremental costs estimated at $143-$266 billion in the U.S. (Doshi et al., 2012) and substantial in other countries as well (e.g., Holden et al., 2013; Le et al., 2013).

In children, ADHD is often comorbid with other psychiatric conditions, such as oppositional defiant disorder (ODD)/conduct disorder (CD), specific learning disorders, mood and anxiety disorders, substance use disorder, and sleep disturbances (Faraone et al., 2015; Cortese et al., 2013a; Cortese, Konofal, & Lecendreux, 2008). Similar rates of comorbidities are reported in adult subjects with ADHD, with OR (95%CI) of 5 (3.0-8.2) for mood disorders, 3.7 (2.4-5.5) for anxiety disorders, 7.9 (2.3-27.3) for drug dependence, and 3.7 (2.2-6.2) for intermittent explosive disorder (Kessler et al., 2006).

Additionally, about 40% of children and 35-70% of adults with ADHD struggle with emotional regulation, regardless of other possible comorbidities (Shaw, Stringaris, Nigg, & Leibenluft, 2014). Emotional dysregulation can be defined as a dysfunction in modifying an emotional state in an adaptive and goal oriented way, resulting in individuals being easily excitable, quick to anger, and prone to intense mood lability (Shaw et al., 2014). This may lead to emotional expressions and experiences that are excessive in relation to social norms and context-inappropriate.

Although emotional dysregulation is not part of the current defining criteria for ADHD, mounting evidence from clinical, neuroimaging and genetic studies suggests that it should be considered as a pivotal component of ADHD (Retz, Stieglitz, Corbisiero, Retz-Junginger, & Rosler, 2012), at least in a subgroup of patients, as it contributes to the burden of ADHD, in terms of impairment on social and occupational functioning (Barkley & Murphy, 2010).

Indeed, since 1995, Wender included symptoms of emotional dysregulation in the Utah Criteria for the diagnosis of ADHD in adults (Wender, 1995). In the Wender’s construct, emotional dysregulation was defined as temper control, affective lability, and emotional over-reactivity. Temper control is associated with continuous irritability, diminished frustration tolerance, and emotional outbursts; affective lability is characterized by frequent and short changes from elevated to depressed or agitated moods, associated with discontent and boredom; emotional overactivity is described as frequent outbursts and excessive emotional reaction in response to everyday stresses. In a more recent paper, Drs. Reimherr, Marchant and colleagues from the Wender’s group noted that the symptoms of hyperactivity, impulsivity and emotional dysregulation were almost always superimposed upon those of inattentiveness (Reimherr, Marchant, Gift, Steans, & Wender, 2015). Besides Wender's construct, other concepts of adult ADHD take into account the emotional experience of ADHD as an additional core component (Brown, 1996; Conners, Erhard, & Sparrow, 1999; Barkley & Murphy, 2006). It has been showed that emotional dysregulation in ADHD is nearly as important in terms of emotional lability and greater in terms of emotional responsiveness than in adult patients with Bipolar Disorder (Richard-Lepouriel et al., 2016).

From a genetic standpoint, preliminary evidence suggests that individuals with ADHD and emotional dysregulation may represent a distinct genetic group, with siblings of probands with ADHD and emotional dysregulation also displaying increased rates of ADHD and emotional lability symptoms, although evidence from other studies is mixed (Shaw et al., 2014). As for the pathophysiological mechanisms underlying emotional dysregulation, two hypotheses have been proposed. According to what Posner and colleagues (Posner, Kass, & Hulvershorn, 2014) termed the “dyscontrol hypothesis”, emotional dysregulation in ADHD arises from impairments in executive dysfunctions in ADHD. More specifically, deficits in top-down inhibitory processes, which are found in a sizeable portion of individuals with ADHD, would lead to abnormal emotional reactions, whilst emotional processing per se would be largely normal. The concept propose by Barkley of deficit of “emotional self regulation” should be considered within this model (Barkley & Murphy, 2010). Alternatively, the affectivity hypothesis posits that emotional processing per se is abnormal, due to dysfunctions in bottom up circuits, encompassing the amygdala, the orbitofrontal cortex, and the ventral striatum, that processes emotional stimuli.

The recommended multimodal treatment of ADHD includes pharmacological and non-pharmacological interventions. Medications for ADHD include psychostimulants (i.e., methylphenidate (MPH) and amphetamines), indicated as first pharmacological choice in some guidelines in adults (e.g., the NICE guidelines, 2014), and non-psychostimulant drugs (e.g., atomoxetine, clonidine, and guanfacine, among others) (Cortese et al., 2013b). A large body of evidence, summarized in several meta-analyses of randomised controlled trials (RCTs), shows that psychostimulants and, to a less degree, non psychostimulants are efficacious, at least in the short and medium term, to control core symptoms of ADHD, in children (Banaschewski et al., 2016) as well as in adults (De Crescenzo, Cortese, Adamo, & Janiri, 2016). Regarding the efficacy of stimulant and non stimulant medications in the management of emotional dysregulation of adults with ADHD, preliminary evidence suggests that both methylphenidate (Reimherr et al., 2007; Retz et al., 2012; Rosler et al., 2010) and atomoxetine (Brown et al., 2011) may be effective for emotional dysregulation but without effect on real comorbid affective conditions (anxiety, depression).

A systematic review/meta-analysis by Moukhtarian et al. (Moukhtarian, Cooper, Vassos, Moran, & Asherson, 2017) included nine double-blind RCTs published up to June 10th, 2015 and found that, taken together, stimulants and atomoxetine had a moderate effect size (SMD=-0.41, 95% CI:-0.57 to -0.25) terms of improvement of emotional dysregulation. The present systematic review/meta-analysis extends in important ways the previous one by Moukhtarian et al. (Moukhtarian et al., 2017), including more than double number of RCTs, unpublished data gathered by study authors or drug companies, and, importantly, presenting effect sizes separately for each ADHD medication. We focused on RCTs of any ADHD medication in adults with ADHD including emotional dysregulation as an outcome.

2. METHODS

The protocol for the present systematic review/meta-analysis is registered on the International Prospective Register of Systematic Reviews PROSPERO (, protocol number: CRD42017068426). Methods were developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Liberati et al., 2009) recommendations. The PRISMA checklist is reported in the Supplemental Material 1. Data were extracted from the published report (journal article) of the study, or, when not available in the published report, from other sources (e.g., or clinical study report (CSR) retrieved via the drug company website) or were provided by the authors/drug company.

2.1 Types of participants

2.1.1 Inclusion criteria

We retained studies including adults (≥ 18 years) meeting DSM-III, III-R, IV, IV-TR or 5 criteria for ADHD or ICD-10 criteria for Hyperkinetic Disorder, regardless of subtype/presentation, gender, IQ and psychiatric or neurological comorbidities. However, we did not retain the study if participants were pharmacologically or non-pharmacologically treated for these comorbidities in addition to the pharmacological treatment of ADHD.

2.1.2 Exclusion criteria

We excluded studies where participants presented with ADHD symptoms above a specific cut-off in ADHD scales, without meeting formal criteria for ADHD as per DSM or ICD criteria.

2.2 Pharmacological treatments

Studies assessing the following medications (oral or transdermal) were retained: methylphenidate, dexmethylphenidate, amphetamines (including lisdexamfetamine), atomoxetine, clonidine, guanfacine, bupropion, modafinil and any antidepressant. We retained studies in which any of these compounds was compared to placebo. We discarded studies with other types of comparator, such as waiting list. We also excluded studies in which any of these medications was compared to any other, without a placebo. Additionally, we discarded studies in which any of these medications was combined to another medication, since, due to drug interactions, it is not possible to determine if the effects on the outcome of interest would be accounted for by the drug of interest or by the association of the two drugs. Furthermore, for similar reasons, we excluded studies where the active medication was administered along with a structured psychotherapy. Whilst previous meta-analyses have included studies with treatment duration of 1 day (e.g., Storebo et al., 2015), we deemed that treatment effects would not be appreciable in less than 1 week, so we retained only studies lasting at least 1 week. In case of papers reporting outcomes at more than one time point, we considered the time point closest to the majority of those in the other studies. When papers reported values for different doses of the same compound, we pooled the values (means and standard deviation), before meta-analysing them.

2.3 Types of studies

2.3.1 Inclusion criteria

We retained only double-blinded RCTs. Both parallel and cross-over designs were included. However, due to possible concerns around carry over effects in cross-over studies without wash out between pre and post cross-over phases, we planned a sensitivity analysis removing cross-over studies without between-phases wash out.

2.3.2 Exclusion criteria

We excluded single blind or open label trials, as well as trials with no appropriate randomization (e.g., quasi randomized).

2.4 Outcome

The outcome for the meta-analysis was the efficacy (as continuous measure, derived from mean and standard deviation) of study drug on emotional dysregulation measured with a validated questionnaire specifically focusing on any aspect related to emotion dysregulation. In case of publications reporting only the total score of a scale including subscales with measures of emotional dysregulation, we contacted the study authors or the drug company manufacturing the compound, to gather relevant data (means and standard deviations) for the present meta-analysis. As per protocol, we planned to conduct separate analyses including outcomes rated by the clinician/investigator, informant and self reported, respectively. However, since this was not feasible due to the heterogeneity of the type of rater across studies, as per protocol, we followed this hierarchy in the selection of the rater: when available, we used outcomes rated by the investigator; if these were not available, we used self-reported measures; finally, if outcomes rated by the investigator or self reported were not available, we used measures provided by a third informant. Indeed, we considered the investigator-rated measure as the most reliable. As for self-reported vs. measures provided by a third informant, we deemed that the patients themselves would be more reliable than a third informant to describe their symptoms of emotional dysregulation.

2.5 Search strategy

We first performed a targeted search in Pubmed, Ovid MEDLINE®, Biological Abstracts®, EMBASE Classic+EMBASE, PsycINFO, BIOSIS Previews, Web of Knowledge/Thomas Reuters databases, from inception to April 1st, 2017, with no language restrictions. The search syntax and strategy were adapted for each database (see Supplemental Material 2).

Additionally, we searched the WHO International Clinical Trials Registry Platform, that includes international trials registries such as (2016), to retrieve possible additional pertinent unpublished studies. To reduce the likelihood of missing relevant studies, we also scanned the references of 63 meta-analyses on pharmacological treatments for ADHD (see Supplemental Material 3). We finally scanned references of retrieved pertinent papers and proceedings of relevant conferences to find additional relevant studies. Further details are reported in the Supplemental Material.

2.6 Study Selection

Retrieved references were independently screened and blindly double-coded for eligibility by two study authors. Any disagreement was resolved by a senior author. If needed, study authors were contacted to gather missing/additional information.

2.7 Study bias assessment

Study quality was assessed independently by pairs of raters from the authorship group using the Cochrane Risk of Bias (RoB) (Cochrane Group 2015). RoB domains included: selection bias, performance bias, detection bias, attrition bias, and other bias. Any disagreement was resolved through consensus.

2.8 Data Extraction and Statistical Analysis

Trial information was entered into RevMan 5.3 (2015). Data extraction was independently performed and cross-checked by two authors. We contacted study authors/drug companies to gather useful unpublished data. Standardized Mean Difference (SMD) was calculated as mean pre- to post-treatment change in the intervention group minus the mean pre- to post treatment change in the control group, divided by the pooled pre-test standard deviation with a bias adjustment. SMDs for each trial were combined using the inverse variance method. Given the inherent heterogeneity of studies, random effects models were used. The I2 statistic was calculated to estimate between-trial SMD heterogeneity. Publication bias was assessed with funnel plots and the Egger’s test Analyses were conducted using RevMan 5.3 (2015) and Comprehensive Meta-Analysis (). We planned to conduct separate meta-analyses for each class of medications. Retrieved data allowed performing three separate meta-analyses, for methylphenidate, atomoxetine, and lisdexamfetamine, respectively. Since we found only one study for bupropion, one for duloxetine and none for the other compounds (see below for details), we did not perform additional meta-analyses for these compounds.

2. RESULTS

3.1 Search

From a pool of 410 potentially relevant references, we retained 23 studies (Adler et al., 2014; Adler et al., 2013; Adler, Clemow, Williams, & Durell, 2014; Biederman et al., 2011; Bilodeau et al., 2014; Brown et al., 2011; DuPaul et al., 2012; Goto et al., 2017; Jain et al., 2007; Marchant, Reimherr, Robison, Olsen, & Kondo, 2011; Medori et al., 2008; Philipsen et al., 2015; Reimherr, Hedges, Strong, Marchant, & Williams, 2005; Reimherr et al., 2007; Retz et al., 2012; Robison et al., 2008; Rosler et al., 2010; Tenenbaum, Paull, Sparrow, Dodd, & Green, 2002; Waxmonsky et al., 2014; Wender, Reimherr, Wood, & Ward, 1985; Wender et al., 2011; Wigal, Wigal, Childress, Donnelly, & Reiz, 2016; Goodman et al., 2017) for the qualitative review and 21 studies (Adler et al., 2014; Adler et al., 2013; Adler et al., 2014; Biederman et al., 2011; Brown et al., 2011; DuPaul et al., 2012; Goto et al., 2017; Jain et al., 2007; Marchant et al., 2011; Medori et al., 2008; Philipsen et al., 2015; Reimherr et al., 2007; Retz et al., 2012; Robison et al., 2008; Rosler et al., 2010; Tenenbaum et al., 2002; Waxmonsky et al., 2014; Wender et al., 1985; Wender et al., 2011; Wigal et al., 2016; Goodman et al., 2017) for the meta-analysis. Figure 1 reports the PRISMA flowchart detailing the screening process. Supplemental Table 1 reports the list of studies retained for the qualitative review and meta-analysis, with their related references. Supplemental Table 2 reports the references discarded, after reading the full text, with reasons for exclusion.

3.2 Characteristics of included studies

Table 1 reports the characteristics of the studies included in the qualitative systematic review and in the meta-analysis. As shown in the table, 13 trials (Biederman et al., 2011; Jain et al., 2007; Marchant et al., 2011; Medori et al., 2008; Philipsen et al., 2015; Reimherr et al., 2007; Retz et al., 2012; Rosler et al., 2010; Tenenbaum et al., 2002; Wender et al., 1985; Wender et al., 2011; Wigal et al., 2016; Goodman et al., 2017) were available for the meta-analysis of the effects of methylphenidate, four of which (Jain et al., 2007; Marchant et al., 2011; Reimherr et al., 2007; Wender et al., 2011) were cross-over trials without washout between phases. Five studies (Adler et al., 2014; Adler et al., 2014; Brown et al., 2011; Goto et al., 2017; Robison et al., 2008) were available for the meta-analysis on atomoxetine, none of which was a cross-over trial. Three studies (Adler et al., 2013; DuPaul et al., 2012; Waxmonsky et al., 2014) were available for lisdexamfetamine. Finally, one trial on bupropion (Reimherr et al., 2005) and another one on duloxetine (Bilodeau et al., 2014) were found, but not meta-analyzed. The duration of the studies was generally 12 weeks or less, with only one study lasting 24 weeks. As shown in Table 1, each of the included study reported only one or two types of raters (self, clinician/investigator, or observer), so that it was not possible to perform separate analyses by type of rater. As such, we followed the above mentioned hierarchy in the selection of the rater as per our pre-registered protocol.

Supplemental Table 3 reports the characteristics of the scales, measuring emotional dysregulation, included in the retained studies. As it appears clear from the table, the constructs related to ED as defined across these tools are not fully overlapping.

3.3 Results of the meta-analyses

The results of the meta-analysis are reported in Figures 2, 3, and 4. The meta-analysis of the 13 methylphenidate studies (Biederman et al., 2011; Jain et al., 2007; Marchant et al., 2011; Medori et al., 2008; Philipsen et al., 2015; Reimherr et al., 2007; Retz et al., 2012; Rosler et al., 2010; Tenenbaum et al., 2002; Wender et al., 1985; Wender et al., 2011; Wigal et al., 2016; Goodman et al., 2017) showed that MPH was significantly more efficacious, compared to placebo, in reducing the severity of emotional dysregulation symptoms, with small-to-medium effect size (SMD=0.34, 95%CI= 0.23-0.45) and moderate heterogeneity across studies (I2= 34%) (Figure 2). In the sensitivity analysis removing the four cross-over studies without between phases placebo (Jain et al., 2007; Marchant et al., 2011; Reimherr et al., 2007; Wender et al., 2011), results were basically unchanged (SMD=0.30, 95%CI= 0.18-0.42, I2 =40%).

The meta-analysis of the five trials on atomoxetine (Adler et al., 2014; Adler et al., 2014; Brown et al., 2011; Goto et al., 2017; Robison et al., 2008) showed a low effect size (SMD=0.24, 95%CI= 0.15-0.34), with no heterogeneity (I2 =0%) (Figure 3).

Finally, the meta-analysis of the three lisdexamfetamine studies (Adler et al., 2013; DuPaul et al., 2012; Waxmonsky et al., 2014) showed a small-to-medium ES (SMD= 0.34, 95%CI= 0.12-0.55, with moderate heterogeneity, I2= 37%) (Figure 4), which increased to a moderate ES (SMD=0.50, 95%CI=0.21-0.8) when removing the only cross-over study (DuPaul et al., 2012).

3.4 Assessment of the risk of bias

As reported in the Supplemental Figures 1 and 2, whilst none of the items of the RoB was rated as high risk in any of the studies, all the items (with the exception of incomplete outcome, which was rated as low risk in more then 50% of the studies) were rated as unclear in the majority of the studies, mainly due to insufficient reporting.

5. Publication bias

The funnel plots (Supplemental figures 3-5), along with the results of the Egger’s test

(Methylphenidate: Intercept: 0.07; SE: 1.05; t-value: 0.07; p value (2-tailed): 0.94; Atomoxetine: Intercept: -0.07; SE: 2.30; t-value: 0.30; p value (2-tailed): 0.78; Lisdexamfetamine: Intercept: -1.71; SE: 0.34; t-value: 5.03; p value (2-tailed): 0.12), were not suggestive of publication bias.

3.6 Unplanned analysis

Supplemental material 4 reports the correlation between ESs of efficacy on ADHD core symptoms and ESs of efficacy on ED, for MPH, ATX and LIS, separately. This analysis was not planned in our protocol but was performed post hoc because it may be informative to interpret our results. We did not find any significant correlation for any drug.

3. DISCUSSION

To our knowledge, this is the first systematic review and meta-analysis of double-blind RCTs exploring the individual efficacy of the most common ADHD medications for emotional dysregulation in adults with ADHD. Available data allowed us to perform three separate meta-analyses: one for methylphenidate, one for atomoxetine, and one for lisdexamfetamine.

All the three meta-analyses revealed that the active compound was significantly more efficacious than placebo in reducing the severity of investigator-rated or self-reported symptoms of emotional dysregulation. However, the effect sizes were small-to-medium, and generally lower than the effect sizes found in previous meta-analyses for the three compounds in reducing core symptoms (i.e., inattention, hyperactivity and impulsivity) of ADHD. As for methylphenidate, the meta-analysis by Castells et al. (Castells et al., 2011) reported a mean ES ~ 0.60. Concerning atomoxetine, the average ES found across studies was ~ 0.47 (De Crescenzo et al., 2016). Finally, lisdexamfetamine has been found associated with the highest ES (~1.1) (De Crescenzo et al., 2016). Therefore, while our results show that psychostimulants and atomoxetine may decrease emotional dysregulation in adults with ADHD, the magnitude of their effect is lower than that found for ADHD core symptoms. Based on our meta-analyses, the ES for lisdexamfetamine was higher than that for methylphenidate, which, in turns, was slightly higher than the ES for atomoxetine. However, we would discourage from building on our results to rank the efficacy of the three compounds in terms of effects on emotional dysregulation, which would require head-to-head trials and, ideally, a network meta-analysis pooling direct and indirect evidence. We note that, after omitting the only cross-over study (DuPaul et al., 2012) the ES for lisdexamfetamine was moderate, rather than small. Due to the limited number of studies (n=3, and n=2 when removing the only cross-over study), it is possible that this is just a casual finding. However we note that, in general, ES estimated with the CAARS were lower than those derived with other scales (e.g., WRAADDS), so another possibility is that the use of the CAARS in the DuPaul et al. study may have contributed to lower ES in this study.

Although our study was not designed to specifically test pathophysiological hypotheses on emotional dysregulation in adults with ADHD, our results do provide evidence which is useful to consider when interpreting current pathophysiological models of emotional dysregulation ADHD. As mentioned in the introduction, two alternative models have been proposed (Posner et al., 2014). According to the first one, emotional dysregulation is considered as an expression of abnormal top-down control due to executive dysfunctions that have been classically described in ADHD. Such executive dysfunctions, also termed “cool” executive dysfunctions, encompass inhibition and working memory. The alternative model posits that emotional dysregulation is accounted for by abnormalities in bottom-up processes related to “hot” executive dysfunctions underpinned by fronto-limbic networks. Our results would suggest that, whilst ADHD drugs effectively act on top-down circuits, they are less effective on bottom-up processes or, alternatively, that only bottom-up circuits are involved in emotional dysregulation in ADHD and ADHD drugs have only partially effective actions on bottom-up networks. The lack of significant correlation between ESs of efficacy on ADHD core symptoms and ESs of efficacy on ED supports a possible dissociation between mechanisms underpinning ADHD core symptoms and those underling ED. To address these hypotheses, future studies specifically testing the action of ADHD medications on circuits underpinning hot executive functions are needed.

Emotional dysregulation is a possible component in different psychiatric disorders, including affective and behavioural disorders, and all these disorders may be comorbid with ADHD (Henry et al., 2012). Further studies should control whether emotional dysregulation can be better interpreted as a transdiagnostic dimension, rather than focusing on symptom-based definitions of a specific disorder (Broome, He, Iftikhar, Eyden, & Marwaha, 2015). These studies should test the efficacy of a specific treatment (i.e., stimulant medications) on emotional dysregulation, in terms of effect sizes, irrespective of the specific psychiatric diagnosis.

Regarding possible clinical implications of our results in the management of ADHD patients, the question is whether ADHD drugs should be used as the first option to improve emotional symptoms, instead of other medications such as antidepressants and/or mood stabilizers, especially when emotional symptoms are particularly relevant. The effect sizes of ADHD drugs on emotional dysregulation are lower than those reported in other studies, and lower that those found on core ADHD symptoms. However, it is not clear whether other medications, such as antidepressants or mood stabilizers, may be more effective in controlling emotional dysregulation within the ADHD realm. Furthermore, considering the (low) effect sizes of these medications on low-intensity emotional symptoms (Fournier et al., 2010), as well as their potential side effects (including irritability or suicidality), it may be argued that the first option should be to explore possible effectiveness of ADHD drugs. Further studies may explore whether adjustments in dosing may improve the efficacy of ADHD drugs on emotional symptoms, or whether other variables (age, gender, ADHD presentation) may affect the clinical response.

Our results should be considered in the light of the strengths and limitations of our study. As for the strengths, we endeavoured to perform a comprehensive and systematic search in several databases, with no language restrictions, as well as in a large number of international trial registries. Of note, we contacted study authors and drug companies to gather additional unpublished data. Another strength is the inclusion of double blind RCT only, which increases the quality of the included studies and reduces the possible bias of non blinded or single blind trials. There are a number of limitations that should be taken into account. First, whilst emotional dysregulation is independent from other comorbidity, arguably its severity may be impacted by comorbid mood disorders. Because individual studies did not provide separate data on comorbid and comorbidity free individuals, we could not assess the impact of comorbidity on the response to the medication. Therefore, future studies should include subgroup analyses limited to comorbidity free participants or focus on specific populations (e.g., adults with ADHD and comorbid depressive disorder). Second, due to the paucity of data, we could not perform separate meta-analyses considering outcomes rated by the investigator, by a third informant and self-rated, respectively. However, considering the effect sizes from individual studies according to the type of rater, we would predict that the results would not substantially change across different raters. We would recommend for future studies to include as many different raters as possible. Third, we could not perform analyses focusing on the subtype (or presentation) of ADHD since individual studies did not provide separate data according to the type (presentation) of ADHD. For the same reason, we were unable to perform separate analyses according to the gender. Therefore, we would encourage future studies to report separate data according to gender, ADHD presentation, and main comorbidities. Fourth, although the scales used in the retained studies all tapped to emotional dysregulation, they focused on different aspects of this construct. More specifically, whilst the BRIEF-A and BADDS consider the neuropsychological aspects of emotional dysregulation related to executive functioning, the CAARS and WRAADS focus on the behavioural aspects of emotional dysregulation symptoms. Arguably, a larger body of evidence will allow to meta-analyze studies using the same scale. Future studies including both scales measuring behavioral and those tapping neuropsychological aspects of ES would be suitable. Furthermore, we note that some aspects related to emotional dysregulation and impulsivity, such as impulsive sexual thoughts, are not taken into account in the available scales. Fifth, as for all meta-analyses, the quality of the present meta-analyses relied on the quality of the individual studies. However, whilst there were several items of the RoB (the state of the art tool to rate possible bias of RCT) that were unclear, in no instance there were items rated at high risk of bias. Finally, heterogeneity in the baseline severity of ED symptoms across studies may limit the treatment effect calculation.

In addition to providing meta-analytic evidence on the effect of ADHD medications on emotional dysregulation, our study suggests future avenues of research in the field. First, as shown by the large number (N=65) of trials that we discarded due to the lack of pertinent outcomes, only a minority of trials so far in adult ADHD had measures of emotional dysregulation, which calls for more studies in the future including outcomes related to emotional dysregulation. Perhaps more importantly, the limited efficacy of available pharmacological treatments calls for additional research on novel compounds and for studies assessing non-pharmacological interventions, as well as multimodal treatment strategies encompassing pharmacological and non-pharmacological strategies aimed at effectively controlling emotional dysregulation in adults with ADHD.

ACKNOWLEDGMENTS

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

We acknowledge Medice, Janssen, Lilly and Dr. Marchant for providing additional unpublished data.

DECLARATION OF CONFLICTS OF INTEREST

Drs. Lenzi and Cortese and Mr. Harris declare no conflicts of interest. Dr. Masi was on the advisory boards for Eli Lilly, Shire, and Angelini; has received research grants from Eli Lilly and Shire; and has been a speaker for Eli Lilly, Shire, Lundbeck, and Otsuka.

References

Adler, L., Tanaka, Y., Williams, D., Trzepacz, P. T., Goto, T., Allen, A. J. et al. (2014). Executive function in adults with attention-deficit/hyperactivity disorder during treatment with atomoxetine in a randomized, placebo-controlled, withdrawal study. J.Clin.Psychopharmacol., 34, 461-466.

Adler, L. A., Clemow, D. B., Williams, D. W., & Durell, T. M. (2014). Atomoxetine effects on executive function as measured by the BRIEF--a in young adults with ADHD: a randomized, double-blind, placebo-controlled study. PLoS.One., 9, e104175.

Adler, L. A., Dirks, B., Deas, P. F., Raychaudhuri, A., Dauphin, M. R., Lasser, R. A. et al. (2013). Lisdexamfetamine dimesylate in adults with attention-deficit/ hyperactivity disorder who report clinically significant impairment in executive function: results from a randomized, double-blind, placebo-controlled study. J.Clin.Psychiatry, 74, 694-702.

American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, DSM-5. American Psychiatric Publishing ed.

Banaschewski, T., Buitelaar, J., Chui, C. S., Coghill, D., Cortese, S., Simonoff, E. et al. (2016). Methylphenidate for ADHD in children and adolescents: throwing the baby out with the bathwater. Evid.Based Ment.Health, 19, 97-99.

Barkley, R. & Murphy, K. (2006). Identifying new symptoms for diagnosing ADHD in adulthood. ADHD Report 14, 7-11.

Barkley, R. & Murphy, K. (2010). Deficient emotional self-regulation in adults with attention-deficit/hyperactivity disorder ADHD: the relative contributions of emotional impulsiveness and ADHD symptoms to adaptive impairments in major life activities. J ADHD Relat Disord. 4, 5-28.

Biederman, J., Mick, E., Fried, R., Wilner, N., Spencer, T. J., & Faraone, S. V. (2011). Are stimulants effective in the treatment of executive function deficits? Results from a randomized double blind study of OROS-methylphenidate in adults with ADHD. Eur.Neuropsychopharmacol., 21, 508-515.

Bilodeau, M., Simon, T., Beauchamp, M. H., Lesperance, P., Dubreucq, S., Doree, J. P. et al. (2014). Duloxetine in adults with ADHD: a randomized, placebo-controlled pilot study. J.Atten.Disord., 18, 169-175.

Broome, M. R., He, Z., Iftikhar, M., Eyden, J., & Marwaha, S. (2015). Neurobiological and behavioural studies of affective instability in clinical populations: a systematic review. Neurosci.Biobehav.Rev., 51, 243-254.

Brown, T. E., Holdnack, J., Saylor, K., Adler, L., Spencer, T., Williams, D. W. et al. (2011). Effect of atomoxetine on executive function impairments in adults with ADHD. J.Atten.Disord., 15, 130-138.

Brown, T. (1996). Brown attention deficit disorder scales. San Antonio: The Psychological Corporation.

Castells, X., Ramos-Quiroga, J. A., Rigau, D., Bosch, R., Nogueira, M., Vidal, X. et al. (2011). Efficacy of methylphenidate for adults with attention-deficit hyperactivity disorder: a meta-regression analysis. CNS.Drugs, 25, 157-169.

Conners, C., Erhard, D., & Sparrow, D. (1999). Conners' Adult ADHD Rating Scales (CAARS). New York: Multi-Healt System.

Cortese, S., Brown, T. E., Corkum, P., Gruber, R., O'Brien, L. M., Stein, M. et al. (2013a). Assessment and management of sleep problems in youths with attention-deficit/hyperactivity disorder. J.Am.Acad.Child Adolesc.Psychiatry, 52, 784-796.

Cortese, S., Holtmann, M., Banaschewski, T., Buitelaar, J., Coghill, D., Danckaerts, M. et al. (2013b). Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents. J.Child Psychol.Psychiatry, 54, 227-246.

Cortese, S., Konofal, E., & Lecendreux, M. (2008). Alertness and feeding behaviors in ADHD: does the hypocretin/orexin system play a role? Med.Hypotheses, 71, 770-775.

De Crescenzo, F., Cortese, S., Adamo, N., & Janiri, L. (2017). Pharmacological and non-pharmacological treatment of adults with ADHD: a meta-review. Evid Based Ment Health, 20, 4-11.

Doshi, J. A., Hodgkins, P., Kahle, J., Sikirica, V., Cangelosi, M. J., Setyawan, J. et al. (2012). Economic impact of childhood and adult attention-deficit/hyperactivity disorder in the United States. J.Am.Acad.Child Adolesc.Psychiatry, 51, 990-1002.

DuPaul, G. J., Weyandt, L. L., Rossi, J. S., Vilardo, B. A., O'Dell, S. M., Carson, K. M. et al. (2012). Double-blind, placebo-controlled, crossover study of the efficacy and safety of lisdexamfetamine dimesylate in college students with ADHD. J.Atten.Disord., 16, 202-220.

Faraone, S. V., Biederman, J., & Mick, E. (2006). The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychol.Med., 36, 159-165.

Faraone, S., Asherson, P., Banaschewski, T., Biederman, J., Buitelaar, J., Ramos-Quiroga, J. et al. (2015). Attention-Deficit/Hyperactivity Disorder. Nature Reviews: Disease Primers, 1:15020 .

Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C. et al. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA, 303, 47-53.

Goodman, D. W., Starr, H. L., Ma, Y. W., Rostain, A. L., Ascher, S., & Armstrong, R. B. (2017). Randomized, 6-Week, Placebo-Controlled Study of Treatment for Adult Attention-Deficit/Hyperactivity Disorder: Individualized Dosing of Osmotic-Release Oral System (OROS) Methylphenidate With a Goal of Symptom Remission. J.Clin.Psychiatry, 78, 105-114.

Goto, T., Hirata, Y., Takita, Y., Trzepacz, P. T., Allen, A. J., Song, D. H. et al. (2017). Efficacy and Safety of Atomoxetine Hydrochloride in Asian Adults With ADHD. J.Atten.Disord., 21, 100-109.

Henry, C., Phillips, M., Leibenluft, E., M'Bailara, K., Houenou, J., & Leboyer, M. (2012). Emotional dysfunction as a marker of bipolar disorders. Front Biosci.(Elite.Ed), 4, 2722-2730.

Holden, S. E., Jenkins-Jones, S., Poole, C. D., Morgan, C. L., Coghill, D., & Currie, C. J. (2013). The prevalence and incidence, resource use and financial costs of treating people with attention deficit/hyperactivity disorder (ADHD) in the United Kingdom (1998 to 2010). Child Adolesc.Psychiatry Ment.Health, 7, 34.

Jain, U., Hechtman, L., Weiss, M., Ahmed, T. S., Reiz, J. L., Donnelly, G. A. et al. (2007). Efficacy of a novel biphasic controlled-release methylphenidate formula in adults with attention-deficit/hyperactivity disorder: results of a double-blind, placebo-controlled crossover study. J.Clin.Psychiatry, 68, 268-277.

Kessler, R. C., Adler, L., Barkley, R., Biederman, J., Conners, C. K., Demler, O. et al. (2006). The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am.J.Psychiatry, 163, 716-723.

Le, H. H., Hodgkins, P., Postma, M. J., Kahle, J., Sikirica, V., Setyawan, J. et al. (2014). Economic impact of childhood/adolescent ADHD in a European setting: the Netherlands as a reference case. Eur.Child Adolesc.Psychiatry., 23, 587-598.

Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gotzsche, P. C., Ioannidis, J. P. et al. (2009). The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ, 339, b2700.

Marchant, B. K., Reimherr, F. W., Robison, R. J., Olsen, J. L., & Kondo, D. G. (2011). Methylphenidate transdermal system in adult ADHD and impact on emotional and oppositional symptoms. J.Atten.Disord., 15, 295-304.

Medori, R., Ramos-Quiroga, J. A., Casas, M., Kooij, J. J., Niemela, A., Trott, G. E. et al. (2008). A randomized, placebo-controlled trial of three fixed dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol.Psychiatry, 63, 981-989.

Moukhtarian, T. R., Cooper, R. E., Vassos, E., Moran, P., & Asherson, P. (2017). Effects of stimulants and atomoxetine on emotional lability in adults: A systematic review and meta-analysis. Eur.Psychiatry, 44, 198-207.

National Institute for Health and Care Excellence (2008). Attention deficit

hyperactivity disorder CG72 .

Philipsen, A., Jans, T., Graf, E., Matthies, S., Borel, P., Colla, M. et al. (2015). Effects of Group Psychotherapy, Individual Counseling, Methylphenidate, and Placebo in the Treatment of Adult Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial. JAMA Psychiatry, 72, 1199-1210.

Polanczyk, G. V., Willcutt, E. G., Salum, G. A., Kieling, C., & Rohde, L. A. (2014). ADHD prevalence estimates across three decades: an updated systematic review and meta-regression analysis. Int.J.Epidemio, 43, 434-42.

Posner, J., Kass, E., & Hulvershorn, L. (2014). Using stimulants to treat ADHD-related emotional lability. Curr.Psychiatry Rep., 16, 478.

Reimherr, F. W., Hedges, D. W., Strong, R. E., Marchant, B. K., & Williams, E. D. (2005). Bupropion SR in adults with ADHD: a short-term, placebo-controlled trial. Neuropsychiatr.Dis.Treat., 1, 245-251.

Reimherr, F. W., Marchant, B. K., Gift, T. E., Steans, T. A., & Wender, P. H. (2015). Types of adult attention-deficit hyperactivity disorder (ADHD): baseline characteristics, initial response, and long-term response to treatment with methylphenidate. Atten.Defic.Hyperact.Disord., 7, 115-128.

Reimherr, F. W., Williams, E. D., Strong, R. E., Mestas, R., Soni, P., & Marchant, B. K. (2007). A double-blind, placebo-controlled, crossover study of osmotic release oral system methylphenidate in adults with ADHD with assessment of oppositional and emotional dimensions of the disorder. J.Clin.Psychiatry, 68, 93-101.

Retz, W., Rosler, M., Ose, C., Scherag, A., Alm, B., Philipsen, A. et al. (2012). Multiscale assessment of treatment efficacy in adults with ADHD: a randomized placebo-controlled, multi-centre study with extended-release methylphenidate. World J.Biol.Psychiatry, 13, 48-59.

Retz, W., Stieglitz, R. D., Corbisiero, S., Retz-Junginger, P., & Rosler, M. (2012). Emotional dysregulation in adult ADHD: What is the empirical evidence? Expert.Rev.Neurother., 12, 1241-1251.

Richard-Lepouriel, H., Etain, B., Hasler, R., Bellivier, F., Gard, S., Kahn, J. P. et al. (2016). Similarities between emotional dysregulation in adults suffering from ADHD and bipolar patients. J.Affect.Disord., 198, 230-236.

Robison, R. J., Reimherr, F. W., Marchant, B. K., Faraone, S. V., Adler, L. A., & West, S. A. (2008). Gender differences in 2 clinical trials of adults with attention-deficit/hyperactivity disorder: a retrospective data analysis. J.Clin.Psychiatry, 69, 213-221.

Rosler, M., Retz, W., Fischer, R., Ose, C., Alm, B., Deckert, J. et al. (2010). Twenty-four-week treatment with extended release methylphenidate improves emotional symptoms in adult ADHD. World J.Biol.Psychiatry, 11, 709-718.

Shaw, P., Stringaris, A., Nigg, J., & Leibenluft, E. (2014). Emotion dysregulation in attention deficit hyperactivity disorder. Am.J.Psychiatry, 171, 276-293.

Simon, V., Czobor, P., Balint, S., Meszaros, A., & Bitter, I. (2009). Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis. Br.J.Psychiatry, 194, 204-211.

Storebo, O. J., Ramstad, E., Krogh, H. B., Nilausen, T. D., Skoog, M., Holmskov, M. et al. (2015). Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane.Database.Syst.Rev., 11, CD009885.

Tenenbaum, S., Paull, J. C., Sparrow, E. P., Dodd, D. K., & Green, L. (2002). An experimental comparison of Pycnogenol and methylphenidate in adults with Attention-Deficit/Hyperactivity Disorder (ADHD). J.Atten.Disord., 6, 49-60.

Waxmonsky, J. G., Waschbusch, D. A., Babinski, D. E., Humphrey, H. H., Alfonso, A., Crum, K. I. et al. (2014). Does pharmacological treatment of ADHD in adults enhance parenting performance? Results of a double-blind randomized trial. CNS.Drugs, 28, 665-677.

Wender, P. H., Reimherr, F. W., Marchant, B. K., Sanford, M. E., Czajkowski, L. A., & Tomb, D. A. (2011). A one year trial of methylphenidate in the treatment of ADHD. J.Atten.Disord., 15, 36-45.

Wender, P. H., Reimherr, F. W., Wood, D., & Ward, M. (1985). A controlled study of methylphenidate in the treatment of attention deficit disorder, residual type, in adults. Am.J.Psychiatry, 142, 547-552.

Wender, P. (1995). Attention deficit hyperactivity disorder in adults. University Press: Oxford.

Wigal, S. B., Wigal, T., Childress, A., Donnelly, G. A., & Reiz, J. L. (2016). The Time Course of Effect of Multilayer-Release Methylphenidate Hydrochloride Capsules: A Randomized, Double-Blind Study of Adults With ADHD in a Simulated Adult Workplace Environment. J.Atten.Disord., pii: 1087054716672335

Table 1. Characteristics of the studies retained in the qualitative systematic review and in the meta-analysis.

First author (year)

Trial registration number |Medication |Max dose intended |N randomized |% males |Length (week) |Age (mean, SD or age range) |Diagn. criteria |Design |Validated relevant scales and subscales | |Adler (2013)

NCT01101022 |LIS vs. PBO |70 mg/day |LIS 79

PBO 80 |LIS 50.6%

PBO 53.8% |10 weeks |18-55

LIS 34.2 (10.58)

PBO 34.9 (11.02) |DSM-IV- TR |Parallel

|BRIEF-A (self-report):

-Emotional control subscale | |Adler (2014) a

NCT00510276

LILLY-B4Z-US-LYDZ |ATX vs. PBO |50 mg bid |ATX 220

PBO 225 | ATX 58.2%

|12 weeks |18-30

Males ATX 128 (58.2)

Males PBO 127 (56.4) |DSM-IV- TR |Parallel |BRIEF-A (self-report):

-Emotional Control

| |Adler (2014) b

NCT00700427

|ATX vs. PBO |100 mg/day |ATX 266

PBO 258 |ATX 56.8%

PBO 60.1% |25 weeks |ATX 33.7 (9.5)

PBO 32.4 (9.2) |DSM-IV- TR |Parallel |BRIEF-A (self-report; informant):

-Emotional Control

| |Biederman (2011)

NCT00181571 |OROS-MPH vs. PBO |84.6±31.6 mg/day |MPH 40

PBO 47 |52%

|6 weeks |19–60 |DSM-IV |Parallel |BRIEF-A (self-report):

-Emotional Control

subscale | |Bilodeau (2014)

NCT0094069 |Duloxetine vs. PBO |60 mg/day |Duloxetine 9

PBO 15 |Duloxetine 44%

Placebo 73%

|6 weeks |Duloxetine 35.7(8.6)

PBO 31.7(9.1) |DSM-IV- TR |Parallel |CAARS (self-report)

-impulsivity/ emotional lability

| |Brown (2011)

NCT00190736

LILLY-B4Z-US-LYCU

|ATX vs. PBO |100 mg/day |ATX 250

PBO 251 |50% |6 month |ATX

37.7 (10.4)

PBO

37.4 (9.9) |DSM-IV- TR |Parallel

|BADDS (Brown Attention Deficit Disorder Scale, self-rated)

-emotion cluster

| |DuPaul (2012) |LIS vs. PBO |70 mg/day |50 |ADHD 62.5%

Controls 54%

|16 weeks |ADHD

20.17 (1.20)

Controls

20 (1.17) |DSM-IV- TR |Cross-over |CAARS (self-report)

-impulsivity/ emotional lability (Used in this meta-analysis)

BRIEF-A (self-report):

-Emotional Control

subscale

| |Goodman (2017) |MPH OROS vs.

PBO |72 mg/day |MPH OROS 178

PBO 179 |MPH OROS 51%

PBO

55% |6 weeks |MPH OROS 36.8 (11.9)

PBO 34.7 (11.6) |DSM-IV |Parallel |BRIEF-A (self-reported)

Behaviour control

(Data provided by Janssen) | |Goto (2017)

|ATX vs. PBO |80 mg/day |ATX 193

PBO 195 |ATX 46.6%

PBO 48.7% |10 weeks |ATX 32.8 (8.1) PBO 31.7 (7.8) |DSM-IV- TR |Parallel |BRIEF-A (self-report and informant):

-Behavioral regulation index (BRI) | |Jain (2007)

|MPH vs.

PBO |80 mg/day |39 |59%

|5 weeks |18-60

|DSM-IV |Cross-over |CAARS (self-report; observer)

-impulsivity/ emotional lability | |Marchant (2011)

|MPH vs.

PBO |30 mg/day |65 |ADHD alone 81% |8 weeks |18-65 |DSM-IV-TR |Cross-over |WRAADDS (investigator rated; self reported) emotional dysregulation

| |Medori (2008)

|MPH vs.

PBO |18 mg, 36 mg, or 72 mg/day |MPH 18 mg/day 101

MPH36 mg/day 102

MPH72 mg/day 102

PBO 96

|54.4 % |5 weeks |18 – 63 |DSM-IV |Parallel |CAARS (self-report)

-impulsivity/ emotional lability

| |Philipsen (2015)

ISRCTN54096201 |MPH vs.

PBO |60 mg/day |433 (total number of randomized subjects)

107: clinical management +PBO

110: clinical management + MPH |43.5% |12 weeks |18-58 |DSM-IV |Parallel |CAARS (observer rated)

-impulsivity/ emotional lability

| |Reimherr (2005)

|Bup vs.

PBO |400 mg/day |35 BUP

24 PBO |72.8% |6 weeks |34.4 (13.4)

|DSM-IV |Parallel |WRAADDS (investigator) emotional dysregulation

(data provided by authors)

| |Reimherr (2007)

|MPH vs.

PBO |90 mg/day

|47 |27.6% |8 weeks |30.6 (10.8) |DSM-IV |Cross-over |WRAADDS (investigator) emotional dysregulation

| |Retz (2012)

NCT00730249 |MPH vs.PBO |40,

60, 80 and 120 mg/ day | ER-MPH 84

PBO 78 |ER-MPH 38%

PBO 56% |8 weeks |ER-MPH

36.6 (10.4)

PBO 38.2 (9.9) |DSM-IV |Parallel |WRAADDS (investigator)

Data on emotional dysregulation subscale

provided by Medice

| |Robison (2008)

LILLY-B4Z-MC-LYAA(2556) (study 1)

and   

LILLY-B4Z-MC-LYAO (study 2)

|ATX vs.

PBO |90 mg/day |ATX 257

PBO 258 |66% |10 weeks |Study I:

PBO 40.3 (11.6)

ATX 40.2 (11.7)

Study II:

PBO 41.2 (11.2) ATX 43.0 (10.3)

|DSM-IV |Parallel |WRAADDS (investigator) emotional dysregulation

| |Rosler (2010)

NCT00619840 |MPH vs.

PBO |60 mg/day |ER-MPH 241

PBO 118 |ER-MPH 50%

PBO 50% |24 weeks |ER-MPH

35.2 (10.1)

PBO

33.8 (10.6) |DSM-IV |Parallel |CAARS (self-report)

-impulsivity/ emotional lability (used in this meta-analysis)

WRAADDS clinician | |Tenenbaum (2002) |MPH vs.

PBO |15 mg/day |85 |Data missing |12 weeks (3 weeks per drug and one week washout per drug) |24-53 |DSM-IV |Cross-over with washout |BADDS (Brown Attention Deficit Disorder Scale) (self and other)

- Affect scale | |Waxmonsky (2014)

NCT01127607

|LIS vs.

PBO |70 mg/day |LIS 14

PBO 14 |LIS 42%

PBO 55% |4 weeks |40.7 (5.5) |DSM-IV |Cross-over with washout |BADDS (Brown Attention Deficit Disorder Scale) (self)

- Affect scale (in ) | |Wender (2011) |MPH vs.

PBO |60 mg/day |116 |Data missing |4-6 weeks |36.9 (8.5) |DSM-IV |Cross-over |WRAADDS (investigator) emotional overreactivity

| |Wender (1985)

|MPH vs.

PBO |90 mg/day |37 |54% |2 weeks

|31.1 (6.7) |Utah criteria |Cross-over with washout |Physician’s target symptoms rating (investigator)

-anger | |Wigal (2016)

NCT02225639 |PRC 063 (multilayer-release MPH) vs.

PBO |100 mg/day |59

|35.6% |2 weeks |18-60

32.2 (11.06)

|DSM-5 |Cross-over with washout |CAARS (self-report)

impulsivity/ emotional lability

| |

Abbreviations (in alphabetical order): ATX: Atomoxetine; BUP: Bupropion; ER-MPH: Methylphenidate extended release; LIS: Lisdexamfetamine; MPH: Methylphenidate; PBO: Placebo.

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