Panic lewis psychiatry

Panic Disorder with or without Agoraphobia Definition and Clinical Description Panic disorder refers to the experience of unexpected panic attacks accompanied by persistent apprehension about their recurrence or behavioral modifications in daily routine as a result of the attacks. While panic attacks can occur in many conditions, including phobias and social anxiety disorder, the panic attack associated with panic disorder is unique in that it occurs spontaneously without an environmental trigger. For example, panic disorder is uniquely associated with nocturnal panic attacks, which spontaneously awaken a patient from sleep. A panic attack is a discrete period of intense fear or discomfort that is characterized by the presence of at least four somatic and/or cognitive symptoms. The most commonly reported symptoms among adolescents with panic attacks appear to be trembling, dizziness/faintness, pounding heart, nausea, shortness of breath, and sweating (43,44). Cognitive symptoms, such as a fear of going crazy or dying, are reported less frequently than somatic ones (44). A diagnosis of panic disorder with agoraphobia is indicated if the patient avoids places or situations in which escape might be difficult or embarrassing. The most commonly avoided settings include those involving large groups of people unknown to the patient, such as restaurants, crowds, and auditoriums (43). Specific Features The most difficult distinction to make when diagnosing panic disorder in youth is the difference between an unexpected panic attack, as required for a diagnosis of panic disorder, and situationally cued attacks that are typical of other anxiety disorders. This task becomes especially challenging given the cognitive predisposition of children to attribute their experiences to external, identifiable, situational factors. Careful attention to the circumstances surrounding attacks will help with this distinction, as panic attacks occurring in the context of another anxiety disorder will occur primarily in the presence of the target stimulus. Additionally, presence of pervasive apprehension about having a panic attack, as opposed to facing a feared stimulus, supports the diagnosis of panic disorder rather than another anxiety disorder. Panic attacks can also be caused by a variety of medical conditions, including hyperthyroidism, hyperparathyroidism, vestibular dysfunction, seizure disorders, and cardiac abnormalities. Appropriate laboratory tests and physical examinations should be used to rule out these causes prior to assigning a diagnosis of panic disorder. In particular, when panic is accompanied by cardiac symptoms, a discussion with a pediatrician as to the need for EKG and cardiac consultation is encouraged. Comorbidity As in adults, anxiety disorders in youth are frequently comorbid with each other and with other types of psychopathology. Rates of comorbidity among anxiety

disorders tend to be somewhat lower in the general population 39% in children (45,46) and 14% in adolescents (47) than in clinic samples (50%) (48). This likely reflects a referral bias; children with multiple disorders, and consequently greater impairment, are more likely to seek treatment. A recent community-based study found panic attacks and social phobia to be highly comorbid with other anxiety disorders. Social anxiety was found to be highly associated with any anxiety disorder (odds ratio [OR] = 14.2) (49). After adjusting for differences in age and gender, the presence of panic attacks was associated with increased likelihood of any anxiety disorder (OR = 4.6), social anxiety (OR = 2.3), specific phobia (OR = 3.4), agoraphobia (OR = 2.9), generalized anxiety disorder (OR = 4.8), overanxious disorder (OR = 3.7), and separation anxiety disorder (OR = 3.1) (50). In clinic samples, SAD is found to be more highly comorbid with other anxiety disorders than GAD and social phobia (51). Children with SAD are more likely to have comorbid specific phobia than children with GAD or social phobia. In contrast, children with GAD and social phobia were more likely to have comorbid mood disorders as compared to children with SAD. With respect to gender differences, in a nonreferred sample, having more than one anxiety disorder during childhood and adolescence was observed almost exclusively in females (52). After comorbidity with another anxiety disorder, depression is the most commonly reported comorbid condition among youth with anxiety disorders (53,54). Depression is 8.2 times as likely in children with anxiety disorders than in children without anxiety disorders (55). Specifically, there is a significant link between GAD and depression that persists into adulthood (6). Children and adolescents with GAD and comorbid MDD report significantly more anxiety symptoms and demonstrate greater functional impairment than GAD youth without MDD (56). P.542

Approximately 20% of children with an anxiety disorder also meet criteria for an externalizing disorder (14,45,57,58). In a selective review of attention deficit/hyperactivity disorder (ADHD), Biederman noted that about 30% of children and adolescents with ADHD also have an anxiety disorder (59). Interestingly, the prevalence of comorbid anxiety disorders increases in adults with ADHD to approximately 50%. In both children and adults with ADHD, females have a higher rate of comorbid anxiety disorders. Girls with the inattentive subtype of ADHD have higher rates of comorbid SAD, while those with the combined type have increased comorbidity with GAD (60). This is in contrast to males with ADHD who have a higher prevalence of oppositional defiant and conduct disorders. Two additional conditions/disorders require mention when discussing comorbidity of pediatric anxiety disorders. First, selective mutism, a disorder characterized by persistent failure to speak in specific settings (school) despite full use of language at home or with family, may be found in younger children with social phobia. Approximately 68% of children with selective mutism also meet diagnostic

criteria for social phobia (61). Second, while school refusal is not a DSM-IV diagnosis, it is a condition that often cooccurs with anxiety disorders, specifically SAD, specific phobia, and social phobia (62). School refusal is characterized by significant difficulty attending school, resulting in a prolonged absence and/or severe emotional upset. These children often display excessive fearfulness, temper outbursts, or complaints of feeling ill when faced with the prospect of going to school (62). The nature of the anxiety associated with school refusal behavior is likely to change with age, as is the nature of the precipitating events. For example, fear of separation is more common in younger school refusers, while socialevaluative fears, such as fears of teachers or peers, are more common in older children. Course of Pediatric Anxiety Disorders Most prospective epidemiological studies examine the longitudinal outcome of anxiety disorders, broadly conceptualized, as opposed to specific conditions (63,64). These studies find a statistically robust association between pediatric anxiety and a range of adult conditions, including both mood and anxiety disorders. However, from the standpoint of effect sizes, these associations are best characterized as modest: Odds ratios tend to fall between 2.0 and 4.0, varying as a function of severity and length of followup. This magnitude of association is somewhat weaker than typically found in longitudinal studies of stability in behavior disorders, such as conduct disorder. In terms of specific anxiety disorders, relatively few longitudinal data examine outcome for any one condition, compared with other conditions. Pine et al. (63) and Poulton et al. (65) provide two of the few examples in community-based samples. While few consistent associations emerge across these studies, data from both suggest that GAD exhibits a robust association with a range of adult conditions, including anxiety disorders and major depression. Data for other conditions, such as SAD or social phobia, appear more variable. Some studies document specific outcomes in these disorders (6), whereas other studies do not (65). Finally, similar conclusions derive from longitudinal studies of pediatric anxiety disorders based in the clinic. As with epidemiological studies, this research finds statistically robust associations with medium effect sizes. While more evidence emerges in these studies to support specificity of outcome, such as an association between SAD and panic disorder, the evidence is far from compelling (22,24,25). Etiological/Biological Theories Anxiety disorders, like most common psychiatric disorders, represent complex conditions that result from interactions among multiple risk factors and underlying predispositions. The majority of proposed etiological theories recognize the complexity of causal pathways, leading to a general, comprehensive model. As illustrated in Figure 5.5.1.1, this comprehensive model of anxiety disorders focuses on four factors: 1) genetic and environmental influences, 2) neural circuitry underlying emotion processing, 3) core psychological processes, and 4) broad behavioral tendencies, including temperament. Each of these components and their influences on the rest of the model will be discussed briefly in turn (Figure 5.5.1.1).

In terms of primary causes, this model implicates significant genetic and environmental influences. Family and twin studies consistently note a strong association between anxiety in parents and their children (29,66). Moreover, twin studies among both children and adults document a statistically significant genetic component to various forms of anxiety (66,67,68). These genetic and environmental influences are unlikely to directly predispose toward anxiety disorders per se. Rather, they are likely to shape more basic psychological processes which in turn influence risk for anxiety. For example, there is evidence P.543 for genetic influences on fear conditioning, the process by which an association is formed between a neutral stimulus, such as a tone or a light, and a noxious stimulus, such as an electric shock (69). Elements of this process are believed to underlie anxiety disorders, although the precise nature of the relationship between fear conditioning and anxiety remains ill specified (70). FIGURE 5.5.1.1. Etiological model of pediatric anxiety disorders. In terms of specific genetic contributions, recent studies have focused on a polymorphism in the promoter region of the serotonin transporter gene (5HTT) involving a 44-bp insertion or deletion. As noted above, in the discussion of GAD, individuals with the short form of the gene (ss or sl) have been shown to have higher neuroticism, harm avoidance, and anxiety than individuals homozygous for the long variant (ll) (71,72). A polymorphism of the variable-number-tandemrepeat in the second intron of the serotonin transporter gene has also been associated with increased risk of anxiety disorders, including OCD and GAD (73). Despite such evidence of a genetic contribution, anxiety disorders generally involve a large environmental component. From an environmental perspective, parents with anxiety disorders may use distinctive child rearing practices that affect risk for anxiety (66,74). For example, parents of anxious youth have been shown indirectly and directly to encourage maladaptive patterns of responding to ambiguous situations (75), exhibit overcontrolling and intrusive behaviors (76,77,78), and model anxious behavior themselves (79). As such, familial associations between parent and child anxiety may result through direct effects of these parenting behaviors, or through interactions between parentchild relationships and a genetically predetermined diathesis. Similar to genetic effects, these influences are unlikely to directly predispose towards anxiety. Rather, they are likely to shape core psychological processes, which in turn give rise to anxiety disorders. There is increasing interest in understanding the interaction between genetic and environmental factors in the development of anxiety disorders. One recent report found an interaction between maternal reports of social support and child 5-HTT status in predicting behavioral inhibition at age 8 (80). Further research on similar interactions will allow for more comprehensive pathophysiologic models of anxiety disorders. As noted above, the primary causes of anxiety, as reflected in genetic and environmental risk factors, influence the development of anxiety by shaping core psychological processes, such as fear conditioning. These psychological processes

reflect the influence of genes and the environment on functional aspects of brain regions involved in fear and reward circuits. These regions include structures of the striatum as well as limbic and paralimbic systems, including the amygdala, orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC) (81,82,83,84,85,86). These areas are highly interconnected and play a significant role in the integration of internal and external experience of emotion. Animal and human studies provide indisputable evidence that the amygdala plays an important role in fear conditioning, a basic process by which fear toward a previously neutral stimulus develops. As a result, it has been implicated as a critical element of the neural circuitry underlying anxiety disorders (87). This is supported by neuroimaging findings that show that anxiety-disordered adults and children demonstrate greater amygdala activity in response to face stimuli than controls (88,89,90). In children, the magnitude of the signal change between fearful and neutral faces has been shown to be positively correlated with child self-report ratings of anxiety (90). A recent study found that this anxiety-related amygdala response to fearful faces is greater when the child attends to his/her internal emotional state than to the features of the face itself (91). Structural imaging studies also document abnormalities in the amygdala among children and adolescents with anxiety disorders. For example, recent voxel-based morphometry findings show decreased left amygdala volume in children with anxiety disorders (92). These results, together with the functional neuroimaging findings, suggest an excitotoxic process may occur in the anxiety disorders, through which amygdala volume is reduced and responsivity increased. This theory of excitotoxicity as a risk factor for psychopathology was first introduced as a model for MDD (93). In light of the association between childhood anxiety disorders and MDD, it is a plausible model for these disorders as well. Nevertheless, relatively few studies examine amygdala volume in the anxiety disorders, and findings appear inconsistent: At least one group has reported an increased amygdala volume in pediatric GAD (94). Beyond the amygdala, the orbitofrontal cortex (OFC) represents a second structure directly implicated in aspects of emotion processing that are perturbed in anxiety disorders. This includes the flexible representation of both negative and positive reinforcers (95). As such, it is likely a critical element of the neural circuitry of anxiety and anxiety disorders. In support of this theory, anxiety induction studies have demonstrated increased activation in areas of the right prefrontal cortex (96,97) and left OFC (98). Pooling data across three groups of anxiety-disordered adults, Rauch and colleagues found consistent activation of the right medial OFC during symptom provocation (99). Magnetic resonance spectroscopy (MRS) studies demonstrate anxiety-related alterations in chemical composition of the OFC that are suggestive of changes in neuronal viability (100,101). Monk et al. (102) report comparable perturbations in pediatric anxiety disorders. Through its connections to the OFC and amygdala, the anterior cingulate cortex (ACC), particularly the rostral-ventral portion, serves to regulate emotional responses, and therefore is likely to be involved in the neural circuitry of anxiety. Studies of healthy adults using anxiety induction have demonstrated a decrease in

activity in ACC (103,104). A similar result has been found in patients with posttraumatic stress disorder (PTSD) who fail to demonstrate normal activation of the rostral ACC when shown combat-related stimuli (105). Through connections with the PFC, this dampening of the rostral ACC signal might serve to lessen cognitive control over threat-related information, which likely leads to the distress characteristic of patients with PTSD when exposed to trauma-related stimuli. In contrast, Rauch et al. (106) used PET to examine regional cerebral blood flow changes in patients with specific phobias during symptom provocation and found significant increases in the ACC, as compared to a control condition. These conflicting results suggest that specific phobias may rely on a different neural mechanism than other anxiety disorders. According to this general model, perturbations in this core circuitry contribute to anxiety disorders through their effects on anxiety-related biases in informationprocessing functions. These functions can be conceptualized as core psychological processes, such as attention and motivation. Independent of research on brain imaging or neural circuitry function, a wealth of research examines the association between variations in anxiety and various core psychological processes. In experimental work, the most consistent cognitive feature associated with fear and anxiety in humans represents an attention bias for stimuli associated with danger (107,108,109,110,111). This bias resembles the high degree of vigilance that animals show for feared scenarios or objects. In human studies, it is most often measured using the dot probe and Stroop paradigms. In the dot probe task, individuals monitor two stimuli presented on a computer screen: One is either a threatening word or picture and the other is a neutral word or picture. P.544 Subjects must press a button when a target appears in place of one of the stimuli, and reaction times to these targets are influenced in individuals with high levels of anxiety by proximity between the threat cue and the target. Studies using dot probe tasks demonstrate a bias toward threatening stimuli in adults and children with anxiety disorders that is not seen in nonanxious controls (112,113,114,115,116). Recording of eye movements during a face dot probe task confirmed that patients are more likely than normal controls to initially look toward a threatening face than a neutral one (117). Interestingly, this orienting toward threat is more likely to occur with brief stimulus presentations (500 ms), suggesting cognitive mechanisms early in information processing (116). The Stroop task requires subjects to name the color of potentially threatening words, such as coronary or snake. Prolonged latency for naming such color-words is presumed to be the result of interference, such that reactions elicited by a fear word interfere with attention to the color of the word. This effect has been demonstrated in both adults (118,119,120,121) and children (122) with anxiety disorders. While similar degrees of attention bias are found across anxiety disorders, the particular stimuli that cause this bias differ. For example, panic disorder patients may show a particularly prolonged latency to panic-related

words, such as smother, while subjects with social phobia may show greater latencies to relevant words such as embarrass. This bias toward threat is also evident in interpretations of ambiguity. Children with anxiety disorders have been shown to be more likely to interpret ambiguous stimuli as threatening. When performing a homophone task during which the subject is asked to write down words he hears on an audiotape, GAD patients display a greater tendency to write down the word associated with the more negative interpretation (pain vs. pane) (123). In a homograph study where children were shown a list of words with neutral and threatening meanings, youth with GAD showed a greater tendency to produce sentences using threatening interpretations than control participants (124). Similar results are found in studies when children diagnosed with anxiety disorders are presented with ambiguous situations and asked to interpret them (75,125). Anxiety-disordered youth are more likely to make a threatening interpretation of these situations than their nonanxious peers. Finally, these core psychological processes are believed to underlie broad behavioral tendencies such as early temperament and later development of anxiety disorders. Behavioral inhibition is a temperamental factor measurable during the first years of life that has been shown to predict later onset of anxiety disorders (126,127). Children with temperaments characterized by behavioral inhibition react to novel situations with signs of reticence or withdrawal. Based on peripheral physiologic data, behavioral inhibition is thought to result from an underlying hypersensitivity within amygdala-based neural circuits (126). While most children with behavioral inhibition do not develop clinical anxiety disorders, behavioral inhibition does predict an elevated risk for childhood anxiety disorders, particularly social phobia (32). Clearly, the development of anxiety and its disorders is a complex process that likely involves biological vulnerabilities as well as environmental influences. Significant advances in basic research have provided a neurobiological framework on which to base hypothesized etiological models. Additionally, advanced research technologies in genetics and neuroimaging have allowed us to test these models with ever increasing sophistication and detail. Continued translation of basic research findings to clinical studies will be essential to the further advancement of our understanding of anxiety disorders. Treatment of Pediatric Anxiety Disorders Over the past two decades, significant advances have been made in the treatment of pediatric anxiety disorders. Cognitive-behavioral and pharmacological interventions have emerged as effective treatments for these disorders. While a few trials have evaluated these treatments for a specific anxiety disorder, most have included children and adolescents with a primary diagnosis of GAD, SAD, or social phobia. In light of the high comorbidity among these disorders, this approach improves the feasibility and generalizability of these studies. The most widely used interventions and their empirical support will be discussed here. Cognitive-Behavioral Interventions Cognitive-behavioral treatments (CBT) have proven to be effective at treating anxiety disorders in children and adolescents (128,129,130). Most cognitive-

behavioral interventions were initially developed for adult anxiety and phobic disorders, so the techniques for children are conceptually and structurally similar but modified according to developmental level. For example, to introduce cognitive restructuring, these treatments use cartoons and thought bubbles to help children learn to identify and then change their thoughts. In addition to cognitive techniques, these treatments include behavioral strategies such as modeling, relaxation skills training, homework, contingency management, and most importantly, exposure to feared situations. The aim of exposures, either imaginal or in vivo (real life), is to provide the patient with opportunities to practice newly learned coping skills in a safe, controlled environment. Feared stimuli or situations are presented in a graduated fashion, beginning with the easiest and ending with the most difficult, so that the child experiences early success in using these new skills. The pace at which the child and therapist move up the hierarchy is determined by these successes. Empirical evidence supports the use of these cognitive-behavioral interventions for pediatric anxiety disorders. Kendall et al. conducted two randomizedcontrolled trials demonstrating the efficacy of a 16-week individual CBT for children with social phobia, GAD, and SAD (129,130). Treatment gains were maintained at 1, 3 (131), and 7 years post-treatment (132). Barrett and colleagues modified Kendall's CBT and added a family-based component that teaches parents how to be effective models for their children and how to encourage coping with feared situations, rather than avoidance. Individual CBT plus the family component was shown effectively to reduce anxiety symptoms and may have had some added benefits, particularly for younger, female children (128). Treatment gains were maintained at 6-year follow-up (133). Group cognitive-behavioral interventions have been shown to be effective for the treatment of socially phobic children and adolescents (134,135,136). Conducting treatment in a group setting provides these children with greater opportunities for in vivo exposures. While this work clearly documents the benefits of CBT in pediatric anxiety disorders, major questions remain concerning the mechanism of these effects. Such questions emerge given limitations in the available studies. In particular, the majority of controlled trials compare CBT to relatively crude comparison conditions, such as a wait-list control. A few trials have used more rigorous designs, whereby a credible attention-control condition is used. Results in these trials are less consistent than in the trials comparing CBT to a wait-list (137,138). Nevertheless, at least one study in pediatric social anxiety disorder demonstrated a superior response to P.545 CBT relative to a credible attention-control intervention. Moreover, ongoing studies are comparing CBT for pediatric anxiety disorders to placebo control. Findings in pediatric MDD using this same contrast recently generated considerable questions on efficacy of CBT in this condition. Results from the comparison of CBT with placebo in the anxiety disorders are thus eagerly anticipated. A more detailed discussion of CBT appears in Chapter 6.2.2. Pharmacological Interventions

Advances in psychopharmacology and the design and implementation of large placebo-controlled studies have led to significant improvement in the treatment of pediatric anxiety disorders. As with CBT, pharmacological agents that have been shown effectively to treat adult anxiety disorders, such as antidepressants and anxiolytics, are now being used to treat children. Benzodiazepines have shown mixed results (31,139) and are not indicated as a first-line treatment in children due to their potential adverse effects. There is also little or no evidence for the efficacy of other anxiolytics, such as buspirone or beta-blockers. While tricyclic antidepressants have demonstrated some efficacy, they have not been shown convincingly to treat pediatric anxiety disorders, beyond the data documenting the efficacy of clomipramine for pediatric OCD. In addition, their side effect profiles do not make them a viable first-line treatment option for children. Overall, efficacy and safety data support the use of selective serotonin reuptake inhibitors (SSRIs) to treat childhood social phobia, SAD, and GAD. In light of this, this section will review only current findings regarding the treatment of pediatric anxiety disorders using SSRIs. A greater discussion of psychopharmacologic agents appears in Chapter 6.1. Early open trials of SSRIs showed promising results for children with mixed anxiety disorders (140,141). Following from these results, the Research Unit on Pediatric Psychopharmacology (RUPP) conducted the largest medication trial of children (ages 617) with a primary diagnosis of SAD, GAD, or social phobia (142). Following a 3-week supportive psychoeducational treatment lead-in, 128 children were assigned to either fluvoxamine or placebo for 8 weeks. The children in the fluvoxamine group had greater reductions in symptoms of anxiety and higher rates of clinical response than the children in the placebo group. On the Clinical Global Impression scale, 48 of 63 (76%) children in the fluvoxamine group were classified as treatment responders, in comparison to only 19 of 65 (29%) children in the placebo group (p < 0.001). In a somewhat smaller randomized placebo-controlled study of 74 children with GAD, social phobia, and/or SAD, fluoxetine was found to be superior to placebo in decreasing symptoms of anxiety (143). Recent studies have demonstrated the efficacy of SSRIs for specific anxiety disorders. For example, Rynn et al. conducted a placebo-controlled study of sertraline with children and adolescents with GAD (144). Beginning at 4 weeks, the sertraline-treated group showed significantly reduced scores on the Hamilton anxiety scale and the Clinical Global Impression (CGI) severity and improvement scales. Recently a multicenter, randomized, double-blind, placebo-controlled trial of children and adolescents with social anxiety disorder concluded that paroxetine is an effective, generally well tolerated treatment for social phobia (145). A total of 322 children and adolescents age 817 either received placebo or paroxetine (1050 mg/day) for 16 weeks. As measured by the CGI-Improvement scale, the odds of responding were significantly greater for paroxetine versus placebo. There have been no placebo-controlled, double-blind trials of the treatment of panic disorder in children. A small, open label study of 12 children and adolescents with panic disorder showed improvement on SSRIs with minimal side effects (146). In a preliminary naturalistic study, 15 of 18 children and adolescents

with panic disorder were considered responders to paroxetine (147). In adults, SSRIs have become the pharmacotherapeutic treatment of choice, and several SSRIs have approved indications for the treatment of panic. Questions have been raised about the safety of SSRIs in children and adolescents. In particular, the Food and Drug Administration (FDA) issued a black box warning in the fall of 2004 concerning the use of SSRIs in this age group. This warning cautioned physicians about the possible adverse behavioral side effects of SSRIs. Specifically, analyses performed by the FDA demonstrated a higher rate of suicidal thoughts and acts in a metaanalysis of randomized controlled trials. These trials had examined approximately 4,000 children and adolescents with various forms of psychopathology, including anxiety. While the overall rate of clinically significant suicidal thoughts or acts was less than 5%, the rate was statistically greater for individuals randomized to SSRIs as compared to placebo. As a result, prescribing clinicians need to be very careful to assess for signs of behavioral activation and/or suicidality when using these treatments. It is also especially important to take a careful history before prescribing that includes signs of mood instability in the patient or family members. Future Directions/Research Challenges Over the past 20 years, significant strides have been made in the development of effective treatments of pediatric anxiety disorders. Cognitive-behavioral treatments and SSRIs have proven to be first-line interventions. However, we have little information about which is more effective, and for whom. The next step is to conduct a study examining these issues. Are medications more effective than CBT; is CBT more effective than medication? Is the combination of CBT plus medications more effective than either alone? Such a study is currently underway and we will have to await the results. In conclusion, this chapter has provided a review of pediatric anxiety disorders, including current findings regarding their prevalence, etiology, and treatment. The study of these disorders is relatively new, as compared to other psychiatric conditions (schizophrenia, major depressive disorder). As a result, our understanding of underlying developmental and neurobiological mechanisms is limited. Continued advances in basic science research, genetics, and neuroscience will allow for further refinement of current models and subsequent development of new interventions for the prevention and treatment of pediatric anxiety disorders. References 1. Marmorstein NR: Generalized versus performance-focused social phobia: Patterns of comorbidity among youth. J Anxiety Disord 2005. 2. Achenbach TM, Howell CT, McConaughy SH, Stanger C: Six-year predictors of problems in a national sample of children and youth: I. Cross-informant syndromes. J Am Acad Child Adolesc Psychiatry 34:336347, 1995. 3. Gurley D, Cohen P, Pine DS, Brook J: Discriminating depression and anxiety in youth: A role for diagnostic criteria. J Affect Disord 39:191200, 1996. 4. Costello EJ, Mustillo S, Erkanli A, Keeler G, Angold A: Prevalence and development of psychiatric disorders in childhood and adolescence. Arch Gen Psychiatry 60:837844, 2003.

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