Efficacy of atomoxetine in the treatment of attention-deficit hyperactivity disorder in patients with common comorbidities in children,adolescents and adults: a review

Abstract

Attention-deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed mental health disorders and is associated with higher incidence of comorbid oppositional or conduct, mood, anxiety, pervasive developmental, and substance-use disorders. Comorbid mental health conditions may alter the presence of symptoms and treatment of ADHD. Atomoxetine (ATX), a nonstimulant medication for the treatment of ADHD, may be prescribed for individuals with ADHD and comorbid conditions despite some risk for certain undesirable side effects and lower effectiveness for the treatment of ADHD than stimulants. In this paper, we review studies utilizing randomized, placebo-controlled trials (RCTs) as well as within-subject designs to determine the effectiveness of ATX in the treatment of children and adults with ADHD and comorbid conditions. The current review uses an expanded methodology beyond systematic review of randomized controlled trials in order to improve generalizability of results to real-world practice. A total of 24 articles published from 2007 to 2015 were reviewed, including 14 RCTs: n = 1348 ATX, and n = 832 placebo. The majority of studies show that ATX is effective in the treatment of ADHD symptoms for individuals with ADHD and comorbid disorders. Cohen’s d effect sizes (ES) for improvement in ADHD symptoms and behaviors range from 0.47 to 2.21. The effectiveness of ATX to improve symptoms specific to comorbidity varied by type but appeared to be most effective for diminishing the presence of symptoms for those with comorbid anxiety, ES range of 0.40 to 1.51, and oppositional defiant disorder, ES range of 0.52 to 1.10. There are mixed or limited results for individuals with ADHD and comorbid substance-use disorders, autism spectrum disorders, dyslexia or reading disorder, depression, bipolar disorder, and Tourette syndrome. Results from this review suggest that ATX is effective in the treatment of some youth and adults with ADHD and comorbid disorders, and may be a treatment option in these patients.

Keywords

ADHD adults atomoxetine attention deficit attention deficit with hyperactivity children and youth comorbidity psychopharmacology review

Introduction

Attention-deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed behavioral health disorders with a lifetime prevalence rate of 8.1% [Kessler et al. 2005b], although rates vary from 13% of men to 5% of women [Holland and Riley, 2014]. Current rates of ADHD are 5.5–9.3% in children [US CDC, 2010] and 4% in adults [Kessler et al. 2006]. Prevalence of ADHD is lower in some countries, possibly due to underdiagnosing [Štuhec et al. 2015c]. ADHD is a neuropsychiatric disorder diagnosed by the presence of inattention with or without hyperactivity and impulsivity for at least 6 months with functional impairment in at least two settings, for example, school, home, or community, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5^th edition [APA, 2013]. Thus, information about a child’s behavior, collected from direct caregivers as well as from sources outside the home is valuable in aiding diagnosis and monitoring response to treatment [Shier et al. 2013].

ADHD is associated with disruptive, mood, anxiety, eating, and substance-abuse disorders [Shier et al. 2013]. Greater severity in the manifestation of symptoms associated with ADHD has been observed for individuals with ADHD and comorbid mental health, substance use, and other developmental disorders [Biederman et al. 2007; Kuhne et al. 1997]. The most common comorbidity with ADHD is oppositional defiant disorder (ODD) with or without comorbid conduct disorder, occurring in 30–67% of youth with ADHD [Steinhausen et al. 2006]. Other comorbidity has been well documented. Rates for comorbid autism spectrum disorder are 20–50% [Rommelse et al. 2010]; major depressive disorder (MDD), 9–38%, bipolar disorder, 10–11%, anxiety/social anxiety disorder, 20–40%, and substance-use disorder (SUD), 15–30% [Anderson et al. 1987; Chang et al. 2009; Kessler et al. 2006; Kunwar et al. 2007].

Stimulants are considered first-line pharmacological agents for the treatment of ADHD as approved by the US Food and Drug Administration. The most common side effects of stimulants include decreased appetite, insomnia, stomach ache, and headache [Handen et al. 2000]. Stimulant medication for treatment of ADHD is associated with several undesirable effects, including increased risk of growth retardation in weight and height in children, tics, increases in blood pressure, and abuse or misuse [Cortese et al. 2013; Katragadda and Schubiner, 2007; Spencer et al. 2008]. Nonstimulant medication, such as atomoxetine (ATX) is a selective presynaptic norepinephrine reuptake inhibitor approved by the US Food and Drug Administration for the treatment of ADHD in children and adults. ATX is the most commonly prescribed nonstimulant medication for the treatment of ADHD and prescribing rates for ATX have significantly increased in some countries over the past decade [Dalsgaard et al. 2013]. ATX is recommended as monotherapy for the treatment of ADHD for youth who do not respond well to stimulants [Pliszka et al. 2006; Shier et al. 2013], followed by buproprion, clonidine, or guanfacine [American Academy of Pediatrics, 2011; Pliszka et al. 2006]. The British Association of Psychopharmacology recommends a similar prescribing practice for adults [Bolea-Alamañac et al. 2014]. Since pharmacotherapy algorithms dictate starting with stimulants first, high rates of ATX observed in the population, concomitant with lower rates of stimulants may indicate inappropriate monotherapy prescribing [Garbe et al. 2012; Štuhec et al. 2015a] since the majority of youth are adequately treated by stimulants. For example, in an observational study of over seven million youth in Germany, only 2% of those prescribed a stimulant medication switched to ATX within the 2-year study period [Garbe et al. 2012]. In another study, only 43% of stimulant nonresponders improved with ATX [Newcorn et al. 2008].

ATX may be prescribed in lieu of stimulants for individuals with ADHD and comorbidity because stimulants may increase symptoms, intensified by comorbid conditions including tics, mania, and suicidal ideation [Garnock-Jones and Keating, 2009; Gerhard et al. 2010; Reichart and Nolan, 2004]. ATX is also commonly believed to have little potential for abuse [Heil et al. 2002]. Nonstimulant medications are less efficacious for the treatment of ADHD; Cohen’s d effect size (ES) for ATX is 0.6–0.7 [Faraone, 2009; Štuhec et al. 2015b; Wigal, 2009] compared with immediate-release stimulants, 0.8–0.99, and long-acting with or without osmotic-release oral-delivery stimulants, 0.8–0.95 [Faraone, 2009; Štuhec et al. 2015b]. Another long-acting stimulant, lisdexamfetamine, was found to have ESs ranging 1.28–1.58 [Faraone, 2009; Štuhec et al. 2015b]. ESs display a similar pattern in adults as published in several reviews or meta-analyses: 0.33–0.40 for ATX [Cunill et al. 2013]; 0.57–0.72 for immediate-release or noncontinuous stimulants [Castells et al. 2011; Epstein et al. 2014]; and 0.85–1.14 for lisdexamfetamine [Maneeton et al. 2014]. Thus, a diminished impact on ADHD symptoms may be expected for individuals receiving nonstimulant versus stimulant medication therapy. Commonly reported side effects of ATX include nausea, decreased appetite, insomnia, dry mouth, irritability, dizziness, and dyspepsia [Durrell et al. 2013]. ATX may be associated with increased risk of suicide behavior in youth [Bangs et al. 2005] and cardiovascular adverse effects [Cortese et al. 2013; Peterson et al. 2008; Štuhec and Švab, 2013]. Warnings from the manufacturer of Strattera ^TM (ATX) [Eli Lilly, 2015] include suicidal ideation, liver injury, severe cardiac events, and worsening of blood pressure and heart rate. Nevertheless, nonstimulant medication may be a first-line treatment for individuals with comorbidity [Hah and Chang, 2005; Shier et al. 2013].

Due to the high prevalence of ADHD and ADHD with comorbid conditions, and the increasing rate of ATX in treatment, a review of published literature on the efficacy of ATX in youth and adults with ADHD and comorbid conditions is warranted. The current investigation reviews the effectiveness of ATX in youth and adults with ADHD and comorbid conditions. Effectiveness is determined by impact of treatment to decrease symptoms of both ADHD and the comorbid condition. This review builds on previous work by Dell’Agnello and colleagues [Dell’Agnello et al. 2009b] by reviewing studies utilizing within-subject designs in addition to randomized controlled trials (RCTs), many of which are industry sponsored. A review and search strategy more inclusive of various study designs may help in generalizability of results to real-world practice. We also make recent the current knowledge of this area over the 9 years that ATX has been in practice, since the publication of any previous review of the efficacy of ATX in individuals with ADHD and common comorbidities.

Methods

An a priori search strategy was developed to identify all studies on the efficacy of ATX in youth and adults with ADHD and comorbid conditions. An online search was conducted in early October 2015 using OVID and PsycINFO from the University of Pittsburgh Health Services Library System. Search terms included the MeSH subheading, attention deficit with hyperactivity, in addition to search terms, attention deficit and ADHD and all variations of these search terms. This resulted in 27,973 unduplicated studies. Search terms for medication included ATX or Strattera^TM (which yielded no additional studies than ATX alone). This resulted in 1179 studies. Combination of ADHD terms with ATX yielded 924 studies. Studies were not eliminated based on design; therefore, no search term was added to specify certain research designs, such as RCTs. Studies were limited to English language, human or humans, and publication years 2007–2015. Duplicates were removed. The resulting search yielded 566 studies.

Titles with or without abstracts were reviewed for relevance and eliminated. Full text for remaining articles were reviewed for final inclusion. Review articles were scanned for relevant publications. Any referenced article in an included study that appeared to be relevant to the topic was reviewed. Finally, the table of contents for the last 5 years of the two journals with the most articles referenced were scanned for relevant articles. Information was abstracted from each article around publication, sample characteristics, dosage, comorbidity, efficacy measures and results. ES was calculated where possible by computing the standardized mean difference as the difference between ATX and placebo (PBO) or difference between final assessment and baseline for within-subject designs divided by the pooled standard deviation. Because studies including research designs in addition to RCT were included, all studies were assessed for quality and given a score based on a 5-point system, including a point for each factor: use of a double-blind RCT design; all diagnoses determined through the Diagnostic and Statistical Manual for Mental Health Disorders or International Classification of Diseases; specification of an intent-to-treat analysis, or last-observation-carried-forward analysis; reporting of ES or data reported so that ES can be computed; adequate description of sample characteristics and measures to support replication. Thus, studies that may introduce bias by not utilizing a blinded, RCT design, excluded participants from final assessment, omitted raw outcome values, permitted adjunctive medication treatment, or did not specify how diagnoses were determined or adequately described participants were included in the review but received lower quality scores. These studies are provided as additional, albeit limited, evidence for effectiveness. Quality scores range from 0 to 5.

Results

Studies were eliminated because they did not include ATX, did not include ADHD, did not include a comorbid condition, were animal studies, or were studies of prescribing practice and not of efficacy, for example, method of action, potential for abuse, or cost. In addition, studies with pregnancy as the comorbid condition were excluded. A total of 477 studies were eliminated by title or abstract. The full text of 89 articles was reviewed and 65 articles were eliminated; 40 studies were excluded for the reasons above, 22 were review articles, and three studies were duplicates. In the final review, 24 articles were included. Of these, 14 studies were RCTs utilizing ATX versus PBO and 10 studies utilized a within-subject design. Nine within-subject studies were prospective, utilizing a pretreatment initiation phase as baseline, and one study was retrospective, in which the baseline period was derived from a previous treatment episode for individuals included in the sample. Further details on the design of each study are outlined below.

Resulting studies include comorbidities in the following areas: SUD [Wilens et al. 2008; Benegal et al. 2013; Thurstone et al. 2010], anxiety disorders [Geller et al. 2007; Adler et al. 2009; Gabriel and Violato, 2011], autism spectrum disorders [Gabriel and Violoto, 2011; Harfterkamp et al. 2012, 2013, 2014; Zeiner et al. 2011; Charnsil, 2011; Fernández-Jaén et al. 2011; Handen et al. 2015]; oppositional defiant disorder [Holzer et al. 2013; Bangs et al. 2008; Dell’Agnello et al. 2009; Dittmann et al. 2011], major depressive disorder [Bangs et al. 2007], bipolar disorder [Chang et al. 2009], dyslexia or reading disorder [Shaywitz et al. 2014; Wietecha et al. 2013; deJong et al. 2009], and Tourette syndrome [Gilbert et al. 2007; Spencer et al. 2008]. A summary of studies is listed in Table 1, including study design, sample size, comorbidity, average age, % of sample that was male, starting ATX dose and maximum ATX dose, trial duration, outcome measure to assess ADHD symptoms, outcome measure to assess symptoms of the comorbid condition, ESs, and quality score. Total sample sizes across comorbid conditions were 1348 ATX and 832 PBO. The majority of studies, 20 of 24, were in children or adolescents. The smallest study included 14 individuals and the largest study included 171 individuals receiving ATX. Male sex is associated with higher prevalence of ADHD [Biederman and Faraone, 2005] and thus, the participant samples included in all but one study are predominantly male. The proportion of male participants in the reviewed studies ranged 30–100%. ATX trial length varied from 4 to 20 weeks. Fourteen studies were conducted in the US and Canada, one in India, one in Thailand, one in Germany, one in Norway, one in Italy, one in Spain, and four in the Netherlands. Unless indicated, the majority of studies excluded participants with psychosis, SUD, major depressive disorder, schizophrenia, bipolar disorder or any other behavioral health condition that could not permit a medication-free, or clean period prior to study participation, or those having a condition requiring ongoing treatment that may confound results. Other comorbid behavioral health conditions not listed above were generally not used as exclusion criteria while physical health conditions such as cardiovascular and seizure disorders were used as exclusion criteria in the majority of the studies. Quality scores ranged 2–5; 58% of the studies had a 4 or 5 quality score. Review of treatment efficacy in individuals with ADHD with comorbidity.

Table 1.

Study characteristics and effect sizes.

Study	Design;n (ATX)n (PBO)	Comorbidity	Patient age; % male	ATX dose;trial length (weeks)	ADHD measure	Effect size	Comorbid condition measure	Effect size	Quality score
Charnsil [2011]	WS n = 12	ASD	10 yrs; 66.7%	0.25–1.2 mg/kg per day; 10 weeks	None		ABC	ns	2
Fernández-Jaén et al. [2011]	WSn = 24	ASD	8 yrs;58.0%	0.4–1.2 mg/kg per day;16 weeks	ADHDRS-IVParentTeacher	1.27^* 0.73^*	CGI-S	1.18^*	3
Handen et al. [2015]	RCTParalleln = 32n = 32	ASD	8 yrs; 85.2%	0.3–1.8 mg/kg per day;10 weeks	SNAP-ADHD	0.80	ABC	ns	5
Harfterkamp et al. [2012]	RCTn = 48n = 49	ASD	10 yrs; 87.6%	1.2 mg/kg per day;8 weeks	ADHDRS-IV	0.87*	None		3
Harfterkamp et al. [2013]	WSn = 88	ASD	10 yrs; 86.4%	1.2 mg/kg per day;20 weeks	ADHDRS-IV	1.54^*	None		3
Harfterkamp et al. [2014]	RCTn = 48n + 49	ASD	10 yrs; 85.6%	1.2 mg/kg per day;8 weeks	None		ABC CSBQ	0.50^* 0.40^*	4
Zeiner et al. [2011]	WSn = 14	ASD	11 yrs; 100%	0.5–1.4 mg/kg per day;10 weeks	ADHDRS-IVParentTeacher	1.32^* 0.54^*	None		3
Bangs et al. [2008]	RCTn = 156n = 70	ODD	9 yrs; 93.4%	0.8–1.2 mg/kg per day;8 weeks	SNAP-IVcombinedinattentive ; hyper/impul	0.52^* 0.52^* 0.44^*	SNAP-IV-ODD	ns	5
Dell’Agnello et al. [2009]	RCTn = 105n = 32	ODD	9 yrs; 92.9%	0.5–1.4 mg/kg per day;8 weeks	SNAP-IV ADHD	0.91^*	SNAP-IV-ODD	0.52^*	5
Dittmann et al. [2011]	RCTn = 121n = 59	ODD	11 yrs; 84.4%	1.2 mg/kg per day;9 weeks	SNAP-IV ADHD	0.72	SNAP-IV-ODD	0.69	5
Holzer et al. [2013]	WSn = 11	ODD	13 yrs; 90.9%	ATX: 0.46–1.8 mg/kg per day + OLZ: 0.02–0.09 mg/kg per day;10 weeks	ADHDRS-IV	1.81^*	MOAS	1.10^*	3
Adler et al. [2009]	RCTn = 171n = 158	Anxiety	38.0 yrs; 53.6%	40–100 mg per day;14 weeks	CAARS	0.47	LSAS	0.40	5
Gabriel andViolato, [2011]	WSn = 29	Anxiety	38 yrs; 30%	80 mg per day;12 weeks	CGI-SASRS	1.43^* 1.28^*	HAM-A	1.51^*	4
Geller et al. [2007]	RCTn = 87n = 89	Anxiety	12 yrs; 62.5%	0.8–1.8 mg/kg per day;12 weeks	ADHDRS-IV	1.0	PARS	0.50	4
Bangs et al. [2007]	RCTn = 72n = 70	MDD	14 yrs; 73.2%	1.2–1.8 mg/kg per day;9 weeks	ADHDRS-IV	0.84	CDRS-R	ns	5
Chang et al. [2009]	WSn = 12	Bipolar	11 yrs; 58.3%	0.5–1.2 mg/kg per day;8 weeks	ADHDRS-IV	2.18	YMRS CDRS-R	ns ns	3
Benegal et al. [2013]	WS retrospectiven = 18	SUD	27 yrs; 100%	Up to 50 mg per day + TAU;7–52 weeks,average = 17 weeks	ASRS	2.21^*	Maximum abstinent (days)	2.09^*	2
Thurstone et al. [2010]	RCTn = 35n = 35	SUD	16 yrs; 78.6%	0.5–1.5 mg/kg per day; older or heavier = 50–100 mg per day;12 weeks	ADHD checklist	ns	No. days using substance in past 28	ns	5
Wilens et al. [2008]	RCTn = 72n = 75	SUD (alcohol)	34 yrs; 85.0%	25–100 mg per day;12 weeks	AISRS	0.48	Drinks per day	ns	4
Gilbert et al. [2007]	WSn = 14	Tourette Syndrome	12 yrs;Unknown	0.8–1.5 mg/kg per day;4 weeks	ADHDRS-IV	1.17*	SICI	n.s.	3
Spencer et al. [2008]	RCTn = 61n = 56	Tourette syndrome	11 yrs; 87.2%	0.5–1.5 mg/kg per day;18 weeks	ADHDRS-IV	0.57	YGTSS	0.40	4
Shaywitz et al. [2014]	WSparalleln = 36	Dyslexia	12 yrs; 66.7%	1.0–1.4 mg/kg per day;16 weeks	ADHDRS-IV	1.79	K-TEADecodingcomprehensivecomposite	0.50, 0.62, 0.61	4
Wietecha et al. [2013]	RCTn = 62n = 58	Dyslexia	12 yrs;62.0%	0.5–1.4 mg/kg per day;16 weeks	ADHDRS-IV	0.53	K-SCT-Teacher	0.77	5
De Jong et al. [2009]	RCTcrossovern = 20	Reading disorder	9 yrs; unknown	0.6–1.2 mg/kg per day;16 weeks	ADHDRS-IV	1.08^*	Lexical decision task	ns	3

Cohen’s d effect size computed using published data.

ABC, Aberrant Behavioral Checklist; ADHDRS-IV, Parent report-Investigator-scored ADHD Rating Scale; ASRS, ADHD Self-Report Scale; AISRS, ADHD Investigator Symptom Rating Scale; CAARS, Conners’ Adult ADHD Rating Scale; CDRS-R, Children’s Depression Rating Scale; CGI-S Clinical Global Impressions, Severity Scale; CGI-I, Clinical Global Impressions, Improvement Scale; CSBQ, Children’s Social Behavior Questionnaire; HAM-A, Hamilton Anxiety Scale; K-TEA, Kaufman Test of Educational Achievement; K-SCT, Kiddie-Sluggish Cognitive Tempo; LSAS, Liebowitz Social Anxiety Scale; MOAS, Modified Overt Aggression Scale; SICI, Short interval cortical inhibition; SNAP-IV, Swanson, Nolan, and Pelham Rating Scale; YMRS, Young Mania Rating Scale; YGTSS, Yale Global Tic Severity Scale; ASD, Autism Spectrum Disorder; ODD, Oppositional Defiant Disorder; PARS, Pediatric Anxiety Rating Scale; MDD, major depressive disorder; SUD, substance use disorder; ns, not significant; ATX, atomoxetine; OLZ, olanzapine, TAU, treatment as usual; RCT, randomized controlled trial; WS, within subject.

Autism spectrum disorders

Seven studies investigated efficacy of ATX in autism, autism spectrum disorder (ASD), with or without pervasive developmental disorder (PDD), n = 266 ATX, and n = 130 PBO. Three studies were RCTs and four studies utilized within-subject designs. Quality scores ranged 2–5, with two studies having a quality score of 4 or 5. Patient characteristics and severity varied across these studies from ‘severe autistic disorder’ [Charnsil, 2011] to inclusion of youth with autism, Asperger’s disorder, and PDD not otherwise specified [Fernández-Jaén et al. 2011]. Four of the seven studies investigated efficacy or effectiveness of ATX on ADHD symptoms using the ADHD rating scale, Parent report-Investigator-scored version (ADHDRS-IV) [DuPaul et al. 1998]. The ADHDRS-IV is an 18-item rating scale that measures the severity of inattentive and hyperactive–impulsive symptoms as established by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition [DSM-IV; APA 1994]. Respondents are asked to rate the occurrence of specific behaviors of the child over the past 6 months on a scale from 0 = never, to 3 = very often. Average baseline scores for these studies ranged from 40.7 (SD = 7.5) to 35.3 (6.5). Harfterkamp and colleagues, performing the only double-blind RCT utilizing the ADHDRS-IV to investigate the efficacy of ATX for ADHD symptoms, found a significantly greater reduction in ADHDRS-IV score for ATX (n = 48) versus PBO (n = 49) over 8 weeks [Harfterkamp et al. 2012]. Change score in the ATX group was −8.2 (8.8) and for PBO −1.2 (7.3), ES = 0.87. Three studies utilizing an open-label, prospective, within-subject design, found a significant improvement in ADHDRS-IV score over 10–20 weeks of treatment [Harfterkamp et al. 2013, Zeiner et al. 2011, Fernández-Jaén et al. 2011]. Zeiner and colleagues report change in ADHDRS-IV parent-reported total score from baseline value of 37.43 (9.17) to post-trial value of 25.14 (9.43), ES = 1.32. Teacher-reported ADHDRS-IV values also showed significant improvement, from 26.46 (14.18) to 19.70 (10.53), ES = 0.54 [Zeiner et al. 2011]. Similar results are reported by Fernández-Jaén and colleagues [Fernández-Jaén et al. 2011]. In this study, teacher-completed ADHDRS-IV values were slightly lower than parent-reported values, while change scores over the 16 weeks of study were similar, 35.31 (6.51) to 25.68 (8.47) and 30.76 (11.54) to 22.46 (11.22) for parent- and teacher-completed ADHDRS-IV at pre and postassessment, respectively. ESs for parent-completed ADHDRS-IV scores were 1.27 and 0.73 for teacher-completed ADHDRS-IV scores. Two participants in this study continued stimulant therapy and 13 (54%) continued to take a neuroleptic; thus, the ability to determine ATX effectiveness in this study is diminished. Harfterkamp and colleagues report significant change in ADHDRS-IV scores over 20 to 28 weeks of treatment from a baseline score of 40.3 (7.1) to 24.9 (12.2), ES = 1.54 [Harfterkamp et al. 2013]. One RCT utilized the Swanson, Nolan, and Pelham Rating Scale ADHD subscale (SNAP-IV) to determine efficacy of ATX on ADHD symptoms and behaviors [Swanson, 1992]. The SNAP-IV is a caregiver- or teacher-completed assessment for monitoring inattention, hyperactivity or impulsivity, and oppositional behavior. The SNAP-IV includes 20 items specific to ADHD and 10 items specific to ODD. Final scores are average ratings for all completed items for the frequency of specific behaviors on a scale from 0 = not at all, to 3 = very much. Handen and colleagues, using a four-group parallel design, randomized youth to receive ATX or PBO with and without adjuvant parent training. Change in SNAP-IV ADHD subscale scores was significantly greater for ATX versus PBO, 2.18 (0.44) to 1.24 (0.56) and 2.20 (0.52) to 1.74 (0.86), ES = 0.80. A nonsignificant difference in change sores between ATX and PBO on the teacher-reported SNAP-IV ADHD subscale was reported in this study [Handen et al. 2015].

Various measures were used to determine the efficacy of ATX on functioning and behavior in youth with ADHD and comorbid ASD. Three studies used the Aberrant Behavioral Checklist (ABC) [Aman et al. 1985]. The ABC is parent-reported ratings on 58 items with subscales of irritability, agitation and crying; lethargy and social withdrawal; stereotypic behaviors; hyperactivity and noncompliance; and inappropriate speech. In a double-blind RCT, significantly greater improvement was observed for ATX versus PBO over 8 weeks on ABC subscales of hyperactivity, inappropriate speech, and stereotypic behavior [Harfterkamp et al. 2014]. Handen and colleagues found mixed results [Handen et al. 2015]. Significantly greater improvement was observed for the hyperactivity subscale for ATX versus PBO over 10 weeks, but no difference was observed for ATX and PBO conditions for all other ABC subscales in the absence of adjuvant parent training. Finally, in an open-label prospective trial, Charnsil found that ABC scores rated by parents did not show significant improvement over 10 weeks in youth with ADHD and comorbid ASD [Charnsil, 2011]. In Harfterkamp’s RCT, a second behavioral assessment, the Children’s Social Behavior Questionnaire (CSBQ), that measures parent-reported ratings of social, communication, and behaviors specific to autism [Hartman et al. 2006], showed no difference between ATX versus PBO [Harfterkamp et al. 2014]. Mixed results were also found for the Clinical Global Impressions scale (CGI) [Guy, 1976]. The CGI rates severity of symptoms and progress based on parent and clinician report on a scale ranging from 0 = normal, not at all, to 7 = extremely ill. In Charnsil’s study, CGI-improvement subscale (CGI-I) improved for some youth, but authors state that overall, scores did not improve over time for the nine study participants [Charnsil, 2011]. CGI-severity subscale scores (CGI-S) in the study by Fernández-Jaén and colleagues showed significant improvement over 16 weeks for 23 participants, from baseline score of 5.37 (0.96) to post-treatment score of 4.20 (1.02), ES = 1.18 [Fernández-Jaén et al. 2011]. This difference in findings among the studies in the effectiveness of ATX to reduce symptoms associated with ASD may be due to outcome and measure utilized, but may also be due to patient characteristics, mainly symptom severity.

Of the seven studies investigating the efficacy of ATX in youth with ADHD and comorbid ASD, only four utilized a primary efficacy measure for ASD functioning and behavior. Findings relating to changes in general levels of functioning and behaviors in youth with ADHD and comorbid ASD are mixed. Most common adverse events (AEs) reported by youth in the four studies that also utilized global measures of functioning and behavior were somnolence, decreased appetite, nausea, irritability, and agitation. The findings from these studies suggest that while ATX may be associated with significantly improved behaviors related to ADHD, the efficacy of ATX on global measures of functioning and behaviors with or without behaviors specific to ASD is less robust. The positive results observed on several ABC subscales in the RCT along with improved global severity are worth noting and suggest that youth with ADHD and ASD may benefit from ATX.

Oppositional defiant disorder

ODD is the most commonly reported comorbid mental health condition for individuals with ADHD [Steinhausen et al. 2006]. Although six studies were found during the search strategy, several of these studies were continuation of previously published studies; thus, results are presented for four studies, n = 393 ATX, and n = 161 PBO. All studies included youth only. Three of the four studies examining the efficacy of ATX in youth with ADHD and comorbid ODD were RCTs. In the fourth study, Holzer and colleagues utilized an open-label, prospective, within-subject design. Their study also included ATX + olanzapine for all participants in its 10-week treatment protocol. While olanzapine dosage was kept stable, the additional medication is a caveat to the interpretation of the findings for ATX for this study [Holzer et al. 2013]. Quality scores ranged 3–5 with three of the four studies having the highest quality score. Three studies, all double-blind RCTs, utilized the SNAP-IV ADHD subscale as the primary efficacy measure for ADHD symptoms and behaviors. In all three studies, significantly greater improvement was observed for SNAP-IV ADHD subscale total scores for ATX versus PBO. Dell’Agnello and colleagues found significantly greater improvement in SNAP-IV ADHD scale scores for ATX versus PBO in 137 randomized youth over 8 weeks [Dell’Agnello et al. 2009a]. Change scores for ATX versus PBO were −8.9 (9.2) and −2.0 (4.7), respectively, ES = 0.91. Also, Bangs and colleagues [Bangs et al. 2008; Hazell et al. 2009], observed similar results over 8 weeks for 226 randomized youth aged 6–12 yrs for the SNAP-IV inattentive subscale and Hyperactivity/Impulsivity subscales. Mean change scores on the inattentive subscale for ATX and PBO were −5.0 (6.0) and −2.2 (4.8), respectively, and for the Hyperactivity/Impulsivity subscale, −4.6 (6.2) and −2.2 (4.5) respectively. ESs in this study ranged from 0.52 to 0.44. Finally, significantly greater improvement was observed in SNAP-IV ADHD total score for 181 youth over 9 weeks, least squares mean treatment group difference, −7.4, 95% CI, −11.0 to −3.8, ES = 0.72 [Dittmann et al. 2011; Wehmeier et al. 2011]. Holzer and colleagues found a significant improvement in ADHDRS-IV score over 10 weeks for 11 youth, 41.95 (3.69) to 26.0 (11.99), ES = 1.81 [Holzer et al. 2013].

All RCTs utilized the SNAP-IV ODD subscale to assess efficacy of ATX on symptoms and behaviors specific to ODD in youth with comorbid ADHD. Mixed results are reported. In the study by Dell’Agnello and colleagues, baseline SNAP-IV ODD scores were 17.2 and 17.5 for ATX and PBO, respectively. Significantly greater improvement was observed for ATX than PBO over 8 weeks, −2.7 (4.1) versus −0.3 (2.6), ES = 0.52 [Dell’Agnello et al. 2009a]. As reported by Dittmann and colleagues, least squares mean treatment group difference with baseline scores of 15.6 and 15.5, ATX and PBO, respectively, were −3.2, 95% CI, −5.0 to −1.5, ES = 0.69 [Dittmann et al. 2011]. In a study by Bangs and colleagues, SNAP-IV ODD scores were similar at baseline, 18.9, and improved equally for ATX and PBO, with a change of −3.7 (5.3) and −2.9 (4.3), respectively, (nonsignificant). Holzer and colleagues, utilizing the clinician–interview completed Modified Overt Aggression Scale (MOAS) [Yudofsky et al. 1986], reported significant improvement in scores over time, 20.45 (6.0) to 12.64 (8.0), ES = 1.10 [Holzer et al. 2013]. Scores on the MOAS reflect the number of difficult behaviors in four domains of aggression; items in the physical aggression domain are weighted highest in the final score.

One study reported a high level of AEs. In the study by Dittmann and colleagues, 70% of youth with fast titration of ATX (0.5 mg/kg/day for 7 days to 1.2 mg/kg/day target dose) experienced AEs versus 31% of youth in the PBO condition [Dittmann et al. 2011]. The most commonly reported AEs in their study were fatigue, nausea, headache, vomiting, upper abdominal pain, and anorexia. Based on the reported results of these studies, ATX is effective in youth with comorbid ADHD and ODD. While mixed findings are reported for the efficacy of ATX to improve symptoms of ODD, the majority of studies suggest that ATX is effective in ODD treatment. ATX is moderately tolerated by individuals with ADHD and comorbid ODD and this can be improved with slow titration of ATX to maximum dose.

Anxiety disorders

Two RCTs investigated efficacy of ATX versus PBO in individuals with ADHD and comorbid social anxiety disorder: one in adults [Adler et al. 2009] and one in youth [Geller et al. 2007]. An additional open-label, prospective, within-subject study investigated ATX in adults with ADHD and comorbid generalized anxiety disorder [Gabriel and Violato, 2011]. In total, 287 subjects were included in the ATX group and 247 subjects in the PBO group. All studies had a quality score of 4 or 5.

In a study by Geller and colleagues, 87 youth randomized to up to 1.8 mg/kg per day of ATX for 12 weeks showed a significantly greater improvement in ADHDRS-IV scores than 89 youth randomized to PBO, with change values of −10.5 and −1.4 for ATX and PBO, respectively, ES = 1.0 [Geller et al. 2007]. Scores on the Pediatric Anxiety Rating Scale (PARS) [Research Unit on Pediatric Psychopharmacology, 2002], a clinician–interview-completed measure of severity on seven items of separation anxiety, social phobia, and generalized anxiety symptoms, also showed significantly greater improvement in the ATX condition, change values of −5.5 and −3.2 for ATX and PBO, respectively, ES = 0.5. Participants in their study met criteria for ADHD with any of the following comorbidities: separation anxiety, generalized anxiety disorder, or social phobia. Their study had one of the highest doses of ATX of the studies reviewed for youth.

In a 14-week, multisite, double-blind RCT of adults with ADHD and comorbid social anxiety disorder, Adler and colleagues found significantly greater reduction on the Conners’ Adult ADHD Rating Scale, Investigator-rated, screening version (CAARS:Inv:SV) [Conners et al. 1999] in 171 adults with ADHD and anxiety disorder receiving ATX versus 158 adults receiving PBO [Adler et al. 2009]. The CAARS is an 18-item assessment of the occurrence of behaviors of hyperactivity and inattention rated on a scale from 0 = not at all, to 3 = very much. Scores reduced from 29.6 (10.4) to 20.9 (11.3) for the ATX condition and 31.2 (9.4) to 25.6 (10.6) for the PBO condition, ES = 0.47. Scores on the Liebowitz Social Anxiety Scale (LSAS), a clinician-rated measure on 24 activities of social interaction and performance situations rated on a severity scale ranging from 0 = none, to 4 = severe, [Liebowitz, 1987] also showed significantly greater improvement for ATX versus PBO, 85.3 (23.6) to 62.4 (29.7) versus 82.1 (21.3) to 67.7 (26.9), ES = 0.40. The participants showing high response on the LSAS during the pretrial PBO period were excluded from the study. ESs indicate small improvement in both ADHD and anxiety symptoms. Change in CAARS total ADHD symptoms scores and LSAS total scores was significantly correlated indicating an association between improved ADHD and anxiety symptoms. AEs were reported significantly more often in ATX versus PBO conditions and included insomnia, nausea, dry mouth, and dizziness; however, discontinuation during the study due to side effects did not differ between groups.

In 27 adults with ADHD and comorbid generalized anxiety disorder, significant improvement was found over 12 weeks for ADHD symptoms on both the CGI-S and ADHD Self-Report Scale (ASRS), an 18-item symptom checklist rated from 0 = never to 4 = very often [Kessler et al. 2005a]. Significant improvement was also found for reported severity of anxiety symptoms including cognitive anxiety and somatic anxiety, on the 14-item Hamilton Anxiety Scale (HAM-A) [Hamilton, 1959; Gabriel and Violato, 2011]. CGI-S scores changed from 4.2 (0.64) to 3.0 (1.0), ES = 1.43 and ASRS scores changed from 47.9 (10.3) to 32.9 (13.0), ES = 1.28. Total HAM-A scores changed from 12.1 (4.2) to 6.7 (2.3), ES = 1.51; significant improvement was also observed for cognitive and somatic anxiety subscales separately. Most common side effects reported were dry mouth (40%), nausea (26%), palpitation (15%), and light-headedness (15%). The percent male population for this study, 30%, was the lowest proportion of males for all studies reviewed.

Interpretation of results for the three studies investigating efficacy of ATX in individuals with ADHD and comorbid anxiety is limited. Only one study investigated ATX in youth; however, with all studies, including two RCTs of higher quality indicating positive results, ATX appears efficacious in the treatment of individuals with ADHD and comorbid anxiety disorder. The proportion of females included in these studies was higher than other studies reviewed at 38–70% which may have impacted results.

MDD and bipolar disorder

The majority of studies included in this review excludes individuals with ADHD and comorbid major depressive disorder, psychosis, and bipolar disorder. Studying these comorbid conditions may be more complex because these individuals are under current treatment with psychotropic medication that cannot be stopped to initiate a clean period before investigating efficacy of ATX alone. Few recent studies have investigated efficacy of ATX in youth or adults with these comorbid disorders. Two studies are included in this review, n = 84 ATX, and n = 70 PBO. Quality scores are 3 and 5.

One multisite, double-blind RCT investigated the efficacy of ATX in adolescents with ADHD and MDD [Bangs et al. 2007]. In a sample of 142 youth, ages 12–18 years, 73.2% male, significantly improved scores on the ADHDRS-IV in ATX versus PBO over 9 weeks were reported but no difference in the Children’s Depression Rating Scale, Revised (CDRS-R) [Poznanski and Mokros, 1999] between conditions was reported. The CDRS-R is a semistructured interview consisting of 17 symptom areas rated on a 7-point scale used to diagnose and monitor depression symptoms. Youth were treated after a 1-week clean period with up to 1.8 mg/kg of ATX per day, a slightly higher dose than used in other efficacy studies. Youth initiating psychotherapy in the month prior were excluded. ADHDRS-IV scores were similar in ATX and PBO conditions at baseline; change scores on the ADHDRS-IV, which were significantly greater in the ATX versus PBO condition, were −13.3 (10.0) and −5.1 (9.9) in the ATX and PBO groups, respectively, ES = 0.84. Improved ADHDRS-IV scores for ATX over PBO indicate efficacy of ATX for ADHD symptoms in youth with ADHD and comorbid MDD. Scores on the CDRS-R were required to be at least 40 at randomization for inclusion criteria; baseline scores were 53.4 (10.9) for ATX and 52.0 (8.9) for PBO. Change scores on the CDRS-R were −14.8 (13.3) and −12.8 (10.4), for ATX and PBO groups, respectively (nonsignificant). Despite the large ES in the change observed between ATX and PBO for ADHD symptoms, it did not directly translate into a similar finding for MDD. It is unclear why such a substantial decrease in depressive symptoms was observed in the PBO condition. In this trial, significantly more AEs were reported for ATX versus PBO for nausea (22% versus 4%, respectively), and decreased appetite (13% versus 0%, respectively). Very few participants reported suicidal ideation and this did not differ between ATX and PBO groups. Thus, ATX appears to be efficacious in the treatment of ADHD symptoms in youth with ADHD and comorbid MDD, but evidence is limited.

One study investigated ATX in the treatment of youth with ADHD and comorbid bipolar disorder. In an open-label, prospective design, Chang and colleagues followed 12 youth, 6–14 years old, with ADHD and comorbid bipolar disorder. Participants continued their current mood-stabilizing medication with dose kept constant 3 weeks prior and during the study trial. Scores on the ADHDRS-IV decreased significantly over 8 weeks from 39.0 (7.7) to 22.1 (7.7), ES = 2.18 [Chang et al. 2009]. The reported presence of manic symptoms as measured by the 11-item clinician-completed, Young Mania Rating Scale (YMRS) [Young et al. 1978] did not change over time, 7.9 (4.7) to 7.4 (4.8), (nonsignificant); nor was significant improvement found in CDRS-R scores, 25.9 (4.0) to 25.2 (5.6). In addition, the authors reported worsening of symptoms in two youths. AEs reported by youth in the study were tiredness, 25%, stomach ache, 25%, agitation, 16%, nausea, 8%, dizziness, 8%, anticholinergic reaction, 8% and suicidal ideation, 8%. A moderate ES indicating substantial change was observed for ADHD symptoms and behaviors over time; however, no association was observed for ATX and improved mania or depression. Based on the limited, recent studies available, ATX appears to be effective in improving ADHD-associated symptoms and behaviors but not symptoms specific to bipolar and MDD. Suicidal ideation was reported by some youth receiving ATX, but in an RCT, report of this AE did not differ between ATX and PBO.

SUD

Three studies investigated efficacy of ATX in individuals with ADHD and comorbid SUD: two in non-nicotine SUD and one specific to alcohol, n = 125 ATX, and n = 110 PBO. Quality scores ranged 2–5 with two studies having quality scores of 4 or 5. Among studies in adults, one double-blind RCT showed a significant improvement in ADHD symptoms in ATX over PBO during a 12-week trial. Wilens and colleagues, in a study specific to alcohol, found baseline scores on the ADHD Investigator Symptom Rating Scale (AISRS) [Spencer et al. 2010], an 18-item clinician–interview measure of ADHD symptom severity rated from 0 = none, to 3 = severe, were similar between groups, 40.6 (7.8) for ATX and 40.1 (7.9) for PBO [Wilens et al. 2008]. Significantly greater improvement was observed for ATX versus PBO over time, −13.6 (11.4) and −8.3 (11.4) respectively, ES = 0.48. In a within-subject, retrospective naturalistic study, ASRS scores following an average of 17 weeks of ATX treatment in 14 young males aged 18–24 years, were significantly lower than scores before treatment initiation 29.32 (9.6) versus 52.68 (11.48), respectively, ES = 2.21 [Benegal et al. 2013]. In a double-blind RCT of 70 adolescents, 13–19 years, nonsignificant results were observed for improved symptoms, self-reported, on the DSM-IV ADHD symptom checklist [APA, 1994] for ATX over PBO as both groups improved significantly, but equally, over time [Thurstone et al. 2010]. Change over 12 weeks of treatment using the ADHD checklist for ATX and PBO conditions was −18.19 versus −19.02, respectively, (nonsignificant).

When considering the association of ATX on substance-use behavior, only one study found a significant association. Benegal and colleagues found significantly greater number of abstinent days during ATX treatment compared with the same individuals during a previous treatment period without ATX, 229.11 (119.37) versus 38.89 (48.21) days [Benegal et al. 2013]. Caveats to interpretation of this finding, however, could be the removal of dropouts from analyses (n = 4, out of 18 participants) and the large amount of variability in reported abstinent days. Number of days using substances in the past month [Thurstone et al. 2010] and drinks per day, proportion of days drinking, number of drinks per drinking day, or proportion of days using substances other than alcohol [Wilens et al. 2008] did not differ between ATX and PBO conditions. This null finding for Thurstone and colleagues may be due to adjuvant motivational and cognitive behavioral therapies [Thurstone et al. 2010]. In their study, significantly more reports of AEs for ATX over PBO were observed for vomiting, but significantly fewer reports were made for muscle cramps and sadness. Based on these findings and the specific populations studied, the efficacy of ATX for reducing symptoms of ADHD is equivocal and ATX appears to have little impact on substance-using behavior in adolescents and adults with ADHD and comorbid SUD.

Tourette syndrome

Two studies investigated the efficacy of ATX in youth with ADHD and comorbid Tourette syndrome, n = 75 ATX, and n = 56 PBO. Quality scores are 3 and 4. In a double-blind RCT by Spencer and colleagues [Spencer et al. 2008; Allen et al. 2005], 116 youth, ages 7–17 years, with ADHD and comorbid Tourette syndrome were randomized to ATX (n = 6) or PBO (n = 56) for 18 weeks. A significantly greater improvement in ADHD symptoms on the ADHDRS-IV was observed for the ATX versus PBO conditions. Change over time for those receiving ATX was −10.4 (11.0) and for PBO −4.4 (9.9), ES = 0.57. Significant differences were also found for the Inattention and Hyperactivity/Impulsivity subscales of the ADHDRS-IV in the expected direction, ES = 0.49 and 0.57 respectively. In an open-label, prospective, within-subject design, Gilbert and colleagues monitored 14 youth with ADHD and Tourette syndrome over 1 month. Scores on the ADHDRS-IV significantly improved over time from 32.0 (8.0) to 22.0 (9.0), ES = 1.17 [Gilbert et al. 2007].

Two very different efficacy measures were used to monitor response to ATX treatment on tics and other symptoms of Tourette syndrome. Gilbert and colleagues used a physiological measure of cortical functioning, short-interval cortical inhibition (SICI) [Gilbert et al. 2007], while Spencer and colleagues [Spencer et al. 2008] used the Yale Global Tic Severity Scale (YGTSS) [Leckman et al. 1989]. Significantly greater improvement was observed in YGTSS scores for ATX versus PBO, −5.1 (7.1) and −2.0 (−8.4), respectively, ES = 0.4. A nonsignificant change, −0.61, in cortical inhibition was observed by Gilbert and colleagues [Gilbert et al. 2007]. Despite a high prevalence of ADHD among those with Tourette syndrome [Denckla, 2006], no other recent studies have been conducted examining the efficacy of ATX in individuals with ADHD and comorbid Tourette syndrome and results remain equivocal.

Dyslexia and reading disorder

Three studies investigated the efficacy of ATX in youth with ADHD and comorbid reading disorder or dyslexia, n = 118 ATX, and n = 58 PBO. Quality scores ranged 3–5; two studies had quality scores of 4 or 5. Two studies investigated efficacy of ATX in youth with ADHD and comorbid dyslexia: a double-blind RCT and an open-label, parallel (two group), within-subject design. Wietecha and colleagues randomized 159 youth with ADHD and dyslexia to ATX or PBO for 16 weeks with an additional follow-up period to 32 weeks. Baseline ratings on the ADHDRS-IV were 37.22 and 37.57 for ATX and PBO, respectively. Change scores on this measure indicated significantly greater improvement for ATX versus PBO, −18.87 and −12.98, respectively, ES = 0.53 [Wietecha et al. 2013]. In an open-label trial, Shaywitz and colleagues found significant improvement in ADHDRS-IV scores for 35 youth with ADHD and comorbid dyslexia over 16 weeks of treatment with ATX, from 36.0 (8.2) to 17.8 (12.3), ES = 1.79 [Shaywitz et al. 2014].

Two different efficacy measures were used to determine impact of ATX on dyslexia in youth with ADHD and comorbid dyslexia. In the Wietecha and colleagues study, significantly greater improvement was observed for sluggish or apathetic behaviors as measured by the Kiddie-Sluggish Cognitive Tempo (K-SCT) [Lee et al. 2013], with scores for ATX over PBO, −6.88 versus −1.64, ES = 0.77 [Wietecha et al. 2013]. Similar results were found by Shaywitz and colleagues on the standardized, Kaufman Test of Educational Achievement for youth in grades 1 through 12 (K-TEA) [Kaufman and Kaufman, 1998] with significant improvement observed on three subscales, reading decoding, 80.2 (7.6) to 84.8 (10.6), ES = 0.50, reading comprehension, 81.6 (10.8) to 89.3 (13.8), ES = 0.62, and reading composite, 80.3 (8.6) to 86.4 (11.4), ES = 0.61 [Shaywitz et al. 2014].

In youth with ADHD and comorbid reading disorder as determined through community-based providers, significantly greater improvement was observed in 36 youth with either ADHD or ADHD with comorbid reading disorder receiving ATX compared with PBO on ADHDRS-IV Scores [de Jong et al. 2009]. In this double-blind crossover study, youth were randomized by order of treatment: ATX–PBO or PBO–ATX. In the 20 youth with ADHD and comorbid reading disorder, baseline score on the ADHDRS-IV was 39.0 (9.1) which decreased to 26.4 (13.7) following ATX treatment and decreased slightly to 36.9 (11.1) following PBO, ES = 1.08. Performance on a lexical decision task [Meyer and Schvaneveldt, 1971], the primary efficacy measure for dyslexia, did not improve differentially between ATX and PBO conditions, 1.9 (0.7) to 2.0 (0.7) and 1.9 (0.7) to 1.8 (0.6), (nonsignificant).

ATX is efficacious in the treatment for youth with ADHD and comorbid dyslexia. This association may also be true for other comorbid learning disabilities. The association between ATX and improvements related to dyslexia including word recognition, comprehension, and reading ability is promising and warrants more attention and research.

Discussion

Evidence for the efficacy of ATX on ADHD symptoms is well established and as in previously published reviews [Dell’Agnello et al. 2009b; Garnock-Jones and Keating, 2009], this review found that the efficacy and effectiveness of ATX are not diminished by the presence of the majority of comorbid disorders studied. ESs for observed improvements in ADHD symptoms in ATX versus PBO or in pre-post within-subject designs ranged from 0.47 to 2.21, indicating moderate-to-large ESs. Overall, the impact of ATX on ADHD symptoms and behaviors in individuals with ADHD and comorbid disorders appears to be reliable and not influenced by specific outcome measure utilized or age of the patient (child versus adult).

Results for the effectiveness of ATX to reduce or improve symptoms and behaviors relating to comorbid conditions are mixed. Results for the effectiveness of ATX on comorbid conditions are more robust for ODD and anxiety in both youth and adults. Results from two RCTs [Dell’Agnello et al. 2009a; Dittmann et al. 2011] support positive findings for efficacy of ATX to improve symptoms of ODD. The third RCT investigating efficacy of ATX to improve ODD symptoms [Bangs et al. 2008] did not find differences between ATX and PBO at endpoint, but did find differences in earlier assessments as well as differences on secondary outcome measures for ODD symptoms. Missing from studies on ATX in youth with ADHD and ODD is a description of ODD subtype: irritable and defiant, or vindictive. These subtypes have been shown to be associated with suicidality, criminal behavior, and comorbid anxiety [Aebi et al. 2015] and it is likely that these traits within ODD may impact response to ATX and other medications. Thus, it is difficult to determine how the responses observed in the current review may generalize to other youth with ADHD and comorbid ODD. Results from two RCTs [Adler et al. 2009; Geller et al. 2007] support efficacy of ATX on anxiety symptoms. The ranges in ES for change observed in symptoms and behaviors related to these comorbid conditions are 0.52 to 1.10 for ODD and 0.40 to 1.51 for anxiety, indicating small-to-large ESs. ODD and anxiety are commonly occurring comorbid conditions with ADHD and effectiveness of ATX in the treatment of these conditions is promising.

Studies failed to show efficacy of ATX for ASD, depression, bipolar, Tourette syndrome, and dyslexia either because of equivocal findings or limited high quality trials available for review. Results for the effectiveness of ATX on ASD-associated behaviors are mixed with one RCT reporting efficacy on ASD symptoms and behaviors and one RCT reporting null findings. ATX may be effective in major depressive disorder and reading disorder but few trials are available to confirm judgement. More research is also needed on the efficacy of ATX in the areas of ADHD with comorbid bipolar disorder and Tourette syndrome. In a review by Cortese and colleagues, the authors conclude that ATX may improve presentation of tics, while stimulants may worsen tics [Cortese et al. 2013]. This finding is consistent with outcomes presented in the current review as measured by the YGTSS in an RCT with over 117 youth [Spencer et al. 2008].

Studies reviewed failed to show a reliable pattern of efficacy for ATX on SUD behavior in young adults with ADHD and comorbid alcohol or non-nicotinic substance use. These studies also failed to show effectiveness for ATX in the treatment of the ADHD symptoms. Wilens and colleagues have found a correlation between change in ADHD symptoms and drug cravings among adults with ADHD and comorbid SUD [Wilens et al. 2008, 2011]. More studies such as this may improve our understanding of how pharmacotherapy may influence symptoms and substance-use behaviors for individuals with ADHD and comorbid SUD.

There are several treatment-related factors that may contribute to reported efficacy. There is reported evidence that maximum efficacy of ATX may not be reached until 10–12 weeks of treatment with ATX [Savill et al. 2015]. This phenomenon was not confirmed in our review, as many trials reported positive findings in under 10 weeks. More studies with longer treatment durations are needed to determine the impact of long-term treatment with ATX on efficacy and AEs. Also, several studies utilized a dosage above the recommended maximum dosage specified by the manufacturer of 1.4 mg/kg per day in youth, while not the case for the highest recommended dosage in adults of 100 mg per day. There does not appear to be a strong relationship between dose and efficacy in the current review as large ESs were found for both high and recommended doses of ATX. Thus, this review supports the practice that prescribing be dictated by individual tolerability and medication response.

Described above, ATX is often prescribed in lieu of stimulants because the latter may increase symptoms exacerbated by comorbid conditions including tics, mania, and suicidal ideation. Withdrawal rates from studies due to AEs did not vary between ATX and PBO in the majority of RCTs; however, many studies reviewed reported that a higher proportion of individuals receiving ATX versus PBO were more likely to experience nausea and decreased appetite. The current review did not find increased report of suicidal behaviors for youth with ADHD and comorbid MDD receiving ATX versus PBO [Bangs et al. 2007]. Only one youth (8%) with ADHD and comorbid bipolar disorder reported suicidal behaviors after receiving ATX [Chang et al. 2009]. One study found a possible negative outcome of decreased cortical functioning in children with ADHD and comorbid Tourette syndrome after receiving ATX [Gilbert et al. 2007]. Aside from this physiological AE, the current review concurs with prior research showing similar reported AEs in individuals with ADHD and comorbid conditions to those in the general ADHD population [Dell’Agnello et al. 2009a]. More research is needed to address cortical functioning in children and adults with ADHD and comorbid conditions.

Data sources used in this review may have limitations. Inclusion of study designs other than RCTs in this review was valuable in supporting the findings and in describing the knowledge base of ATX in the treatment of ADHD with comorbidity. While of lower methodological quality, these studies provide an assessment of the effectiveness of ATX in environments similar to those environments experienced by the general clinical community in which individuals are prescribed medication and monitored over time. The impact of these studies on effectiveness of ATX to treat ADHD and comorbid conditions was interpreted conservatively. ESs reported in this review were provided for reference and not intended for combined analysis as different outcome assessments were utilized across studies. ESs may have been influenced by study design and reporting of outcomes. Faraone and colleagues found larger ESs for crossover versus parallel-design studies and for studies reporting outcome values versus change scores [Faraone et al. 2006]. In the current review, the largest ESs were observed in studies utilizing within-subject designs, thus providing another reason to interpret results from lower quality studies cautiously. Many studies included in this review had small sample sizes and may not have had adequate power to discern differences between treatment groups. The majority of studies did not address or present results from power calculations. Finally, inclusion of studies utilizing within-subject designs may have increased the risk of publication bias which may have influenced the findings of this review.

Conclusion

Results from this review suggest that the efficacy and effectiveness of ATX to treat symptoms of ADHD are not diminished by the presence of comorbid disorders. Moderate-to-large ESs (0.47–2.21) were reported for improvements in ADHD symptoms. Efficacy of ATX in the treatment of comorbid conditions showed mixed results. Evidence did not support efficacy of ATX for ASD, depression, bipolar, Tourette syndrome, dyslexia, and SUD, either because of equivocal findings or limited high quality trials available for review. Findings for ATX in the treatment of comorbid anxiety and ODD were more robust. Moderate ESs in youth were reported for symptoms of ODD (0.52–1.10) and small-to-large ESs were reported for symptoms of anxiety (0.40–1.51), suggesting that these youth may benefit from ATX monotherapy treatment.

Footnotes

Conflict of interest statement

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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