7
ADHD and Dysthymic Disorder: Toward Understanding This Common Comorbidity in Children and Adolescents Alasdair Vance, MD, PhD, and Jo Winther, BA, MAppSc(Psych) Corresponding author Alasdair Vance, MD, PhD Academic Child Psychiatry Unit, Royal Children’s Hospital, University of Melbourne, Gatehouse Street, Parkville VIC 3052, Melbourne, Australia. E-mail: [email protected] Current Attention Disorders Reports 2009, 1: 145151 Current Medicine Group LLC ISSN 1943-4561 Copyright © 2009 by Current Medicine Group LLC Attention-deficit/hyperactivity disorder (ADHD) and dysthymic disorder (DD) are common childhood psychiatric disorders that have a greater-than-chance association. To date, their relationship has not been systematically examined despite their frequent co-occurrence in children and adolescents referred to clinical health services. This article defines ADHD and DD, reviews their characteristics, and outlines the emerging evidence from phenomenological and cognitive neuroscience studies regarding their assoc- iation. ADHD and, separately, DD are significant drivers for oppositional defiant disorder symptoms in children and adolescents. ADHD and DD both have elevated levels of neurological subtle signs, spatial working memory deficits, and right frontal-stria- tal-parietal underactivation compared with healthy control participants. ADHD and DD both also have elevated levels of parental psychopathology, with the comorbid group having significantly higher levels than those with ADHD or DD alone. We explore the clinical implications of these findings. Introduction Attention-deficit/hyperactivity disorder (ADHD) is a common childhood psychiatric disorder characterized by developmentally inappropriate levels of hyperactivity, inattention, and impulsivity [1]. It affects more males than females both before and after puberty. Similarly, dysthymic disorder (DD) is a highly prevalent childhood psychiatric disorder, with a point prevalence of 1% to 2% [2]. DD is the most common childhood depressive disorder in clini- cally referred samples. DD is characterized by low and/or irritable mood for more days than not for 1 year or more, along with at least two of the following symptoms: poor concentration/ difficulty making decisions, poor appetite/overeating, insomnia/hypersomnia, low energy/fatigue, low self- esteem, and feelings of hopelessness [1]. In particular, DD is associated with impairing levels of inattention [1], as poor attention, difficulty concentrating, and diffi- culty with decision making have been clinically observed in children with DD [2–5]. These symptoms of DD are thought to impair cognitive development and functioning in academic domains [6]. DD affects boys and girls equally before puberty [7], has a chronic course throughout childhood and early adolescence into adulthood, and has a poor prognosis if undiagnosed or untreated. Indeed, its average age at onset is 2 years earlier than that of major depressive disorder (MDD), and it is a primary risk factor for the development of MDD and attendant self-harm in early adolescence [8]. A greater-than-chance association of ADHD and DD has been demonstrated [9]. According to Kovacs et al. [2], ADHD is the most prevalent preexisting con- dition associated with DD, which lasts almost 2.5 years longer in the presence of a co-occurring externalizing disorder [7]. Nevertheless, despite their clinical impor- tance, ADHD and DD remain poorly understood. This article outlines the emerging evidence from recent phe- nomenological and cognitive neuroscience studies about the association between ADHD and DD. Clinical impli- cations are also explored. Phenomenological Studies Oppositional defiant disorder Oppositional defiant disorder (ODD) is the most common reason for referral of children and adolescents to mental health services. The greater-than-chance association of ODD with ADHD and depressive disorders is a replicated finding in epidemiological studies [10,11]. Furthermore,

ADHD and dysthymic disorder: Toward understanding this common comorbidity in children and adolescents

Embed Size (px)

Citation preview

Page 1: ADHD and dysthymic disorder: Toward understanding this common comorbidity in children and adolescents

ADHD and Dysthymic Disorder: Toward Understanding This Common Comorbidity in Children and AdolescentsAlasdair Vance, MD, PhD, and Jo Winther, BA, MAppSc(Psych)

Corresponding authorAlasdair Vance, MD, PhD

Academic Child Psychiatry Unit, Royal Children’s Hospital,

University of Melbourne, Gatehouse Street, Parkville VIC 3052,

Melbourne, Australia.

E-mail: [email protected]

Current Attention Disorders Reports 2009, 1:145–151Current Medicine Group LLC ISSN 1943-4561

Copyright © 2009 by Current Medicine Group LLC

Attention-defi cit/hyperactivity disorder (ADHD) and dysthymic disorder (DD) are common childhood psychiatric disorders that have a greater-than-chance association. To date, their relationship has not been systematically examined despite their frequent co-occurrence in children and adolescents referred to clinical health services. This article defi nes ADHD and DD, reviews their characteristics, and outlines the emerging evidence from phenomenological and cognitive neuroscience studies regarding their assoc-iation. ADHD and, separately, DD are signifi cant drivers for oppositional defi ant disorder symptoms in children and adolescents. ADHD and DD both have elevated levels of neurological subtle signs, spatial working memory defi cits, and right frontal-stria-tal-parietal underactivation compared with healthy control participants. ADHD and DD both also have elevated levels of parental psychopathology, with the comorbid group having signifi cantly higher levels than those with ADHD or DD alone. We explore the clinical implications of these fi ndings.

IntroductionAttention-defi cit/hyperactivity disorder (ADHD) is a common childhood psychiatric disorder characterized by developmentally inappropriate levels of hyperactivity, inattention, and impulsivity [1]. It affects more males than females both before and after puberty. Similarly, dysthymic disorder (DD) is a highly prevalent childhood psychiatric disorder, with a point prevalence of 1% to 2% [2]. DD is

the most common childhood depressive disorder in clini-cally referred samples.

DD is characterized by low and/or irritable mood for more days than not for 1 year or more, along with at least two of the following symptoms: poor concen tration/diffi culty making decisions, poor appetite/overeating, insomnia/hypersomnia, low energy/fatigue, low self-esteem, and feelings of hopelessness [1]. In particular, DD is associated with impairing levels of inattention [1], as poor attention, diffi culty concentrating, and diffi -culty with decision making have been clinically observed in children with DD [2–5]. These symptoms of DD are thought to impair cognitive development and functioning in academic domains [6].

DD affects boys and girls equally before puberty [7], has a chronic course throughout childhood and early adolescence into adulthood, and has a poor prognosis if undiagnosed or untreated. Indeed, its average age at onset is 2 years earlier than that of major depressive disorder (MDD), and it is a primary risk factor for the development of MDD and attendant self-harm in early adolescence [8].

A greater-than-chance association of ADHD and DD has been demonstrated [9]. According to Kovacs et al. [2], ADHD is the most prevalent preexisting con-dition associated with DD, which lasts almost 2.5 years longer in the presence of a co-occurring externalizing disorder [7]. Nevertheless, despite their clinical impor-tance, ADHD and DD remain poorly understood. This article outlines the emerging evidence from recent phe-nomenological and cognitive neuroscience studies about the association between ADHD and DD. Clinical impli-cations are also explored.

Phenomenological StudiesOppositional defi ant disorderOppositional defi ant disorder (ODD) is the most common reason for referral of children and adolescents to mental health services. The greater-than-chance association of ODD with ADHD and depressive disorders is a replicated fi nding in epidemiological studies [10,11]. Furthermore,

Page 2: ADHD and dysthymic disorder: Toward understanding this common comorbidity in children and adolescents

146 I ADHD Comorbidities

independent relationships exist among ODD, ADHD, and depressive disorders [10]. Our group examined the specifi c relationships among ODD, ADHD, and DD in primary school–age children with ADHD combined type (ADHD-CT) [12]. We found that the three core symptom domains of ADHD (15% of the variance) and DD (8% of the variance) made signifi cant independent contributions to the prediction of ODD symptoms.

The signifi cant independent contribution of DD symptoms to ODD patterns of behavior in children with ADHD extended the association of ODD with depres-sive disorders (primarily MDD) reported by Angold et al. [10]. Furthermore, this fi nding was consistent with the known increase in severity of ODD symptoms when ODD is comorbid with depressive disorders [13] but extended this association to DD symptoms. It implied that a set of biological and/or psychosocial risk factors common to ADHD and DD may predispose children with DD to develop ODD and/or vice versa, whether ADHD is present or not. We now examine a biological and a psychosocial risk factor while recognizing that the factors investigated overlap these domains.

Neurological subtle signsThe association between neurological subtle signs and ADHD-CT is well known: Taylor et al. [14–16] have shown that increased neurological “soft signs” are assoc-iated with pervasive hyperactivity (the equivalent of ADHD as defi ned by the DSM-IV). Also, Piek et al. [17] compared primary school–age boys with ADHD with a control group and determined that the ADHD group had an increased parental report of motor and language delay together with increased sensorimotor incoordination. Furthermore, replicated evidence suggests an association of neurological subtle signs with emotional (depressive and/or anxiety) disorders [18–20]. Our group investigated the association between neurological subtle signs and ADHD-CT and DD [21•].

Both the ADHD-CT and DD groups had signifi -cantly increased neurological subtle signs compared with the healthy control group (Cohen’s d = 1.59, 1.69, respectively). Importantly, they did not differ from each other. This fi nding suggests that DD may have some neurobiological features in common with ADHD, which is consistent with reported fi ndings that common familial neurobiological risk factor(s) exist for ADHD and depres-sive disorders [22,23].

Parental psychopathologyADHD is associated with increased rates of parental psychopathology, particularly parental adult ADHD, anxi-ety disorders, depressive disorders, antisocial personality disorder, and alcohol and substance abuse disorders, along with negative controlling parenting [24–26]. Similarly, DD is clearly associated with increased rates of parental mood disorders along with increased levels of psychosocial adversity, particularly perceived lack of family support

and negative relationships with parents [27,28]. Our group examined the association between parental psychopathol-ogy and ADHD-CT and DD, alone and in combination [29]. The ADHD and DD group had signifi cantly higher total parental psychopathology than the ADHD alone and DD alone groups. The effect sizes of the differences between the ADHD and DD and the ADHD alone and DD alone groups were about 1 SD and 0.5 SD, respectively (Cohen’s d = 0.81, 0.55). This implied an additive effect.

In summary, the biological and psychosocial risk factors presented seemed to be common to ADHD and DD and may be additive in their effects. We now explore the cognitive neuroscience construct of spatial working memory given its known association with inattentive symptoms prominent in ADHD and DD.

Cognitive Neuroscience StudiesBehavioral spatial working memory paradigmDefi cits in neuropsychological measures of attention [30] and memory [31] have been reported in children and adolescents with MDD and/or DD, although MDD and DD have not been examined separately. Adolescents with MDD have shown an affective attentional bias and evidence of cognitive impulsivity and impaired perfor-mance on visual memory tasks [32]. Furthermore, there are known associations of inattentive symptoms with impaired performance on neuropsychological measures such as visuospatial working memory (VSWM) [33,34]. This is consistent with the known overlap of the neu-ral substrates that subserve visuospatial attention and VSWM [35,36•], specifi cally right hemisphere–domi-nant acti vation in frontal and parietal brain regions [37]. Evidence of “executive” defi cits associated with DD in children and adolescents includes poor decision making [3] and poor performance on the Stroop task [30]. Adults with DD have shown performance defi cits on the Trail Making Task B and the Wisconsin Card Sorting Test. However, to date, VSWM has not been investigated in children and adolescents with DD. This will be important so that it can be ascertained whether VSWM impairments are developmental stage independent.

Further examination of the neuropsychological profi le of DD using measures of VSWM is supported by the fi nd-ings described subsequently. Disruption to frontostriatal neural networks has been associated with impairments in attention and VSWM [32–34]. Furthermore, models of the brain–behavior relationship between VSWM and the prefrontal cortex (PFC) are well supported by single neuronal fi ring rates in alert primates [38], studies of behavior following the development of focal PFC lesions in adult humans [39], and studies of patterns of regional cerebral blood fl ow (rCBF) in healthy humans performing VSWM tests [40]. The experimental VSWM paradigm can be applied to studies of children and adolescents with-out modifi cation [34]. Also, VSWM is largely nonverbal such that defi cits in verbal functioning observed in chil-

Page 3: ADHD and dysthymic disorder: Toward understanding this common comorbidity in children and adolescents

ADHD and Dysthymic Disorder I Vance and Winther I 147

dren with depressive disorders do not confound testing [6]. From a clinical viewpoint, most children with DD develop MDD (76%), suggesting that childhood DD is a “window of opportunity” for early identifi cation of and intervention against the development of MDD [2]. This suggests the importance of specifi c studies that character-ize DD in children, including clarifi cation of associated neuropsychological impairments such as VSWM.

Hence, our group investigated the association of DD with VSWM in children 6 to 12 years of age by examining the VSWM performance of medication-naive prepubertal children with DD [41]. Prepubertal children with DD demonstrated impaired VSWM performance that worsened as the cognitive demands of the VSWM task increased. Defi cits were also evident in the “spatial span” and “strategy” components of VSWM in the DD group. These fi ndings indicate that children with DD are impaired in their ability to maintain spatial information “online” in VSWM and in their ability to develop a systematic search strategy during task performance. Correlational analyses implied that defi cits in the main tenance and manipu lation of spatial information in VSWM contrib-uted to the impairment in overall VSWM ability displayed by the DD group. Furthermore, the VSWM impairment remained after we co-varied for spatial span. This implies that the executive component of VSWM is dysfunctional in children with DD.

These results extended the fi ndings of Matthews et al. [32] in adolescent girls with MDD. First, prepubertal children—boys and girls—with DD also manifest impaired VSWM performance. Second, spatial span is impaired in this younger group, unlike the adolescent sample. Third,

the executive component of VSWM is also dysfunctional in this younger group, despite their spatial span defi cits. Finally, these additional cross-sectional fi ndings in the younger group may refl ect depressive disorder–related pro-cesses rather than premorbid vulnerability alone.

Dysfunction in fronto-striatal-parietal neural net-works is associated with impaired ability to manipulate spatial information in VSWM [36•,37,42]. The VSWM performance defi cits—especially strategy—suggest that DD in children is associated with dysfunction in these fronto-striatal-parietal neural networks. In addition, defi cits in spatial span ability suggest that dysfunction involves the mid-ventrolateral, prefrontal, and posterior parietal cortical regions in DD [43].

Fronto-striatal-parietal dysfunction is also assoc-iated with clinically signifi cant inattention [34,42]. Furthermore, dysfunction in neural networks involving the dorsolateral PFC (DLPFC), anterior cingulate cortex, and striatal brain regions [44•] is thought to underpin the association of inattention and working memory. Given that the children with DD were signifi cantly more inat-tentive and that inattentive symptoms were signifi cantly associated with VSWM impairments, dysfunction in DLPFC-linked frontostriatal neural networks is impli-cated in childhood DD. However, the observed defi cits of VSWM may be linked to symptoms of inattention in general rather than DD specifi cally [21•].

Recently, our group compared VSWM performance of children with ADHD-CT alone; ADHD-CT and DD; and DD alone [45]. Children with ADHD-CT and DD were indistinguishable on their VSWM performance but differed in their approach to completing the VSWM task (Fig. 1). The ADHD-CT group relied on spatial span and strategy, whereas the DD group depended on strategy alone. As age increased, VSWM ability improved in all groups (Fig. 2).

Figure 1. Between-search errors (BSEs) by task diffi culty for atten-tion-defi cit/hyperactivity disorder combined type (ADHD-CT) alone, ADHD-CT and dysthymic disorder, and dysthymic disorder alone groups. BSE 2, 3, 4, 6, and 8 refer to BSEs for the respective box condi-tions (increasing task diffi culty). Vertical bars represent standard error bars. (From Vance [45]; with permission.)

Figure 2. Linear regressions of between-search error (BSE) and age for attention-defi cit/hyperactivity disorder combined type (ADHD-CT) alone, ADHD-CT and dysthymic disorder, and dysthymic disorder alone groups. (From Vance [45]; with permission.)

Page 4: ADHD and dysthymic disorder: Toward understanding this common comorbidity in children and adolescents

148 I ADHD Comorbidities

In summary, VSWM performance is signifi cantly impaired in ADHD and DD, with span and strategy impaired in both disorders. However, children and ado-lescents with ADHD rely mainly on span, whereas those with DD rely mainly on strategy. We now examine recent functional MRI (fMRI) spatial working memory fi ndings to elucidate key implicated brain regions.

fMRI spatial working memory paradigmSeminal structural and functional neuroimaging research has been conducted in children and adolescents with ADHD. Decreased volumes of prefrontal cortical, basal ganglia (primarily striatal), and temporal brain regions have been demonstrated, while increased volumes in parietal brain regions have been noted [42,46]. Apart from the signifi cant fMRI response inhibition paradigm studies in ADHD, recent VSWM fMRI paradigm studies have demonstrated decreased activation of right prefrontal cortical, striatal, and parietal brain regions in children and adolescents with ADHD [42,46]. In contrast, there is a striking lack of structural and functional neuroim-aging research in children and adolescents with DD, especially given its clinical importance. Hence, it is dif-fi cult to determine any key research directions based on the extant literature. Steingard et al. [47] have reported decreased frontal lobe volume and increased ventricu-lar size in children and adolescents with DD. Lyoo et al. [48] showed a decreased size of the corpus callosum genu in young adults with “minor depression” (DD or depres-sive personality disorder), while Trimble and van Elst [49] demonstrated increased amygdala volumes in adults with DD and temporal lobe epilepsy. Furthermore, Sarikaya et al. [50] reported decreased rCBF in inferior frontal (bilateral), superior frontal (right), posterior temporal (left), and parietal (bilateral) brain regions in adults with DD. However, it remains unclear whether these fi ndings are also evident in children and adolescents with DD. In con-trast, more evidence implicates the PFC, striatal, temporal, and amygdala brain regions in children and adolescents with MDD. Tutus et al. [51] noted decreased rCBF in the left anterofrontal and temporal brain regions in adolescents with MDD, while Kowatch et al. [52] reported decreased rCBF in the anterior thalamus, left parietal, and right caudate brain regions and increased rCBF in the mesial, right superior anterior, and left inferior lateral tempo-ral brain regions. Thomas et al. [53] reported decreased amygdala activation in depressed adolescents and contrast-ing increased amygdala activation in anxious adolescents. However, there are also replicated fi ndings of increased amygdala volume and activation in children and adoles-cents with MDD [46]. In addition, using fMRI, Killgore and Yurgelen-Todd [54] recently demonstrated increased medial orbitofrontal cortex and rostral anterior cingulate cortex activation in healthy adolescents experiencing a sad mood and demonstrating a sad affect. Furthermore, they noted that depressed mood correlated positively with left DLPFC and anterior cingulate cortex activity and

negatively with right DLPFC activity, consistent with affective lateralization seen in adulthood [46].

The adult MDD functional neuroimaging literature is much more developed: decreased activity in the left dorso-lateral and dorsomedial PFC and hippocampus along with increased activity in the subgenual PFC, bilateral postor-bital cortex, left ventrolateral PFC, and anterior insula are known associations [46]. Grimm et al. [55] recently noted the increased activity of the ventromedial PFC, pregenual anterior cingulate cortex, posterior cingulate cortex, sub-genual cingulate cortex (SGCC), and insula. Furthermore, Wagner et al. [56] linked increased rostral anterior cin-gulate cortex activity with decreased orbitofrontal cortex, left dorsolateral, dorsomedial PFC, and SGCC volumes. In addition, Liotti et al. [57] investigated healthy adults in the state of sadness. They demonstrated increased activity in the SGCC and insula associated with decreased activ-ity of the right DLPFC and posterior parietal cortex. In addition, this group hypothesized that direct and indirect connections between the right DLPFC and SGCC may be associated with respective reciprocal deactivation and hyperactivation of these brain regions that in turn sub-serve diminished attention in a sad mood. Given 1) these same frontoparietal brain regions subserve VSWM, 2) DD is characterized by chronic sad and/or irritable mood and has a greater-than-chance association with inattention, and 3) the behavioral neuroscience VSWM data presented earlier suggest that the inattention in the DD participants is subserved by decreased VSWM performance, our group examined the robust VSWM mental rotation fMRI probe in postpubertal adolescents and prepubertal children with categorically and dimensionally defi ned DD [46]. Both DD groups examined had signifi cant inattentive symptoms. Based on our previous work using the same fMRI mental rotation probe in children and adolescents with ADHD-CT [42,58], we hypothesized that 1) the postpubertal adolescents would activate the right inferior parietal cor-tex (Brodmann area [BA] 40), the right superior parietal (BA 7), and the right middle frontal (BA 10) regions less; and 2) the prepubertal children would activate less the right parieto-occipital areas (cuneus and precuneus, BA 19), the right inferior parietal lobe (BA 40), and the right caudate nucleus. Based on the current DD literature, we could not make any systematic predictions.

The adolescent DD sample demonstrated decreased activation of the right DLPFC and right parietal/precuneus regions, which was consistent with the fi ndings of Liotti et al. [57] of deactivation of this brain region in healthy adults in the state of sadness. Interestingly, the fi nding by Wagner et al. [56] of increased activity in ventromedial PFC (BA 10) is consistent theoretically with the presented fi ndings because the DD group activated this region less than the healthy control group. Decreased activation may signify an abnormally high basal level of activity in a par-ticular brain region or a failure to induce activation from a normal or decreased basal level of activity [46]. Some cau-tion with these interpretations is warranted because these

Page 5: ADHD and dysthymic disorder: Toward understanding this common comorbidity in children and adolescents

ADHD and Dysthymic Disorder I Vance and Winther I 149

are the fi rst data published for adolescents with carefully diagnosed DD, whereas the work of Liotti et al. [57] and Wagner et al. [56] is based on healthy adults and adults with MDD, respectively. It remains unclear whether their fi ndings relate to children and adolescents who are healthy or who have MDD, DD, or both conditions.

Importantly, the adolescent DD fi ndings are remark-ably consistent with our group’s previous fi ndings in adolescent ADHD-CT using the same fMRI mental rotation paradigm [42,58]. Two interconnected neural network systems seemed to be activated less in the ADHD-CT group compared with the healthy control participants: 1) the “action-attentional” system (including BA 46, 39, 40) that subserves disengaged, reoriented, and maintained attentional focus and inhibition of contex tually irrelevant stimuli [58] and 2) the superior parietal (BA 7) and mid-dle frontal (BA 10) areas that are involved in visuospatial manipulation [42,58]. This probably refl ects the similarly high levels of inattention evident in both disorders given that inattentive symptoms are part of the core symptom domains of both conditions.

The child DD sample demonstrated a qualitative pat-tern of decreased activation of the right DLPFC and right parietal/precuneus regions similar to that of the adoles-cent DD group, which was consistent with the fi ndings by Liotti et al. [57] of deactivation of this brain region in healthy adults in the state of sadness. The fi ndings by Grimm et al. [55] of increased basal activity in the pos-terior cingulate cortex and pregenual anterior cingulate cortex (BA 31 and 32) in adults with MDD are theoreti-cally consistent with the presented fi ndings because the DD group activated these regions less than the healthy control group. Furthermore, the decreased activation in the right insula of the DD group is consistent with previ-ous studies suggesting increased basal activity in the insula region in adults with MDD and healthy adults in the state of experiencing a sad mood and observed to have a sad affect [46]. Again, some caution with these interpretations is warranted because these are the fi rst data published for children with carefully diagnosed DD, whereas the work of Liotti et al. [57] and Grimm et al. [55] is based on healthy adults and adults with MDD, respectively. It remains unclear whether their fi ndings relate to children and adolescents who are healthy or who have MDD, DD, or both conditions.

The decreased activation of the right VLPFC and right inferior temporal region in the children with DD implicates decreased function of the ventral visuospatial pathway involved in object permanence [42,58]. Furthermore, the right striatal region was activated less in the prepubertal DD participants, which is consistent with a more wide-spread inactivation of right frontal-striatal-parietal neural networks known to subserve visuospatial attention and VSWM [42,58]. This widespread frontal-striatal-pari-etal inactivation was again remarkably consistent with our group’s previous fi ndings in prepubertal ADHD-CT using the same fMRI mental rotation paradigm [42].

As in these prepubertal ADHD-CT participants, these activation differences occurred despite a lack of behav-ioral performance difference on the mental rotation task, suggesting that activation differences are not simply due to poorer performance among the DD group. Rather, these activation differences may refl ect a dysfunctional use of the same and/or a different strategy that the children with DD use to complete the VSWM fMRI task, aside from the conscious willed approach taken by each child. As in the adolescents with DD, this probably refl ects the similarly high levels of inattention evident in both ADHD-CT and DD, given that inattentive symptoms are part of the core symptom domains of both conditions.

In summary, the expected key right frontal-stria-tal-parietal brain regions were activated less in the DD children and adolescents than they had been in those with ADHD. In addition, key prefrontal cortical and insula brain regions known to be associated with depressive disorders and sad mood were activated less in the DD children and adolescents.

Clinical ImplicationsWe now note some key clinical implications that arise from the above fi ndings that are emerging from the literature.

Early identifi cation of children and adolescents with ADHD and DD is imperative for the following reasons. First, both disorders are common and independent drivers of ODD behavior, the primary reason for referral to pub-lic mental health services. Second, boys are increasingly affected by both before puberty, and both disorders are associated with working memory defi cits that are known to contribute to learning diffi culties and language acquisi-tion diffi culties. Third, both disorders increase the risk of MDD and self-harm potential. Furthermore, the presence of ADHD increases the risk of prolonging DD. Fourth, ADHD and DD share common biological and psychoso-cial risk factors that may be additive in their effect—that is, they are worse in the presence of the comorbid state as opposed to in children and adolescents with ADHD or DD alone. Finally, whereas ADHD and DD have common defi cits, such as spatial working memory and right fron-tal-striatal-parietal underactivation, they also differ in the specifi c cognitive and neurological processes affected that comprise these common defi cits.

Hence, children and adolescents with ADHD and DD need to be referred to a specialist multidisciplinary team that can comprehensively assess both disorders and prioritize specifi c and targeted psychological and/or medication treatments for both. In particular, careful multi-informant reports from the child/adolescent and his or her parent(s) and teacher(s) are needed to adequately assess ADHD (mainly from parent/teacher reports) and DD (mainly from child/adolescent self-reports). Compre-hensive appraisal of language abilities and learning skills is necessary given the manifest association of working memory impairments with ADHD and DD. Also, a thor-

Page 6: ADHD and dysthymic disorder: Toward understanding this common comorbidity in children and adolescents

150 I ADHD Comorbidities

ough and careful risk assessment is necessary because of the increased self-harm potential of both ADHD and DD and the enhanced risk of developing MDD. This latter risk also requires careful ongoing longitudinal assess-ment, particularly across puberty, to ensure that MDD is identifi ed and managed early.

Specifi c and targeted psychological and/or medi cation treatments need to be evaluated in trials (eg, working memory training for adolescents and appropriate children with ADHD and DD). Comprehensive parent management training, child skills training, and teacher management training programs run in conjunction should be consid-ered. Encoding strategies, task persistence strategies, and organizing and prioritizing strategies need to become part of the skill base of children and adolescents with ADHD and DD. Educational and/or language remediation must be implemented where indicated. In addition, parent and child communication and relationship skills train-ing, emotional regulation training, and parental referral for tailored treatment of identifi ed psychopathology (eg, ADHD, depressive disorders, alcohol/drug abuse/dependence disorders) need to be considered on a case-by-case basis. Furthermore, the potential synergism between medication treatments (eg, stimulant medication for ADHD and selective serotonin reuptake inhibitor medication for DD) and the implemented psychological treatments needs to be assessed and maximized.

ConclusionsADHD and DD are commonly comorbid and associated with substantial ongoing morbidity, including a signifi -cantly increased risk of MDD and attendant self-harm. They appear to have common biological and psychosocial risk factors that may be additive in their effects (eg, spatial working memory and right frontal-striatal-parietal under-activation). However, different contributing cognitive and neural processes are evident in ADHD and DD that may require more specifi c and targeted intervention.

DisclosureNo potential confl icts of interest relevant to this article were reported.

References and Recommended ReadingPapers of particular interest, published recently,have been highlighted as:• Of importance•• Of major importance

1. American Psychiatric Association: Diagnostic and Statisti-cal Manual of Mental Disorders, edn 4. Washington, DC: American Psychiatric Association; 1994.

2. Kovacs M, Akiskal HS, Gatsonis C, et al.: Childhood-onset dysthymic disorder: clinical features and prospective natu-ralistic outcome. Arch Gen Psychiatry 1994, 51:365–374.

3. Ferro T, Carlson GA, Grayson P, et al.: Depressive disorders: distinction in children. J Am Acad Child Adolesc Psychiatry 1994, 33:664–670.

4. Masi G, Favilla L, Mucci M, et al.: Depressive symptoms in children and adolescents with dysthymic disorder. Psycho-pathology 2001, 34:29–35.

5. Mitchell J, McCauley E, Burke PM, et al.: Phenomenology of depression in children and adolescents. J Am Acad Child Adolesc Psychiatry 1988, 27:12–20.

6. Kovacs M, Goldston D: Cognitive and social cognitive-development of depressed children and adolescents. J Am Acad Child Adolesc Psychiatry 1991, 30:388–392.

7. Kovacs M, Obrosky S, Gatsonis C, et al.: First-episode major depression and dysthymic disorder in childhood: clinical and sociodemographic factors in recovery. J Am Acad Child Adolesc Psychiatry 1997, 36:777–784.

8. Klein DN, Norden KA, Ferro T, et al.: Thirty-month natu-ralistic follow-up study of early-onset dysthymic disorder: course, diagnostic stability, and prediction of outcome. J Abnorm Psychol 1998, 107:338–348.

9. Biederman J, Newcorn J, Sprich S: Comorbidity of attention defi cit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry 1991, 148:564–577.

10. Angold A, Costello EJ, Erkanli A: Comorbidity. J Child Psychol Psychiatry 1999, 40:57–87.

11. Maughan B, Rowe R, Messer J: Conduct disorder and oppo-sitional defi ant disorder in a national sample: developmental epidemiology. J Child Psychol Psychiatry 2004, 45:609–621.

12. Vance A, Arduca Y, Sanders M: The associations of oppositional defi ant behavior in children with attention defi cit hyperactivity disorder, combined type (ADHD-CT). J Affect Disord 2005, 86:329–333.

13. Loeber R, Burke JD, Lahey BB: Oppositional defi ant and conduct disorders: a review. J Am Acad Child Adolesc Psychiatry 2000, 39:1468–1484.

14. Taylor E, Schachar R, Thorley G, et al.: Conduct disorder and hyperactivity: I, Separation of hyperactivity and antisocial conduct in British child psychiatric patients. Br J Psychiatry 1986, 149:760–767.

15. Taylor E, Everitt B, Schachar R, et al.: Conduct disorder and hyperactivity: II, A cluster analytic approach to the identifi cation of a behavioural syndrome. Br J Psychiatry 1986, 149:768–777.

16. Taylor E, Sandberg S, Thorley G, et al.: The Epidemiology of Childhood Hyperactivity. Institute of Psychiatry Maudsley Monograph. London: Oxford University Press; 1991.

17. Piek JP, Pitcher TM, Hay DA: Motor coordination and kinaesthesis in boys with attention defi cit hyperactivity disorder. Dev Med Child Neurol 1999, 41:159–165.

18. Shaffer D, Schonfeld I, O’Connor P: Neurological soft signs: their relationship to psychiatric disorder and intel-ligence in childhood and adolescence. Arch Gen Psychiatry 1985, 42:342–351.

19. Pine DS, Shaffer D, Shonfeld IS: Persistent emotional disorders in children with neurological soft signs. J Am Acad Child Adolesc Psychiatry 1993, 32:1229–1236.

20. Pine DS, Wasserman GA, Fried JE, et al.: Neurological soft signs: one-year stability and relationship to psychiatric symptoms in boys. J Am Acad Child Adolesc Psychiatry 1997, 36:1579–1586.

21.• Vance A, Arduca Y, Sanders M, et al.: ADHD, combined type, dysthymic disorder and anxiety disorders: differential patterns of neurodevelopmental defi cits. Psychiatry Res 2006, 143:213–222.

This article was the fi rst to parse neurodevelopmental defi cits related to DD from anxiety disorders. It affi rms the importance of careful clinical examination of children with early-onset depressive disorders.22. Faraone SV, Biederman J: Do ADHD and major depres-

sion share familial risk factors? J Nerv Ment Dis 1997, 185:533–541.

23. Mick E, Biederman J, Santangelo S, et al.: The infl uence of gender in the familial association between ADHD and major depression. J Nerv Ment Dis 2003, 191:699–705.

Page 7: ADHD and dysthymic disorder: Toward understanding this common comorbidity in children and adolescents

ADHD and Dysthymic Disorder I Vance and Winther I 151

24. Biederman J, Faraone SV, Keenan K, et al.: Familial association between attention defi cit disorder and anxiety disorders. Am J Psychiatry 1991, 148:251–256.

25. Biederman J, Faraone SV, Keenan K, et al.: Evidence of familial association between attention defi cit hyperactivity disorder and major affective disorders. Arch Gen Psychiatry 1991, 48:633–642.

26. Befera MS, Barkley RA: Hyperactive and normal girls and boys: mother child interaction, parent psychiatric studies and child psychopathology. J Child Psychol Psychiatry 1985, 26:439–452.

27. Klein D, Riso L, Donaldson SK, et al.: Family study of early-onset dysthymia: mood and personality disorders in relatives of outpatients with dysthymia and episodic major depression and normal controls. Arch Gen Psychiatry 1995, 52:487–496.

28. Lizardi H, Klein D: Parental psychopathology and reports of the childhood home environment in adults with early-onset dysthymic disorder. J Nerv Ment Dis 2000, 188:63–70.

29. Vance A: ADHD, combined type in primary school age children: investigations of its association with oppositional defi ant, dysthymic and anxiety disorders. In Attention Defi cit Hyperactivity Disorder (ADHD) Research. Edited by Larimer MP. New York: Nova Press; 2005:59–94.

30. Cataldo MG, Nobile M, Lorusso ML, et al.: Impulsivity in depressed children and adolescents: a comparison between behavioural and neuropsychological data. Psychiatry Res 2005, 136:123–133.

31. Lauer RE, Giordani B, Boivin MJ, et al.: Effects of depres-sion on memory performance and metamemory in children. J Am Acad Child Adolesc Psychiatry 1994, 33:679–685.

32. Matthews K, Coghill D, Rhodes S: Neuropsychological functioning in depressed adolescent girls. J Affect Disord 2008, 111:113–118.

33. Kempton S, Vance A, Maruff P, et al.: Executive function and attention defi cit hyperactivity disorder: stimulant medication and better executive function performance in children. Psychol Med 1999, 29:527–538.

34. Barnett R, Maruff P, Vance A, et al.: Abnormal executive function in attention defi cit hyperactivity disorder: the effect of stimulant medication and age on spatial working memory. Psychol Med 2001, 31:1107–1115.

35. Smyth MM: Interference with rehearsal in spatial working memory in the absence of eye movements. J Exp Psychol 1996, 49:940–949.

36.• Awh E, Vogel EK, Oh SH: Interactions between attention and working memory. Neuroscience 2006, 139:201–208.

This article clearly presents the common neurobiological underpin-nings of attentional and working memory systems in humans and nonhuman primates.37. Awh E, Jonides J: Spatial selective attention and spatial

working memory. In The Attentive Brain. Edited by Para-suraman R. Cambridge, MA: MIT Press; 1998:353–380.

38. Goldman-Rakic PS: Circuitry of primate prefrontal cortex and regulation of behavior by representational memory. In Handbook of Physiology, the Nervous System Higher Functions of the Brain, vol V. Edited by Plum F. Bethesda, MD: American Physiological Society; 1987:373–417.

39. Owen AM, Roberts AC, Hodges JR, et al.: Contrasting mechanisms of attentional set-shifting in patients with frontal lobe damage or Parkinson’s disease. Brain 1993, 116:1159–1175.

40. D’Esposito M, Detre JA, Alsop DC, et al.: The neural basis of the central executive system of working memory. Nature 1995, 378:279–281.

41. Franklin T, Lee A, Hall N, et al.: The association of visuospatial working memory with dysthymic disorder in pre-pubertal children. Psychol Med 2009 Jul 17 (Epub ahead of print).

42. Vance A, Silk T, Rinehart N, et al.: Right parietal dysfunc-tion in children with attention defi cit hyperactivity disorder, combined type: a functional MRI study. Mol Psychiatry 2007, 12:826–832.

43. Owen AM, Evans AC, Petrides M: Evidence for a two-stage model of spatial working memory processing within the lateral frontal cortex: a positron emission tomography study. Cereb Cortex 1996, 6:31–38.

44.• Castellanos FX, Sonuga-Barke EJS, Milham MP, et al.: Characterizing cognition in ADHD: beyond executive dysfunction. Trends Cogn Sci 2006, 10:117–123.

This article outlines an infl uential current model for understand-ing how different prefrontal cortical neural networks may lead to cognitive defi cits as fi nal common pathways in ADHD.45. Vance A: Stimulant medication response in ADHD and

comorbid anxiety disorder. In A Handbook of ADHD. Edited by Bellgrove M, Fitzgerald M, Gill M. Chichester, United Kingdom: Wiley; 2007:331–354.

46. Vance A: ADHD and dysthymic disorder in children and adolescents: recent insights from cognitive neuroscience and functional magnetic resonance imaging. In Attention Defi cit Hyperactivity Disorder Research. Edited by Gordon SM, Mitchell AE. New York: Nova Press; 2009:1–35.

47. Steingard RJ, Renshaw PF, Turgelen-Todd D, et al.: Struc-tural abnormalities in brain magnetic resonance images of depressed children. J Am Acad Child Adolesc Psychiatry 1996, 35:307–311.

48. Lyoo IK, Kwon JS, Lee SJ, et al.: Decrease in genu corpus callosum in medication naïve early onset dysthymia and depressive personality disorder. Biol Psychiatry 2002, 52:1134–1143.

49. Trimble MR, van Elst LT: The amygdala and psycho-pathological studies in epilepsy. Ann N Y Acad Sci 2003, 985:461–468.

50. Sarikaya A, Karasin E, Cermik TF, et al.: Evaluation of dysthymic disorder with technetium-99 brain single-photon emission tomography. Eur J Nucl Med 1999, 26:260–264.

51. Tutus A, Simsek A, Sofuoglu S, et al.: Changes in regional cerebral blood fl ow demonstrated by single-photon emission computed tomography. Psychiatry Res 1998, 83:169–177.

52. Kowatch RA, Devous MD Sr, Harvey DC, et al.: A SPECT HMPAO study of regional cerebral fl ow in depressed ado-lescents and normal controls. Prog Neuropsychopharmacol Biol Psychiatry 1999, 23:643–656.

53. Thomas KM, Drevets WC, Dahl RE, et al.: Amygdala response to fearful faces in depressed and anxious children. Arch Gen Psychiatry 2001, 58:1057–1063.

54. Killgore WD, Yurgelen-Todd DA: Ventromedial prefrontal activity correlates with depressed mood in adolescent children. Neuroreport 2006, 17:167–171.

55. Grimm S, Boesonger P, Beck J, et al.: Altered negative BOLD responses in the default-mode network during emotion processing in depressed subjects. Neuropsycho-pharmacology 2009, 34:932–943.

56. Wagner G, Koch K, Schachtzabel C, et al.: Enhanced rostral anterior cingulate cortex activation during cognitive control is related to orbitofrontal volume reduction in unipolar depression. J Psychiatry Neurosci 2008, 33:199–208.

57. Liotti M, Mayberg HS, Brannan SK, et al.: Differential limbic-cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders. Biol Psychia-try 2000, 48:30–42.

58. Silk T, Vance A, Rinehart N, et al.: Decreased frontal-striatal-parietal activation in attention defi cit hyperactivity disorder, combined type (ADHD-CT): an fMRI study. Br J Psychiatry 2005, 187:282–283.