A Conceptual Review of The Comorbidity of Attention-Deficithyperactivity

Clinical Psychology Review 28 (2008) 12661280
Contents lists available at ScienceDirect
Clinical Psychology Review
A conceptual review of the comorbidity of attention-decit/hyperactivity disorder and anxiety: Implications for future research and practice
Matthew A. Jarrett , Thomas H. Ollendick
Child Study Center, Department of Psychology, Virginia Polytechnic Institute and State University, 460 Turner Street, Suite 207, Blacksburg, VA 24060, United States
a r t i c l e
i n f o
a b s t r a c t
Although approximately 25% of children with attention-decit/hyperactivity disorder (ADHD) exhibit an anxiety disorder, the comorbidity of ADHD and anxiety has been given less attention than comorbidity of ADHD and oppositional or conduct disorders. While it is true that comorbidity between ADHD and these externalizing disorders is more prevalent (approximately 50%), the comorbidity of ADHD and anxiety deserves careful scrutiny in its own right in as much as this comorbidity may have important implications for etiology, assessment, and treatment. The primary purpose of the current review is to examine the methodological and substantive reasons for the comorbidity of ADHD and anxiety. Methodological areas include denitional issues and informant characteristics, while substantive areas include genetics, temperament, neurobiological and neuropsychological functioning, family inuences, and temporal relations between ADHD and anxiety. The study of the comorbidity of ADHD and anxiety will be advanced through a more precise phenotypic classication of ADHD and the integration of research in adjacent elds such as temperament and genetics with current research on the psychopathology of ADHD. 2008 Elsevier Ltd. All rights reserved.
Article history: Received 17 December 2007 Received in revised form 5 May 2008 Accepted 9 May 2008 Keywords: ADHD Anxiety Comorbidity
Contents Methodological reasons for the comorbidity of ADHD and anxiety . Substantive reasons for the comorbidity of ADHD and anxiety. . . 2.1. Genetic inuence . . . . . . . . . . . . . . . . . . . . 2.2. Temperament . . . . . . . . . . . . . . . . . . . . . . 2.3. Neurobiological and neuropsychological functioning . . . . 2.4. Family inuences . . . . . . . . . . . . . . . . . . . . 2.5. Temporal relations between ADHD and anxiety . . . . . . 3. Summary, conclusions, and future directions . . . . . . . . . . . 3.1. Summary and conclusions . . . . . . . . . . . . . . . . 3.2. Future directions for research . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1267 1269 1269 1271 1272 1273 1274 1275 1275 1276 1277
Although strong evidence supports the clinical validity of attention-decit/hyperactivity disorder (ADHD; Barkley, 2006), ADHD remains a heterogeneous disorder with multiple etiologies (Nigg, 2006b; Nigg & Casey, 2005). At the symptom level, an
Corresponding author. Tel.: +1 540 231 2024; fax: +1 540 231 8193. E-mail address: mjarrett@vt.edu (M.A. Jarrett). 0272-7358/$ see front matter 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.cpr.2008.05.004
M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280
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ADHD prole can involve various combinations of the core symptoms of the disorder: inattention, hyperactivity, and impulsivity. The challenge of appropriately dening ADHD can be seen in the changes to diagnostic criteria over the years. Attention-decit disorder (ADD) was rst introduced in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III; American Psychiatric Association, 1980) and included two subtypes: ADD with hyperactivity (ADD + H; inattention, hyperactivity, impulsivity) and ADD without hyperactivity (ADD/WO; inattention and impulsivity). DSM-III-R subsequently dropped the subtype approach and introduced the general disorder of attention-decit/hyperactivity disorder (ADHD; inattention, hyperactivity, impulsivity; American Psychiatric Association, 1987). Finally, DSM-IV returned to the subtype approach and included three subtypes of the disorder based on the two primary symptom dimensions of inattention and hyperactivityimpulsivity: ADHD, predominantly inattentive type (ADHD-I), ADHD, combined type (ADHD-C), and ADHD, predominantly hyperactive/impulsive type (ADHD-H/I; American Psychiatric Association, 1994). In addition to the problem of dening the disorder, ADHD is often found to be highly comorbid with other disorders, including both internalizing (13% to 51%) and externalizing disorders (43% to 93%), suggesting that pure ADHD is the exception rather than the rule (Jensen et al., 2001; Jensen, Martin, & Cantwell, 1997). Given heterogeneity in both core and covarying symptomatology, comorbidity has become an important ADHD topic of inquiry in the last 10 to 15 years, leading some authors to advocate for distinct comorbid subtypes of ADHD (Barkley, 2006; Jensen et al., 2001; Jensen et al., 1997). Studies to date have focused primarily on the comorbidity of ADHD and externalizing disorders with fewer studies examining the comorbidity of ADHD and internalizing disorders like the anxiety disorders. One reason for this lag in research is that ADHD is comorbid with externalizing disorders at a rate higher than anxiety disorders (Angold, Costello, & Erkanli, 1999; Biederman, Newcorn, & Sprich, 1991b; Jensen et al., 1997). At the same time, the comorbidity of ADHD and anxiety is substantial with an average comorbidity rate of 25% found in epidemiological and clinical samples (Biederman et al., 1991b; Jensen et al., 1997; Tannock, 2000). In recent years, Pliszka, Carlson, and Swanson (1999) and Tannock (2000) reviewed the comorbidity of ADHD and anxiety with a specic focus on clinical management of the disorder. These past reviews have been valuable in suggesting important directions for clinical practice. In contrast, the current review will focus more specically on theoretical and conceptual reasons underlying the comorbidity of ADHD and anxiety. In addition, the review will examine both methodological and substantive reasons for the comorbidity of ADHD and anxiety. Given that the review is primarily focused on ADHD and its comorbidities, the anxiety disorder literature will not generally be reviewed, but comprehensive reviews are available (Ollendick & Seligman, 2006; Silverman & Ginsburg, 1998). In relation to ADHD, the review will focus primarily on the ADHD-C subtype. At this point in time, ADHD-H/I has a limited research base (Barkley, 2006) and ADHD-I is more controversial and may be qualitatively different from ADHD-C (Diamond, 2005; Milich, Balentine, & Lynam, 2001). In addition, the review will focus primarily on pre-pubertal children, as the majority of the research on ADHD has been conducted within this age group. Data on adolescents will be presented when available. Finally, it should be noted that Schatz and Rostain (2006) recently reviewed comorbidity of ADHD and anxiety but focused primarily on neuropsychological functioning. The current review is broader in scope, focusing on multiple reasons for the comorbidity of ADHD and anxiety and drawing from research in adjacent elds to offer promising directions for future research. 1. Methodological reasons for the comorbidity of ADHD and anxiety Substantive reasons for comorbidity (see below) are often of more theoretical interest; however, from a practical standpoint, artifactual or methodological reasons for the comorbidity of ADHD and anxiety cannot be ignored when examining rates of comorbidity. Although a recent meta-analysis of epidemiological studies concluded that methodological reasons can be eliminated as the major cause of comorbidity (Angold et al., 1999), they have still presented a major challenge to the study of comorbidity. Methodological differences across studies include differences in denitions of ADHD symptoms, sources of information, and diagnostic thresholds used to dene disorder (Szatmari, Offord, & Boyle, 1989). A review of all methodological concerns is outside the scope of this paper, so the current section will focus on two areas that seem most important in resolving some of the methodological dilemmas in ADHD comorbidity research: namely, denitional issues and the combinatorial strategies that are used in arriving at diagnoses. Changes in the diagnostic criteria of ADHD were commented upon in the introduction, and similar changes have occurred to the denitions of anxiety disorders. In the change from DSM-III-R to DSM-IV, Tannock (2000) noted that the three anxiety disorders that were originally considered disorders of childhood and adolescence (i.e., separation anxiety disorder (SAD), overanxious disorder (OAD), and avoidant disorder) were reduced to only one childhood-specic disorder (i.e., SAD). OAD and avoidant disorder were subsumed under generalized anxiety disorder (GAD) and social phobia (SOP), respectively. These changes make it particularly difcult to compare lines of research based on different criteria, and they have resulted in a number of inconsistent ndings. Nosological issues related to symptom overlap also pose a challenge for ADHD and anxiety research. Tannock (2000) noted that the new increased overlap between symptoms of ADHD and GAD (e.g., restlessness, irritability, sleep disturbance, and difculty concentrating) could serve to increase comorbid rates of ADHD and GAD in DSM-IV studies. The most common hypothesis regarding ADHD and anxiety overlap is that anxiety may lead to either worry or intrusive thoughts that manifest as inattention or that restlessness/nervousness presents as hyperactivity or impulsivity. Common DSM-IV symptoms that could account for this overlap include poor concentration, difculty sustaining attention, and nervousness/restlessness. Few empirical studies have addressed this issue, but some limited data are available. Milberger, Biederman, Faraone, Murphy, and Tsuang (1995) examined the overlap of ADHD and GAD in adults and found that 75% of the sample still met criteria for ADHD and 76% of the sample still met criteria for GAD after removing common symptoms. Unfortunately, this study did not examine symptom overlap in relation to ADHD-I, the subtype of the disorder that would presumably be most affected by common symptoms. Although symptoms of
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hyperactivity and impulsivity may be less problematic in relation to symptom overlap, more data are needed to validate this conclusion, particularly given ndings that certain types of anxiety appear to manifest as anxious impulsivity (Epstein, Goldberg, Conners, & March, 1997; Nigg, Goldsmith, & Sachek, 2004). Such a form of anxiety could lead to restless behavior that could be interpreted as hyperactivity. Another challenge for research on ADHD and anxiety is study-specic denitions of psychopathology. As noted earlier, some studies have pooled diagnostic data to create groups. As noted by Caron and Rutter (1991), comorbidity within these pooled categories is not taken into account when such methods are used (e.g., comorbidity among anxiety disorders). Studies have also utilized both DSM-IV symptom approaches to measuring psychopathology as well as dimensional approaches that use different but related constructs (e.g., attentional problems on a dimensional rating scale). Mennin, Biederman, Mick, and Faraone (2000) noted that there has been considerable variability in the denitions of anxiety in studies examining the comorbidity of ADHD and anxiety. Using a Receiver Operating Characteristic (ROC) analysis to dene a meaningful anxiety phenotype, Mennin et al. (2000) used what they termed a gold standard of anxiety Anxiety/Depression on either the Child Behavior Checklist (CBCL) or Youth Self Report (YSR) greater than 70, a positive family history of anxiety, and social problems as indicated by the Social Adjustment Inventory for Children and Adolescents (SAICA) to examine the number of anxiety disorders needed to classify children with ADHD with and without the gold standard. The study found that having two or more anxiety disorders correctly identied a large number of children with ADHD as meeting the gold standard while maintaining a reasonable false positive rate. The categories of three or more anxiety disorders and one or more anxiety disorders were less effective in identifying the gold standard. This study subsequently advocated for researchers to categorize anxiety using the criterion of two or more anxiety disorders. Other studies have shown that the effect of using multiple comorbidities as the grouping variable may be problematic. August, Realmuto, MacDonald, Nugent, and Crosby (1996) found that when cases involving ADHD in combination with one additional diagnosis were considered, comorbidity rates increased to 18% for oppositional deant disorder (ODD), 7% for conduct disorder (CD), 3% for mood problems, and 6% for anxiety problems. When involving two or more additional diagnoses, rates increased to 32% (ODD), 12% (CD), 30% (mood), and 34% (anxiety). August et al. (1996) proposed that this nding may be due to parental overreporting of psychopathology, but it may be that these children with multiple comorbidities simply experience symptoms in multiple domains. Using the criterion of multiple comorbidities could serve to inate the rates of other comorbidities, but it may be valuable in identifying a phenotype that matches a certain criterion (Mennin et al., 2000). Nosological and denitional issues are also compounded by informant effects. Lilienfeld (2003) reviewed methodological concerns in studies of comorbidity and noted that method covariance due to shared modes of assessment and informant biases can contribute to methodological problems. Over the past few decades, researchers have recommended a multi-informant assessment to obtain a complete diagnostic picture of the child (Ollendick & Hersen, 1993). However, inclusion of multiple informants poses unique challenges in the study of comorbidity. Lilienfeld (2003) noted that informants may overestimate or underestimate comorbidity due to implicit personality theories. For example, halo effects in relation to reporters may have serious implications for research on ADHD and anxiety. Gershon (2002) indicated that teachers often see inattention in ADHD boys in the context of externalizing behaviors, which may result in the under-identication of inattention in children only exhibiting inattention (e.g., girls). Moreover, teachers may develop implicit theories about classroom behavior and exhibit a halo effect in that they tend to notice inattention only in the context of disruptive behavior (Abikoff, Courtney, Pelham, & Koplewicz, 1993; Gershon, 2002). Lilienfeld (2003) notes that another challenge is the issue of a unique information source vs. unique behaviors exhibited in a particular setting. For example, when parents and teachers disagree on a child's behavior, it may be that the informants are rating behaviors that are only exhibited in one setting or they may simply be biased in their ratings. In reality, both of these inuences are most likely operative, making it particularly challenging to utilize information from multiple informants. Additional studies are needed to disentangle reporter bias from context-specic behaviors (Epstein et al., 2005). Given these discrepancies, researchers have looked for the best informants and strategies for combining child, parent, and teacher reports of psychopathology (Jensen, 2003; Youngstrom, Findling, & Calabrese, 2003). Unfortunately, the inclusion of multiple sources has resulted in signicant disagreement among child, parent, and teacher informants (De Los Reyes & Kazdin, 2005; Grills & Ollendick, 2003). Youngstrom et al. (2003) examined common decision strategies for combining information from multiple informants including disjunctive, conjunctive, and compensatory rules. The disjunctive rule would result in a diagnosis when a parent OR child endorses a diagnosis. The conjunctive rule would require a parent AND a child to both endorse a diagnosis. Finally, the compensatory rule allows for information from different sources to be combined to form an aggregate measure. For example, high scores from a parent informant could be offset by low scores from a child informant. Using these different strategies, Youngstrom et al. (2003) found that comorbidity rates varied from 5% to 74%, indicating the powerful effect of combinatorial strategies on rates of comorbidity. Jensen (2003) added to these denitions by proposing a discriminative strategy. This strategy would allow the clinician to determine when to use one, another, or multiple informants. Such a strategy sacrices standardization but allows the clinician to determine the validity of various reports. Although this approach has intuitive appeal, concerns about the biases of clinicians should be considered when employing this strategy. For example, clinicians may be selective in the data they use to conrm a working hypothesis about diagnoses. Overall, Jensen (2003) concluded that clinicians should split rst rather than combine information, since greater specicity is needed in the study of informant discrepancies and such specicity is lost when data are combined. Finally, Jensen concluded that no one combinatorial strategy has sufcient evidence to work effectively at this time. Although most studies of methodological issues have examined comorbidity at a general level, a few studies in the ADHD literature are relevant to the comorbidity of ADHD and anxiety specically. Pliszka (1992), for example, found that half of the children with ADHD who met criteria for OAD by their own report did not meet criteria for anxiety according to parent report, suggesting that parents may be unaware of child anxiety. Tannock (2000) compared two groups of children with ADHD and
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anxiety. These groups included one group in which children endorsed anxiety and another group in which children denied anxiety but parents reported anxiety. Only children who endorsed anxiety themselves showed lower levels of self-condence and impairment in daily activities. These studies suggest that disagreement on anxiety in children with ADHD is common and that there are clinical correlates of disagreement, which is clearly a methodological concern for studies using more than one informant. Discrepancy itself has also been conceptualized as a way to understand the nature and severity of ADHD and its co-occurring disorders (McGrath, Handwerk, Armstrong, Lucas, & Friman, 2004; Volpe, DuPaul, Loney, & Salisbury, 1999). Among children rated by parents as having elevated Attention Problems on the Child Behavior Checklist (CBCL), Volpe et al. (1999) found that children who endorsed an ADHD diagnosis (in agreement with their parents) reported signicantly more anxiety and depression symptoms than children who did not endorse an ADHD diagnosis. In a more recent analysis of parentchild agreement in adolescents, McGrath et al. (2004) reported a similar trend when comparing a parent plus child ADHD group to a parent-only ADHD group. Finally, Jarrett, Wolff, and Ollendick (2007) found that children who agreed with their parent on the presence of ADHD reported more symptoms of anxiety and depression on child self-report measures. In addition, these effects did not seem to be due to social desirability or a general tendency to overendorse psychopathology. Interestingly, the parent + child ADHD group did not differ from the parent-only ADHD group on anxiety diagnoses obtained from a consensus diagnosis meeting utilizing multiple measures and informants (see Grills & Ollendick, 2003, for details). The implication of these ndings is that a child may also possess internalizing problems when both a parent and a child agree on the presence of ADHD. This nding suggests that research studies that use parentchild agreement on ADHD (i.e., the conjunctive rule) as a diagnostic strategy may be articially increasing rates of internalizing disorders in the sample (at least for child report). In summary, it is clear that there are many methodological challenges in the study of ADHD and anxiety. The comorbidity of ADHD and anxiety seems to be a real phenomenon that cannot be explained solely by symptom overlap; nonetheless, this overlap certainly has some inuence on rates of comorbidity. One of the most valuable recommendations for future studies is to utilize different denitional approaches and combinatorial strategies to determine the effect of these inuences on comorbidity ndings (Youngstrom et al., 2003). In addition, there should be a greater focus on theoretical reasons for discrepancy in order to better understand why parentchild, parentteacher, motherfather, and teacherchild discrepancies are commonly observed (De Los Reyes & Kazdin, 2005). As for issues such as informant biases, few recommendations can be provided at this time, although some statistical approaches such as conrmatory factor analysis and structural equation modeling have shown promise in removing random error in parent and teacher measures of child behavior (Epstein et al., 2005; Keiley, Lofthouse, Bates, Dodge, & Pettit, 2003; Pillow, Pelham, Hoza, Molina, & Stultz, 1998). Systematic error such as reporter biases may be more problematic, but comparing objective behavior with informant ratings may be one way to account for such biases (Epstein et al., 2005). 2. Substantive reasons for the comorbidity of ADHD and anxiety Although methodological issues clearly exist in the study of comorbidity, substantive reasons for the observed comorbidities must also be examined carefully. A number of authors have outlined possible substantive explanations for comorbidity (Angold et al., 1999; Caron & Rutter, 1991; Lilienfeld, 2003) and Tannock (2000) has outlined a series of hypotheses regarding the specic comorbidity of ADHD and anxiety. These pathways include 1) attention problems as secondary to anxiety; 2) the development of anxiety following the chronic failure experienced by children with ADHD; 3) the two disorders having relatively separate and distinct etiologies and treatment responses (e.g., ADHD and anxiety involving different genes); and 4) a separate disorder in and of itself, currently unclassied with a distinct course, etiology, and treatment response (e.g., ADHD and anxiety having a unique set of genes that differ from ADHD and anxiety individually). These hypotheses assume that the relationship between ADHD and anxiety is not a spurious relationship resulting from symptom overlap or independent associations with a third variable such as ODD or CD. Evidence to date suggests that the comorbidity between ADHD and anxiety is not epiphenomenal (Angold et al., 1999). In order to evaluate these hypotheses, this section will review substantive areas that appear to have promise in elucidating the observed comorbidity. These areas include 1) genetic inuences, 2) temperament, 3) neurobiological and neuropsychological functioning, 4) family inuences, and 5) temporal relations between ADHD and anxiety. 2.1. Genetic inuence Research on the genetics of psychopathology has surged in the last decade, partially due to the multidisciplinary focus of the developmental psychopathology movement (Rutter & Sroufe, 2000). Studies have generally evaluated the heritability of ADHD as a single disorder, but recent studies have addressed comorbidity through familial association studies and alternative procedures for classifying symptomatology among twins (e.g., latent class analysis). One line of research on genes and dopamine (Cook et al., 1995; Faraone, Doyle, Mick, & Biederman, 2001; Swanson et al., 2000) has been highly inuential and has led to a signicant body of research on genes and ADHD (see Levy & Hay, 2001) However, these studies have not directly addressed the comorbidity of ADHD and anxiety and will not be reviewed further. In addition, a line of research has emerged examining endophenotypes, or phenotypes that are more closely linked to the specic neurobiological substrates of the disorder, but this line of research has also not been directly linked to anxiety in ADHD. In turn, this research area will not be reviewed; however see Doyle et al. (2005) for a systematic review. Finally, some studies have extended beyond behavioral genetics to explore the molecular genetics of ADHD. These studies too are outside the scope of this paper (see Faraone & Biederman, 1998; Faraone et al., 2005). In the following section, general ndings in ADHD genetic research will be reviewed followed by a description of two approaches that are most relevant to ADHD and anxiety comorbidity research: latent class analysis in twin studies and familial association studies.
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The strongest evidence for heritability of ADHD comes from twin studies of ADHD which have found heritability to range from .6 to .9 (Levy, Hay, McStephen, Wood, & Waldman, 1997; Nadder, Silberg, Eaves, Maes, & Meyer, 1998; Sherman, McGue, & Iacono, 1997). One of the debates among genetic researchers is whether ADHD should be conceptualized as a diagnostic category or a quantitative trait (Faraone et al., 1992; Todd, 2000a). Deater-Deckard, Reiss, Hetherington, and Plomin (1997) note that genetic research has been divided based on whether the population studied is considered normal or abnormal, as studies of normal development have utilized continuous measures of traits and studies of abnormal development have relied on categorical diagnoses. Levy et al. (1997) addressed this issue with regard to ADHD by examining whether ADHD is better conceptualized as a category or a continuum. The study found that ADHD is best viewed as an extreme of behavior that varies throughout the entire population. Evidence for this conclusion came from the nding that ADHD was not signicantly more heritable as a disorder than as a trait. In addition to a dimensional view of ADHD, genetic studies have sought to better categorize the phenotype of ADHD. Recent studies have utilized latent class analysis (LCA), a statistical clustering technique (McCutcheon, 1987), in population-based samples of twins to test for the heritability of naturally-occurring clusters of ADHD symptomatology. When conducted with twin samples, the relative prevalence of monozygotic and dizygotic pairs in which both twins are in the same latent class serves as an index of heritability. These studies have found the heritability of DSM-IV ADHD subtypes to be high in girls (70% to 85% depending on the subtype) and have provided evidence for the independent transmission of inattentive and hyperactive/impulsive symptoms (Todd, 2000a). Although studies have used LCA in conjunction with DSM symptom domains (i.e. the two domains of inattention and hyperactivityimpulsivity), these studies have also used LCA to classify ADHD symptom domains in the population. The majority of studies conducted on ADHD have resulted in eight heritable subtypes of ADHD symptoms (Hudziak et al., 1998; Neuman et al., 1999; Rasmussen et al., 2002, 2004; Todd et al., 2001; Volk, Neuman, & Todd, 2005). These subtypes include a no-symptom class, a talkative class, three classes representing mild or moderate symptomatology of the three DSM-IV subtypes, and three classes representing severe symptomatology associated with the three DSM-IV subtypes (Todd, 2000a). It should be noted that DSM-IV subtypes have not clearly mapped onto the specic latent classes (e.g., ADHD-H/I on the severe hyperactive class), suggesting that DSM-IV subtypes and LCA subtypes may be identifying and subsequently examining different phenotypic groups (Todd et al., 2001). The strongest evidence in relation to the DSM-IV is for two ADHD subtypes: ADHD-I and ADHD-C (Todd, 2000b). There is some evidence, though, for a less common latent class reecting ADHD-H/I (Hudziak et al., 1998). Finally, the evidence from LCA studies suggests that ADHD reects two or more continua (e.g., inattention, hyperactive-impulsive, combined) and latent classes reect points along these continua. This view implies the presence of a number of genetic forms of ADHD (Todd, 2000b). Although several studies have examined core ADHD symptoms, few studies have examined the clustering of ADHD symptomatology and covarying symptomatology (Neuman et al., 2001; Todd et al., 2001; Volk, Neuman, & Todd, 2005). In relation to ADHD and anxiety, only one study was found that utilized LCA of ADHD and anxiety disorders. Neuman et al. (2001) used LCA to identify subtypes of ADHD taking into account comorbidity with SAD, ODD, and depression. The study found three ADHD categories of interest: an inattentive subtype without comorbidity, a second inattentive subtype with ODD symptoms, and a combined inattentive/hyperactive-impulsive type with ODD, SAD, and depressive symptoms. A handful of other studies have provided data on the clustering of ADHD and covarying symptomatology. Todd et al. (2001) found that the majority of conduct problems occurred in the latent class that most closely represented ADHD-C (i.e., severe combined). In contrast, the latent class most closely resembling ADHD-I contained few children with conduct problems. It should be noted, though, that both of these studies utilized female twins, so the results may be restricted to females with ADHD. Volk et al. (2005) examined male and female twins and found that LCA of ADHD symptoms resulted in the categories of few ADHD symptoms and severe inattentive being most frequent. LCA of ODD, CD, and depressive symptoms resulted in classes of ODD, depression, and two composite classes: ODD/CD and ODD/CD/depression. These ndings support the view of ODD/CD as a distinct clinical entity. ODD, CD, and depression occurred primarily in individuals in the ADHD-C latent class, while ODD-only also occurred primarily in ADHD-C latent class. It should be noted, though, that these disorders also frequently occurred for less severe latent classes as well. Generally, internalizing and externalizing disorders did not cluster differentially within the ADHD latent classes (i.e., inattentive, hyperactive-impulsive, combined). Although few conclusions can be drawn from these limited data, ADHD-C seems to be associated with greater internalizing and externalizing problems than ADHD-I. Interestingly, these studies have found some evidence for the comorbidity of ADHD-I and ODD, a prole that has received little attention in the ADHD research literature. Another valuable approach that has been used in the ADHD literature is familial association. Family studies have found that the risk of ADHD among family members is about ve times greater than the population prevalence of the disorder. Faraone, Tsuang, and Tsuang (1999) have outlined three models for familial transmission. In relation to ADHD and anxiety, these models are the following: 1) A common underlying risk factor that would be evidenced by similarly elevated rates of anxiety in relatives of probands with ADHD + anxiety and probands with ADHD-only; 2) A distinct subtype interpretation that would be evidenced by relatives of ADHD + anxiety probands showing higher rates of anxiety than ADHD-only probands and also evidence of cosegregation in families (i.e., ADHD + anxiety in relatives); and 3) independent transmission that would be evidence by equally high rates of ADHD in relatives of ADHD + anxiety and ADHD-only probands but higher rates of anxiety in ADHD + anxiety probands (Braaten et al., 2003). Biederman, Faraone, Keenan, Steingard, and Tsuang (1991a) examined the familial association between DSM-III-dened ADD and anxiety disorders and found that relatives of probands with ADHD + anxiety were two times more likely to have an anxiety disorder than probands with ADHD-only. In a subsequent study, Biederman et al. (1992) examined DSM-III-R-dened ADHD and also found support for independent transmission even with the more stringent criterion of at least two anxiety disorders in ADHD + anxiety probands. Finally, Braaten et al. (2003) expanded upon past research to include both males and females utilizing DSM-III-R
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criteria. Once again, the risk for anxiety disorders was signicantly higher among the relatives of probands with ADHD + anxiety in comparison to probands with ADHD-only, while the two groups did not differ on risk for ADHD. Overall, results from this line of research suggest that ADHD and anxiety are independently transmitted in families, as relatives of probands with ADHD + anxiety are not more likely to have both conditions together (i.e., cosegregation) but are more likely to have anxiety only. In summary, evidence suggests that ADHD and anxiety have independent genetic transmission and are not good candidates for resolving genetic heterogeneity (Faraone, 2000). At the same time, most of this evidence comes from familial association studies which cannot fully disentangle genetic from environmental sources of familial transmission (Faraone et al., 1999). Twin studies are needed to address this issue. New approaches such as LCA seem to offer promise for future genetic studies on ADHD and anxiety comorbidity, since the LCA approach can more accurately categorize symptomatology in the population. Such an approach should help to more closely tie the ADHD phenotype to genotype (Todd, 2000a). Finally, Faraone (2000) noted that long-term outcome may also be used to solve issues of genetic heterogeneity. For example, genetic inuences may be responsible for persistent and remitting forms of ADHD. Future longitudinal studies will be needed to examine genetic heterogeneity in relation to long-term outcome. 2.2. Temperament Temperament can be dened as individual differences in constitutionally-based reactivity and self-regulation (Rothbart, 2004). Given the focus on individual differences, temperament researchers have historically utilized a trait perspective with a specic focus on traits emerging early in life. This approach has evolved over time from descriptions of infant behavioral tendencies (Thomas & Chess, 1977) that addressed how concerns to more modern approaches that address the what and the why (Rothbart, 2004). For example, current trait conceptualizations are thought to be more clearly tied to brain-based systems than past approaches. Currently, the trait approach most often utilized comes from the work of Rothbart, Ahadi, Hershey, and Fisher (2001). These researchers have identied three broad temperamental traits: extraversion/surgency, negative affectivity, and effortful control. Although affective traits have been extensively studied in relation to temperament, the construct of effortful control has added to this literature, providing evidence for the self-regulation of affect. Effortful control has been dened as the ability to withhold a dominant response in order to perform a subdominant response (Rothbart, 2004). In response to this new dimension, the eld of temperament research has come to view behavior as a result of the interaction of reactive or affective systems (e.g., extraversion/surgency or negative affectivity) and regulatory systems (e.g., effortful control). Temperament research has primarily addressed normal development, but some research has examined temperamental traits in relation to psychopathology. Derryberry and Rothbart (1997) have noted that too little effortful control coupled with high approach (e.g., aggression) is likely to lead to externalizing problems and impulsivity in children, while too little effortful control coupled with high avoidance (e.g., fear) is likely to lead to internalizing problems. Support for this idea has come from research studies showing that low effortful is a risk factor for the development of internalizing problems and externalizing problems (Calkins & Fox, 2002; Lonigan, Vasey, Phillips, & Hazen, 2004). Thus, effortful control is conceptualized as a regulator of underlying affective tendencies such as approach and avoidance. Although the temperament approach has historically existed independent from ADHD research, the approach may be valuable in understanding the etiology of ADHD. From a neuropsychological perspective, ADHD research has focused on both affective and cognitive inuences but has utilized different constructs from temperament research. One of the most inuential theories of ADHD involves decits in motivation (Quay, 1988). This theory draws from the work of Gray (1982) who posited that behavior is inuenced by two primary brain-based systems: the behavioral inhibition system (BIS) and the behavioral approach system (BAS). Quay (1988) proposed that ADHD involves an underactive BIS or a lack of inhibition. Other theories have posited that executive functioning decits may be the core decit in ADHD (Barkley, 1997). Although Barkley (1997) has commented most forcefully on the cognitive effects of executive functioning decits, his theory also addresses the regulation of affect. Barkley (1997) proposes that emotions, once elicited, come to be moderated or regulated by self-directed, executive actions. In comparing the neuropsychological dimensions examined in ADHD research to the traits proposed by temperament researchers, executive functioning can be seen as analogous to effortful control, and motivation can be seen as analogous to the affective traits of extraversion/surgency (BAS) and negative affectivity (BIS). Although these constructs are not entirely synonymous, temperament research and ADHD research seem to be studying similar dimensions (i.e., reactivity and regulation), so a unication of these elds would be valuable in better understanding the interaction of cognition and emotion. Nigg et al. (2004) have utilized a temperament perspective to outline a multiple pathway model for ADHD. Within this model, the overarching principles are that ADHD evolves from the interaction of reactive and regulatory processes. Nigg and colleagues suggest that some children with ADHD may be impaired from reactive processes, regulatory processes, or their combination. Although Nigg et al. (2004) focus primarily on externalizing problems associated with ADHD, they do describe two developmental pathways that are relevant to anxiety. According to pathway V (ADHD-C/anxiety), the authors speculated that such a pathway may involve weak regulatory control at 12 years of age with low hostility but high negative withdrawal (i.e., anxiety). They also speculated that the clinical prole may involve executive decits and anxiety. This pathway was in contrast to pathway VI (primary or secondary ADHD-I), which involved cognitive regulation that is disrupted due to high anxiety. The clinical presentation would involve inattentiveness on continuous performance tests (CPTs) but adequate performance on executive functioning tasks. The prole might also include high anxiety, anxious impulsivity, and overarousal. In comparing these two pathways, the key differentiating factor seems to be neuropsychological functioning. Interestingly, pathway V (ADHD-C/anxiety) involves early regulatory decits in the context of high negative withdrawal or anxiety. Such a
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pathway may involve two early temperamental risks: poor effortful control and high negative withdrawal. In the second pathway, high anxiety interferes with what would be normal regulatory development and subsequently serves to interfere with the development of regulatory abilities. This latter pathway was hypothesized to lead to inattentiveness but not executive functioning decits. In addition, this pathway may not stem from the genetic inuences implicated in ADHD but rather from the secondary inuences of anxiety. Although this model does not entirely address all issues related to comorbidity and ADHD subtype differences, it does present a unique view on the study of ADHD, as it outlines a developmental model of cognition and emotion interaction and predicts behavioral and neuropsychological proles that should be observed in the clinic based on the particular etiological pathway. This integrative model of temperament and ADHD has led to subsequent conceptual and empirical work on the relationships between temperamental traits and psychopathology (Martel & Nigg, 2006; Nigg, 2006a). At the same time, there have been limitations to this empirical work. Although conceptual models have recognized that cognition and emotion are interactive, few empirical studies have examined the true interaction of these systems. For example, past studies have often examined executive functioning or effortful control in tasks that do not involve affect. Although these studies may show that executive functioning skills or effortful control are intact, they do not address the question of whether these skills are intact or how they operate in the context of emotion. More recent studies have sought to tackle these interactional issues empirically by examining cognition in the context of emotion (Calkins, in press; Hongwanishkul, Happaney, Lee, & Zelazo, 2005; Perez-Edgar, Fox, Cohn, & Kovacs, 2006). Few studies have examined these issues in relation to ADHD, but some promising research in this area will be reviewed in the following section. 2.3. Neurobiological and neuropsychological functioning Research has shown a strong neurobiological basis for ADHD (Faraone & Biederman, 1998), but the core of the disorder remains unclear. Over the years, ADHD has been viewed as a disorder of motivation (Quay, 1988), self-regulation (Douglas, 1988, 1989), response inhibition (Barkley, 1997), arousal (Sergeant, Oosterlaan, & van der Meere, 1999), and more recently, disinhibition (Nigg, 2001). Studies have found group differences (e.g., ADHD vs. controls) for each of these decits, but these ndings can be misleading, since not all children with ADHD exhibit decits in these areas. Indeed, heterogeneity in neuropsychological functioning has been the rule, in opposition to the hypothesis of a universal decit. Alternatively, an ADHD prole may involve decits in one or more of these areas. For example, Nigg, Willcutt, Doyle, and Sonuga-Barke (2005) found that only 35%50% of children with ADHD-C had response inhibition decits, a decit that is thought to be primary in one current conceptualization of ADHD (Barkley, 1997). In addition, the hypothesis regarding a motivational or affective decit has led to mixed results across studies (Daugherty & Quay, 1991; Matthys, van Goozen, de Vries, Cohen-Kettenis, & van Engeland, 1998). Schatz and Rostain (2006) recently reviewed the comorbidity of ADHD and anxiety with a particular emphasis on neuropsychological functioning. The authors concluded that anxiety in ADHD may partially inhibit impulsivity and response inhibition decits and make working memory decits worse. As noted earlier, Pliszka (1989, 1992) found that presence of OAD resulted in decreased impulsivity on laboratory task performance for children with ADHD. More recent studies have also shown that anxiety serves to increase response inhibition (Manassis, Tannock, & Barbosa, 2000; Oosterlaan & Sergeant, 1998a). Other reviews have challenged this nding. For example, Oosterlaan and Sergeant (1998b) did not nd that anxiety increased response inhibition in their meta-analysis. Schatz and Rostain (2006) note that Oosterlaan and Sergeant (1998b) have speculated that certain response inhibition tasks may not be challenging enough to evoke an anxious response, which may account for some of the discrepancies in ndings across studies. This observation is consistent with the movement of cognition and emotion interaction in temperament research, as the argument of Oosterlaan and Sergeant (1998b) suggests that response inhibition in the presence of anxiety is different than response inhibition when anxiety is not present. As noted by Schatz and Rostain (2006), there is currently a lack of research on the effect of comorbidity and gender on laboratory task performance. One study applicable to this issue that was not reviewed by Schatz and Rostain (2006) is a study by Newcorn et al. (2001). In this study, Newcorn et al. (2001) specically examined comorbidity and gender using a continuous performance test (CPT). Children with ADHD + ODD/CD were more impulsive than inattentive while children with ADHD + anxiety were more inattentive than impulsive on the CPT. Girls were less impaired than boys on most of the CPT indices and girls with ADHD + anxiety made fewer CPT impulsivity errors than girls with ADHD-only. Overall, the total group of children with ADHD and anxiety did not make fewer CPT impulsivity errors than children with ADHD-only, suggesting that anxiety does not mitigate impulsivity. Finally, few studies have examined the type of anxiety that may improve response inhibition. Epstein et al. (1997) examined the effect of child-reported anxiety on the Conners' Continuous Performance Test (CPT) and found that physiological anxiety increased response inhibition, while cognitive anxiety served to decrease response inhibition. Few conclusions can be drawn at this time, given the paucity of research in this area, but it will be valuable for future studies to examine the type of anxiety experienced by the child with both state and trait measures, particularly since some studies have found that state-related anxiety has important effects on laboratory task performance (Roth et al., 2004). Schatz and Rostain (2006) also reviewed studies that have found working memory decits in children with ADHD and anxiety. Tannock, Ickowicz, and Schachar (1995) found that children with ADHD + anxiety made more errors on a working memory task than children with ADHD-only. Once again, though, state-related effects may affect such ndings, as a study in adults found that working memory may be decreased due to situational anxiety rather than poor working memory (Roth et al., 2004). As noted earlier, measure of subjective distress could be benecial in future studies with anxious individuals in order to more adequately disentangle the inuences of long-standing decits and situational decits due to task-related anxiety.
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Finally, one line of research has looked at sluggish cognitive tempo (SCT) in children with ADHD. Lahey, Schaughency, Hynd, Carlson, and Nieves (1987) found that children with ADD/WO showed a sluggish cognitive tempo (SCT) on laboratory tasks and were not more impulsive than controls (unlike the ADD + H group). In recent years, work on sluggish cognitive tempo has reemerged in an examination of the ADHD-I subtype. Multiple studies have found that there may be two types of inattention: inattention with high SCT and inattention with low SCT (Carlson & Mann, 2002; McBurnett, Pffner, & Frick, 2001). In addition, the high SCT group has been associated with higher levels of depression, withdrawal, and anxiety compared to the low SCT group (Carlson & Mann, 2002). Although the inclusion of SCT items has proven valuable in factor-analytic studies, they did not prove valuable in a recent study using LCA (Todd, Rasmussen, Wood, Levy, & Hay, 2004), so future studies using this alternative classication approach will be needed to better understand the value of including SCT measures in research studies. Although studies have examined neuropsychological functioning in children with ADHD and anxiety, only a limited number of studies have examined issues such as gender, externalizing disorder comorbidity, and ADHD subtype. In addition, the research in the neuropsychological domain has lacked the cognition and emotion integration that was previously discussed in the temperament section of this review. More recently, studies have come to focus more on the integration of these two domains using a neuropsychological perspective, although these studies have more often occurred in the neuropsychological and temperament literatures rather than the ADHD literature. Hongwanishkul et al. (2005) have differentiated between hot and cold executive functioning tasks. Hot tasks are thought to involve affective aspects of executive function and are thought to involve the orbitofrontal cortex. In contrast, cool executive function tasks are more purely cognitive and are hypothesized to involve the dorsolateral prefrontal cortex. Although it is well-accepted that the prefrontal cortex is involved in regulating subcortical areas associated with emotion, emerging research indicates that certain components of the prefrontal cortex (e.g., orbitofrontal cortex) may be specialize in regulating affect. This nding suggests that executive functions should be conceptualized as multidimensional and dependent on context-related effects. Although ADHD has a long history of neuropsychological research, recent advances in knowledge have led to a signicant body of research examining brain functioning in children with ADHD. Nigg and Casey (2005) outlined an integrative theory of ADHD based on the cognitive and affective neurosciences. The authors describe developmental pathways to ADHD from a neuroscience perspective and focus on three brain structures: the prefrontal cortex, the basal ganglia, and the cerebellum. Decits in one or more of these areas are proposed to lead to the ADHD phenotype. Nigg and Casey (2005) go beyond this conceptualization to include additional pathways that might involve affective brain systems: extreme approach (e.g., over-reactivity in the nucleus-accumbens circuit) and fearless non-avoidance (e.g., under-reactive amygdala-frontal circuit). Given that both theories of ADHD and temperament rely on biological bases, a theoretical model based in brain systems may serve as the common ground for these two areas of research. The challenge for future models will be to understand the interaction of affectively-based brain structures (e.g., the amygdala) and brain structures and systems specically implicated in ADHD (e.g., fronto-striatal loop, cerebellum). In relation to ADHD anxiety, a possible brain system candidate may be the amygdala-frontal circuitry. Finally, Levy (2004) reviewed theories of ADHD and noted that while Barkley (1997) implicates executive functioning (i.e., prefrontal functioning) in ADHD, Quay (1988) implicates an underactivated BIS (i.e., septo-hippocampal functioning). Modern approaches to neuroscience have revealed the workings of the mesolimbic dopamine system and have shown that reward and delay of reinforcement are determined by tonic and phasic dopamine responses (i.e., dopamine release and re-uptake at the synapse). When impaired, this system results in fearless and impulsive behavior primarily at the site of the nucleus accumbens, a brain structure often described as the interface between limbic and motor systems (Mogenson, Jones, & Yim, 1980). More recently, greater understanding of the nucleus accumbens has revealed that the structure also receives inputs from the amygdala, hippocampus, and prefrontal regions. The convergence of these inputs allow for synaptic gating of the nucleus accumbens. Levy (2004) notes that impairment of this mechanism by lowered prefrontal cortex inhibition allows greater amygdala (i.e., fear) input. Although the mechanisms involved in this process are beyond the scope of this paper, this theory serves to integrate theories of both cortical and subcortical malfunction in ADHD and can account for the comorbidity of ADHD and anxiety. Future research in this area will be necessary to further understand the relationships between these neurobiological processes and important psychological outputs such as cognition, emotion, and behavior. 2.4. Family inuences Family characteristics of children with ADHD have been extensively studied (Johnston & Mash, 2001), although few studies have been devoted to family factors associated with comorbidities. The studies to date in this area have focused primarily on the comorbidity of ADHD and ODD or CD (Johnston & Mash, 2001; Pffner et al., 1999; Pffner, McBurnett, Rathouz, & Judice, 2005) with few studies examining family factors associated with ADHD and anxiety comorbidity. However, in recent years, there has been increased interest in the family characteristics of children with ADHD and anxiety (Kepley & Ostrander, 2007; Pffner & McBurnett, 2006; Pffner et al., 1999). Pffner et al. (1999) found a strong association between parental anxiety disorders and comorbid anxiety disorders in children with ADHD. Such a nding is consistent with research on anxiety showing that parental anxiety is associated with child anxiety (Beidel & Turner, 1997; Last, Hersen, Kazdin, Orvaschel, & Perrin, 1991; Martin, Cabrol, Bouvard, Lepine, & Mouren-Simeoni, 1999). In a more recent study, Pffner and McBurnett (2006) examined family correlates of comorbid anxiety disorder in children with ADHD. Drawing from the literature examining parenting characteristics of children with anxiety disorders, the authors noted that Chorpita and Barlow (1998) have described two parenting styles that are considered to be associated with child anxiety: high overprotection and low care. The authors also commented on the speculation of Chorpita and Barlow (1998) that the combination
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of these parenting styles could be especially strong in contributing to child anxiety. Finally, the authors noted that it is unclear how parental anxiety combines with parenting practices to affect child anxiety, although some data from studies examining anxious children without ADHD suggests that both factors are problematic (Moore, Whaley, & Sigman, 2004; Whaley, Pinto, & Sigman, 1999). Pffner and McBurnett (2006) found that comorbid anxiety in children with ADHD was associated signicantly with maternal anxiety, overprotectiveness, and a lack of positive parenting. In contrast with past studies of children with anxiety disorders only, parental lack of warmth and excessive negativity were not associated with child anxiety in these children with ADHD. In the most recent study to date, Kepley and Ostrander (2007) compared children with ADHD-only, ADHD + anxiety, and controls on measures of family environment and found that the family environments of children with ADHD and anxiety showed greater parental control and less independence. Kepley and Ostrander (2007) concluded that these families exhibit a family environment that is insular, dependent, and discouraging of autonomy. Families of children with ADHD and anxiety also showed relatively high levels of family conict and low levels of expression and cohesion. Although research on the family environments of children with ADHD and anxiety is limited, extant ndings suggest that children with ADHD and anxiety exhibit family environments that are similar to children with ADHD but also exhibit characteristics that have been found in families with anxiety disorders. This combination of family factors may be related to the nding of greater psychosocial adversity and stress in families with ADHD and anxiety (Tannock, 2000). Since only a few studies have explored this topic, future studies will need to address additional comorbidities such as ODD and CD in the presence of anxiety, given that the presence of externalizing disorders has proven important in understanding the relationship between ADHD and anxiety in other research domains. 2.5. Temporal relations between ADHD and anxiety Although several studies have examined the development of ADHD symptomatology over time (Biederman et al., 2006; Willoughby, 2003), few studies have examined the relationships between ADHD and anxiety over time. The studies to date have consisted of both longitudinal studies and retrospective studies of adults. Szatmari et al. (1989) found that 17% of girls and 21% of boys with ADD had at least one anxiety or mood disorder in childhood, while these rates increased to 50% and 24% in the adolescent years. In contrast, other studies following children with hyperactivity over time have found low rates of anxiety (1%) and depression (3%) at 18 years of age (Gittelman, Mannuzza, Shenker, & Bonagura, 1985; Mannuzza et al., 1991). It should also be noted that these ndings held up when the participants were evaluated in their mid-twenties (Mannuzza, Klein, Bessler, Malloy, & LaPadula, 1998). Claude and Firestone (1995) found few differences in anxiety (6% vs. 15%) or depression (8% vs. 4%) when comparing ADHD and control adolescents at 19 years of age. In contrast, Biederman et al. (1996) found that children diagnosed with ADHD in childhood exhibited signicantly more lifetime diagnoses of anxiety and depression in mid-adolescence than a nonADHD comparison group. More specically, the researchers found rates of 35% for anxiety disorders and 45% for depression in the group with a history of ADHD diagnosis. Safren, Lanka, Otto, and Pollack (2001) examined the ADHD histories of adults diagnosed with GAD and social phobia. Adults with GAD had a signicantly higher proportion of childhood ADHD diagnoses than adults with social phobia. In addition, the rate of childhood ADHD was substantial for the GAD group (32%). In the social phobia group, only 3% of the group had childhood ADHD, and the one person who did have childhood ADHD also had co-occurring GAD. Temporally, GAD emerged after the onset of ADHD in all cases (according to patient report), suggesting that ADHD may give rise to GAD symptomatology (e.g., worry). Peterson, Pine, Cohen, & Brook (2001) found that ADHD symptoms in adolescence predicted more OCD symptoms in early adulthood, and OCD in adolescence predicted more ADHD symptoms in adulthood. Fischer, Barkley, Smallish, and Fletcher (2002) followed-up young adults with a history of ADHD diagnosis. Rates of major depression were signicantly higher for this group than controls (26% vs. 12%). Vance et al. (2002) also examined changes in anxiety disorders over a two-year period in children with ADHD-C and found no decrease in parent report of social phobia and OCD but a decrease in specic phobias. In contrast, child report of anxiety resulted in decreases in GAD and SAD but not social phobia and specic phobias. Finally, Bagwell, Molina, Kashdan, Pelham and Hoza (2006) compared a group of adolescents diagnosed with ADHD in childhood to a community-recruited group of adolescents without ADHD. The groups did not differ on rates of anxiety or mood disorders, but anxiety and mood disorders in adolescence were predicted by social problems and externalizing problems in childhood. Childhood internalizing symptoms did not predict internalizing problems in adolescence. Bagwell et al. (2006) noted that many past studies failed to examine comorbidity with externalizing problems, a potential confound which presumably contributed to the mixed results in past studies. For example, Gittelman et al. (1985) and Mannuzza et al. (1991) excluded individuals with primarily aggressive behavior, which resulted in a sample with almost no comorbid CD. In comparison, the Biederman et al. (1996) study had signicant rates of comorbid ODD and CD. The Fischer et al. (2002) study found an association between antisocial personality disorder (APD) and depression, suggesting that ADHD and conduct problems may be responsible for the association between ADHD and depression (Bagwell et al., 2006). Overall, the ndings from these studies suggest that there is some risk for the development of anxiety in children diagnosed with ADHD, although considerable variability exists and has been associated with assessment methods and sample characteristics. In addition, these mixed results point towards potentially multiple developmental pathways depending on factors such as ADHD subtype, externalizing disorder comorbidity, and gender. Although not reviewed here, the development of additional psychological difculties in adolescence may be mediated by peer relations, a speculation supported by current conceptualizations of the role of peers in the development of psychopathology (Deater-Deckard, 2001). Although there is a substantial literature on ADHD and peer relations (Bagwell, Molina, Pelham, & Hoza, 2001; Blachman & Hinshaw, 2002; Maedgen & Carlson, 2000; Matthys, Cuperus, & van Engeland, 1999), most studies have focused on peer rejection in children with ADHD, while few have examined peer neglect, a
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construct examined in peer relations research (Rubin, Bukowski, & Parker, 1998). Such an area may be promising for future research on the development of anxiety in children with ADHD, particularly for children who may not exhibit comorbid externalizing problems. In addition, there may be differential relationships based on gender. Gaub and Carlson (1997) noted that research indicating increased peer problems for girls over time suggests that girls may be susceptible to peer rejection or neglect in comparison to boys. This view has led to increased interest in the peer relationships of girls with ADHD (Blachman & Hinshaw, 2002). Finally, diagnosis of ADHD has a unique criterion that may serve to inuence the study of the temporal relations of ADHD and anxiety (i.e., age-of-onset before age seven). For example, Sukhodolsky et al. (2005) noted that ADHD requires an onset before age seven, while OCD and other anxiety disorders may occur at any time in childhood or adolescence. This criterion has been the subject of controversy, as some authors have argued for maintaining the criterion while others have argued against it (Applegate et al., 1997; Rucklidge & Tannock, 2002). A change to this criterion could introduce an additional methodological confound in the study of ADHD and anxiety and would presumably increase the rate of comorbidity of ADHD and anxiety if the age-of-onset was broadened. In relation to anxiety, past studies have found that an early age-of-onset is associated with greater symptom severity (McGee, Williams, & Feehan, 1992; Rucklidge & Tannock, 2002). Connor et al. (2003) examined parent- and teacher-reported internalizing and externalizing problems in a clinically-referred sample of children with ADHD. An earlier age-of-onset was associated with greater parent-reported aggressive symptoms and a later age-of-onset was associated with greater parentreported internalizing symptoms. It should be noted that these ndings were observed only for parent report, so it may be that these associations may have been due to informant biases or aggressive symptoms simply being noticed earlier than internalizing symptoms (Connor et al., 2003). In contrast, Wilens et al. (2002) found that 28% of preschoolers and 33% of school-age children with ADHD had at least two or more anxiety disorders with age-of-onset occurring around 2.6 years of age for the pre-school group and 3.0 years of age for the school-age group. Although the study by Connor et al. (2003) suggests that internalizing problems follow the onset of externalizing problems, Wilens et al. (2002) found that anxiety disorders occurred much earlier. Once again, it may be that sample characteristics such as the presence of ODD or CD or informant biases accounted for the discrepancy. Future longitudinal studies will be needed to better understand the temporal relationships between ADHD and anxiety at all stages of development. 3. Summary, conclusions, and future directions 3.1. Summary and conclusions It is clear that the study of ADHD and anxiety comorbidity is a complex area that seems to become even more complex when both methodological and substantive concerns are taken into consideration. Given this state of affairs, it is difcult to determine exactly how to proceed in the study of ADHD and anxiety comorbidity. Nonetheless, in the following section, ndings from this review will be evaluated and tentative recommendations for future research will be offered. In addition, the available evidence to date will be used to evaluate the hypotheses put forth by Tannock (2000) in relation to ADHD and anxiety. In relation to the hypotheses proposed by Tannock (2000), it may not be the case that only one hypothesis is correct, as there may be potentially multiple pathways to the development of ADHD and anxiety. As noted earlier, Nigg et al. (2004) have hypothesized two pathways for ADHD and anxiety. One pathway involves early regulatory decits in combination with high anxiety. The second pathway proposes that ADHD may be the secondary result of high anxiety. This latter pathway would reect the rst hypothesis put forth by Tannock (2000). In relation to the second hypothesis (i.e., failure experiences related to ADHD leading to anxiety) proposed by Tannock (2000), Nigg et al. (2004) suggest that anxiety or more generally, affect, is present prior to the development of regulatory abilities, a perspective supported by research in normally developing children (Rothbart, 2004). At the same time, some research also supports the notion that maladaptive levels of anxiety may develop after the onset of ADHD (Safren et al., 2001). Unfortunately, research on longitudinal relationships has not progressed to the point where the relationship between ADHD and anxiety over time is clearly understood. In addition, confounding factors such as externalizing comorbidity, age, gender, and ADHD subtype have not been thoroughly examined, so future longitudinal research will be needed to understand the temporal relationships between ADHD and anxiety. The current research suggests that anxiety may either precede or follow ADHD depending on the particular developmental pathway. Finally, Tannock's (2000) hypotheses three and four address the issue of whether ADHD and anxiety have a common etiology and treatment response or whether these disorders have relatively distinct and separate etiologies and treatment responses. In evaluating these hypotheses, it is important to note that there may be separate answers for etiology and treatment response. For example, research in areas such as genetics and family factors suggests that the effects of ADHD and anxiety may be additive rather than interactive (Braaten et al., 2003; Kepley & Ostrander, 2007). In contrast, research on treatment response has found differential treatment response to behavioral treatment for children with ADHD and anxiety (MTA Cooperative Group, 1999b; March et al., 2000). Cantwell (1995) has proposed eight domains that can be used to determine whether a disorder is etiologically distinct. These domains include: clinical phenomenology, demographic factors, psychosocial factors, biological factors, family genetic factors, family environmental factors, natural history, and intervention response. Jensen et al. (1997) applied these criteria to the study of ADHD comorbid subtypes, and for ADHD and anxiety in particular, found evidence for one area with strong evidence (treatment response in relation to medication), three areas with preliminary evidence (clinical phenomenology, psychosocial factors, and biological characteristics), and one area with controversial evidence (distinctive course and outcome). Since the time of this review, new ndings have contradicted past ndings for clinical phenomenology (e.g., the effect of anxiety on impulsivity) and
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treatment response (i.e., response to methylphenidate), although a differential response to behavioral treatment has been found in the MTA Study (MTA Cooperative Group, 1999b; March et al., 2000). In a more recent study, Jensen et al. (2001) examined the more specic groups of ADHD-only, ADHD + anxiety, ADHD + ODD/CD, and ADHD + ODD/CD + anxiety using the criteria of Cantwell (1995). Jensen et al. (2001) found that only the ADHD + anxiety and ADHD + ODD/CD groups differed on baseline characteristics. Age was the only signicant interaction, as children with ADHD with anxiety and conduct problems were signicantly older. Interestingly, few interactive effects were found for baseline characteristics, although interactive effects were found for treatment response. Jensen et al. (2001) concluded that the four groups reviewed represent distinct comorbid subtypes, although the only evidence to support this claim seemed to be differential response to treatment rather than differences on baseline characteristics. Although delineation of separate subtypes is clearly valuable, it seems that more knowledge is needed before concluding that these subtypes are etiologically distinct (at least for the subtypes involving anxiety). One of the primary challenges in studying internalizing and externalizing disorder comorbidity is determining whether anxiety serves as a protective or exacerbating force (Keiley et al., 2003; Lilienfeld, 2003). The research to date has yielded mixed results, which may be due to different informants reporting anxiety (parents vs. children), different sample characteristics, and different methodological approaches. Kerr, Tremblay, Pagani, and Vitaro (1997) have proposed that different aspects of anxiety may function in different ways in relation to conduct problems. It seems that a similar perspective should be taken toward the study of ADHD comorbidity, as questions must move beyond the role of internalizing problems or anxiety to the roles of worry, separation fears, and obsessive thoughts from both trait and state perspectives. In addition, the concept of anxious impulsivity presented by some researchers (Epstein et al., 1997; Nigg et al., 2004) suggests that anxiety may not always serve to inhibit impulsivity. Finally, given that many of the effects in the literature have been found to be additive, it is also recommended that ndings from the anxiety literature be merged more with research on ADHD. For example, Pffner and McBurnett (2006) have reviewed anxiety disorder research to generate hypotheses about family environments in children with ADHD and anxiety. Similar integrative approaches to the study of ADHD and anxiety and other factors should be pursued in the future. Finally, the role of anxiety must also be considered within a context. Although psychopathology research often focuses on enduring behavioral tendencies, it is also important to consider situational inuences. Wright, Zakriski, and Drinkwater (1999) compared children with internalizing problems, externalizing problems, and a mixture of both. No differences were found on base-rate measures, but interesting relationships were found when context was considered. Internalizers showed elevated rates of withdrawal and depression in aversive situations only. Externalizers showed aggression only in response to teasing or threat from peers. Finally, the mixed groups showed a mixture of aggression and withdrawal in a number of different situations, including situations that involved non-threatening interactions. Similar context effects must also be considered for neuropsychological and observational tasks, as it is important to consider state-related effects in the measurement of enduring tendencies (Roth et al., 2004). 3.2. Future directions for research Since the time of Caron and Rutter's (1991) seminal paper on comorbidity, there has been a signicant body of research on comorbidity in psychopathology. However, the difculties and complexities of comorbidity research lead us back to one of their primary questions: Does comorbidity matter? Even after years of comorbidity research, this question is difcult to answer, and it may be that comorbidity matters for certain purposes but not for others. From a practical and clinical standpoint, the answer is clearly yes. In the case of ADHD and anxiety, research on comorbidity has shown differences in clinical characteristics, physiology, laboratory task performance, treatment response, family factors, and a number of other variables. (Epstein et al., 1997; Jensen et al., 1997; Jensen et al., 2001; Pffner & McBurnett, 2006; Pliszka, 1989, 1992; Schatz & Rostain, 2006; Urman, Ickowicz, Fulford, & Tannock, 1995). Such information is valuable to clinicians who may need to alter assessment or treatment practices to account for comorbid conditions. At the same time, it is becoming increasing clear that the DSM system is not clearly carving nature at it joints, as research continues to show that the dichotomous disorders that we attempt to study are more dimensional in nature (Levy et al., 1997). It does seem that we are stuck with the DSM system for the foreseeable future, though, and future studies based on this system will be needed to answer practical questions that will inform assessment and treatment. As Rutter and Sroufe (2000) note, categorical decisions will be required for practical decision-making even if the underlying structure of psychopathology is dimensional. In relation to the etiology of ADHD and anxiety, the answer to Caron and Rutter's question is less clear. The evidence presented in the current review suggests that ADHD and anxiety seem to be independently transmitted conditions based on behavioral genetic research studies. In addition, little evidence to date supports the notion that comorbid ADHD and anxiety exhibits a prole with a distinct etiology. At the same time, the work of Nigg et al. (2004) suggests that the complex interplay of anxiety and ADHD may have implications for the development of a comorbid pattern (e.g., elevated anxiety leading to regulatory decits that present as ADHD symptomatology). Finally, a broader issue that needs to be addressed is the nature of psychopathology. If ADHD and anxiety are dimensional in nature, it may not be fruitful to examine etiology in relation to diagnosable disorders. In order to better understand etiological processes, there must be a more precise denition of the ADHD phenotype which may include multiple forms of ADHD. For example, endophenotypes are currently being examined in ADHD research, but it is clear that the phenotype itself has not been clearly dened when such high rates of comorbidity are consistently found in research studies. It may be that alternative methodological approaches need to be considered such as cluster analysis, taxometrics, and latent class analysis to capture the combination of factors that seem to dene the phenotype (e.g., females with inattention, intellectual impairment, and a sluggish cognitive tempo). Phenotypic precision is also highlighted by Todd (2000a) who notes that most genetic studies have utilized DSM-IVdenitions of ADHD. In turn, this system of classication will often yield a diagnosis with a low relative risk ratio, a measure of the chance of nding genes associated with a disorder, which makes the search for particular genes more difcult.
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Future studies will need to utilize alternative methods to more clearly dene the phenotype if progress is to be made in behavioral and molecular genetics. Finally, a greater understanding of the etiology of ADHD will require an integration of developmental and clinical research literatures in order to better understand the relationships between cognition and emotion. As Nigg et al. (2004) noted, temperament may contribute less to the diagnostic work of the clinician but instead holds value in understanding the origins, comorbidities, and developmental outcomes of ADHD (p. 42). Finally, although the focus of the current review was primarily related to research concerns, additional clinical implications are important to consider in relation to ADHD anxiety. One of the more surprising ndings in the treatment literature that is relevant to ADHD and anxiety is that ADHD is a disorder that has shown a relatively poor response to cognitivebehavioral treatments while anxiety disorders are highly responsive to cognitivebehavioral interventions. One of the clinical distinctions often made between children with ADHD and children with anxiety is that children with ADHD tend to think too little while children with anxiety tend to think too much. In turn, the lack of cognitive skills in children with ADHD leads to the inability to regulate anxiety via the cognitive components of an intervention. Although this distinction is helpful, it may be that this distinction is somewhat articial and an overly broad generalization. For example, Nigg et al. (2005) found that only 35%50% of children with ADHD-C had response inhibition decits, an executive functioning decit that is thought to be primary in one current conceptualization of ADHD (Barkley, 1997). In turn, it may not be that all children with ADHD think too little. In thinking about these possible subgroups, it may be valuable to consider the distinction in relation to the two ADHD and anxiety pathways proposed by Nigg et al. (2004). One pathway suggests early regulatory difculties that lead to inability to regulate anxiety, while another pathway suggests that elevated anxiety leads to cognitive or regulatory dysfunction. In the latter pathway, it seems that the regulatory functions (e.g., executive functioning) are intact but are compromised when high anxiety is present. Future behavioral and cognitivebehavioral interventions may prove most valuable with this latter pathway. For example, if regulatory functions are intact (i.e., the presumed decit in many models of ADHD), a behavioral or cognitivebehavioral intervention that serves to reduce anxiety symptoms may simultaneously reduce both ADHD and anxiety symptoms. Given the nding from the MTA Study that children with ADHD and anxiety respond equally well to behavioral treatment and to medication treatment, one may wonder how the combination of behavioral treatment for managing ADHD symptoms and exposure treatment for anxiety symptoms would affect clinical outcomes. Future research will be needed to better understand how this unique subgroup of ADHD children responds to psychosocial treatments that combine elements of both treatments. References
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A Conceptual Review of The Comorbidity of Attention-Deficithyperactivity

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Clinical Psychology Review 28 (2008) 12661280

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Clinical Psychology Review

M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280

M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280

M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280

M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280

M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280

M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280

M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280

M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280

M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280

M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280

M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280

M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280

M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280

M.A. Jarrett, T.H. Ollendick / Clinical Psychology Review 28 (2008) 12661280

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