Pediatric Generalized Anxiety Disorder

1. Pediatric Generalized Anxiety Disorder Andel V. Nicasio, MSEd University of Central Florida 7936 Child Psychopathology October 23, 2013

2. Aims of this presentation Illustrate the historical evolution of Generalized Anxiety Disorder (GAD) Review the DSM-5 taxonomy for GAD Explain etiology, onset, prevalence and course of GAD Review the main theoretical and conceptual models of GAD Present a new theoretical model for pediatric GAD

3. Aim 1 Illustrate the historical evolution of Generalized Anxiety Disorder (GAD)

4. Nosology and Historical Developments • 18th Century - Anxiety was considered a medical illness (Berrios, 1996). • 19th Century - Freud viewed Anxiety as resulting from sexual libido unable to find discharge either because of inadequate sexual activity or by inhibitions due to repression (Haggard et al. 2008). • Distinguished between Anxiety Neurosis from Neurasthenia, a condition first described by George Beard in 1868. • Neurasthenia at the time was a common diagnosis that broadly included anxiety symptoms among other symptoms (e.g., easy fatigability), many of which are now characteristics of chronic fatigue syndrome. • Later, Freud modified his theory - “Anxiety was more closely related to fear, occurring in response to perceived dangers, either external or internal. This led to focus on the ego, one of whose functions is to anticipate and negotiate danger situations”(Haggard et al. 2008 , p. 471).

5. GAD in the DSM DSM-I Anxiety Reaction DSM-II Anxiety Neurosis DSM-III GAD (1 month duration) Panic Disorder GAD (6 month duration) Includes Overanxious Disorders of Childhood Anxiety Disorders NOS DSM-IV

6. Diagnostic criteria for GAD in DSM-III A - Generalized persistent anxiety is manifested by symptoms from three of the following four categories: (1) Motor tension: shakiness, jitteriness, jumpiness, trembling, tension, muscle aches, fatigability, inability to relax, eyelid twitch, furrowed brow, strained face, fidgeting, restlessness, easy startle (2) Autonomic hyperactivity: sweating, heart pounding or racing, cold, clammy hands, dry mouth, dizziness, light-headedness, paresthesias(tingling in hands or feet), upset stomach, hot or cold spells, frequent urination, diarrhea, discomfort in the pit of the stomach, lump in the throat, flushing, pallor, high resting pulse and respiration rate (3)Apprehensive expectation: anxiety, worry, fear, rumination, and anticipation of misfortune to self or others (4) Vigilance and scanning: hyperattentiveness resulting in distractibility, difficulty in concentrating, insomnia, feeling “on edge,” irritability, impatience B - The anxious mood has been continuous for at least one month. C - Not due to another mental disorder, such as a depressive disorder or schizophrenia. D - At least 18 years of age

7. Diagnostic criteria for GAD in DSM-III-R A - Unrealistic or excessive anxiety and worry (apprehensive expectation) about two or more life circumstances, e.g., worry about possible misfortune to one’s child (who is in no danger) and worry about finances (for no good reason), for a period of six months or longer, during which the person has been bothered more days than not by these concerns. In children and adolescents, this may take the form of anxiety and worry about academic, athletic, and social performance. B - If another Axis I disorder is present, the focus of the anxiety and worry in A is unrelated to it, e.g., the anxiety or worry is not about having a panic attack (as in panic disorder), being embarrassed in public (as in social phobia), being contaminated (as in OCD), or gaining weight (as in anorexia nervosa). C - The disturbance does not occur only during the course of a mood disorder or a psychotic disorder. D - At least 6 of the following 18 symptoms are often present when anxious (do not include symptoms present only during panic attacks): Motor tension - (1) trembling, twitching, or feeling shaky; (2) muscle tension, aches, or soreness; (3) restlessness; (4) easy fatigability. Autonomic hyperactivity - (5) shortness of breath or smothering sensations; (6) palpitations or accelerated heart rate (tachycardia); (7) sweating, or cold clammy hands; (8) dry mouth; (9) dizziness or lightheadedness; (10) nausea, diarrhea, or other abdominal distress; (11) flushes (hot flashes) or chills; (12) frequent urination; (13) trouble swallowing or “lump in throat”. Vigilance and scanning - (14) feeling keyed up or on edge;(15) exaggerated startle response; (16) difficulty concentrating or “mind going blank” because of anxiety; (17) trouble falling or staying asleep; (18) irritability. E -It cannot be established that an organic factor initiated and maintained the disturbance, e.g., hyperthyroidism, caffeine intoxication.

8. DSM-III-R DSM-IV • Motor tension (1) trembling, twitching, or feeling shaky (2) muscle tension, aches, or soreness (3) restlessness (4) easy fatigability • Autonomic hyperactivity (5) shortness of breath or smothering sensations (6) palpitations or accelerated heart rate (tachycardia) (7) sweating, or cold clammy hands (8) dry mouth (9) dizziness or lightheadedness (10) nausea, diarrhea, or other abdominal distress (11) flushes (hot flashes) or chills (12) frequent urination (13) trouble swallowing or “lump in throat” Vigilance and scanning (14) feeling keyed up or on edge (15) exaggerated startle response (16) difficulty concentrating or “mind going blank” because of anxiety (17) trouble falling or staying asleep (18) irritability (1) restlessness or feeling keyed up or on edge (2) being easily fatigued (3) difficulty concentrating or mind going blank (4) irritability (5) muscle tension (6) sleep disturbance (difficulty falling or staying asleep, or restless unsatisfying sleep)

9. Aim 2 Review the DSM-5 taxonomy for GAD DSM-5 GAD Model

10. What is Generalized Anxiety Disorder?

11. DSM-5 Taxonomy of GAD • Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities (such as work or school performance). • The individual finds it difficult to control the worry. • The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms having been present for more days than not for the past 6 months): Note: only one item is required for children. • Restlessness or feeling keyed up or on edge • Being easily fatigued • Difficulty concentrating or mind going blank • Irritability • Muscle tension. • Sleep disturbance (difficulty falling or staying asleep, or restless, unsatisfying sleep)

12. DSM-5 Taxonomy of GAD • The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. • The disturbance is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition (e.g., hyperthyroidism). • The disturbance is not better explained by another mental disorder (e.g. anxiety or worry about having panic attacks in panic disorder, negative evaluation in social anxiety disorder [social phobia], contamination or other obsessions in OCD, separation from attachment figures in SAD, reminder of traumatic events in PTSD, gaining weight in anorexia nervosa, physical complains in somatic symptom disorder, perceived appearance flaws in body dysmorphic disorder, having a serious illness in illness anxiety disorder, or the content of delusional beliefs in schizophrenia or delusional disorder).

13. GAD in the DSM-5 • Children with GAD tend to worry excessively about their competence or the quality of their performance. During the course of the disorder, the focus of worry may shift from one concern to another.

14. Associated Features Supporting Dx • Muscle tension – trembling, twitching, feeling shaky, and muscle aches or soreness. • Somatic symptoms – sweating, nausea, diarrhea • Exaggerated startle response • Symptoms of autonomic hyperarousal – (e.g. accelerated heart rate, shortness of breath, dizziness) are less prominent than in panic disorder. • Other conditions associated with stress (e.g. irritable bowel syndrome, headaches) frequently accompany GAD.

15. GAD Prevalence • 12-month prevalence is 0.9% among adolescents and 2.9% among adults in the general community of U.S. • In other countries, the 12-month prevalence is 0.4% - 3.6%. • Lifetime morbid risk is 9.0% • Prevalence of diagnosis peaks in middle age and declines across the later years in life. • European-descent individuals tend to experience GAD more frequently than non-European descent (i.e., Asian, African, Native American and Pacific Islander). • Persons from developed countries are more likely to report that they have experience GAD than those from nondeveloped countries.

16. Onset and Course of GAD • Many people with GAD report that they have felt anxious and nervous all of their lives. • The median age at onset is 30 y/o. • Age at onset is spread over a broad range. • Symptoms of worry and anxiety may occur early in life, but are then manifested as an anxious temperament. • Symptoms tend to be chronic and wax and wane across lifespan, fluctuating from syndromal to subsyndromal forms of disorder. • Rates of full remission are very low.

17. Gender Differences and Comorbidity • More frequently diagnosed in females (55-60%) than males. In epidemiological studies 2/3 are females. • Female and males appear to have the same symptoms, but present different patterns of comorbidity. • Comorbidity – People with GAD are likely to have met, or currently meet, criteria for other anxiety and unipolar depression disorder. • Comorbidity with substance abuse, conduct, psychotic, neurodevelopmental, and neurocognitive disorders LESS common. Females - Comorbidity confined to anxiety disorders and unipolar depression. • Males - Comorbidity more likely to extend to substance abuse disorders.

18. GAD Risk and Prognosis Factors • Temperamental – Behavioral inhibition, negative affectivity (neurotism), and harm avoidance have been associated with GAD. • Environmental – No environmental factors have been identified as specific to GAD or necessary or sufficient for making the diagnosis. • Genetic and physiological – 1/3 of the risk of experiencing generalized anxiety disorder is genetic, and these genetic factors overlap with the risk of neurotism and are shared with other anxiety and mood disorders, particularly MDD.

19. Culture • Considerable cultural variation in the expression of GAD. • In some cultures somatic symptoms predominate, but in other cultures cognitive symptoms predominate. • Cultural expressions are more evident in the initial presentation; over time more symptoms tend to be reported. • Important to consider the social and cultural context when evaluating whether worries about certain situations are excessive.

20. Differential Diagnosis

21. DSM-5 Model

22. Aim 3 • Literature Review of Pediatric GAD

23. Prevalence • Anxiety is the most common mental disorder in children and adolescents (Anderson et al. 1987). • Prevalence rates range from 6% to 20% (Costello et al. 2004). • Generalized Anxiety Disorder • In community samples, prevalence rates range from 0.1% (Merikangas et al., 2010) to 3.3% (Kessler et al., 2005). • In clinical samples, prevalence rates range from 3% (Chorpita et al., 2005) to 15% (Ebesutaniet al., 2010).

24. Comorbidity • Isolated cases of “pure” anxiety disorders (no co-occurring dx) are relatively rare (Comer & Olfson, 2010). • About 70–80% with a lifetime anxiety disorder and 60–90% with an anxiety disorder in the past year meet criteria for at least one additional disorder (Kessler et al. 2006, Lampe et al. 2003, Jacobi et al. 2004, Torres et al. 2008). • Individuals with SP, GAD, and SAD are at 15, 9, and 6 times increased odds, respectively, for having a co-occurring anxiety disorder (Grant et al. 2005, Stinson et al. 2007, Ruscioet al. 2008).

25. Cont… Comorbidity • Those diagnosed with 12-month GAD, SAD, and SP are at 19, 5, and 3 times increased odds, respectively, for having a co-occurring mood disorder (Merikangas et al. 2002, Grant et al. 2005, Stinson et al. 2007). • GAD or SP are at greatest risk for co-occurring bipolar disorder. • In cases of co-occurring anxiety and mood disorders, onset of anxiety disorders typically occurs prior to mood disorders (Brady & Kendall,1992)

26. Rate and comorbidity

27. GAD - Lifetime Prevalence

28. GAD Comorbidity Walkup, J. T. et al (2008) - Child-Adolescent Multimodal Treatment Study: GAD was the most common disorder; however, GAD, SAD, and SoP were highly comorbid.

29. GAD Comorbidity Separation Anxiety Disorder Social Phobia Generalized Anxiety Disorder Walkup, J. T. et al (2008)

30. Onset • Among all Anxiety Disorders, GAD has the latest mean and median age at onset (early 30s) (Grant et al. 2005, Kessler et al. 2005, Liebet al. 2005). • However, substantial numbers of children and adolescents do meet full criteria (Albano & Hack 2004 , Comer et al. 2004 , Robin et al. 2005 , Alyahri& Goodman 2008). • In community samples, 0.1% for children 8-11 y/o and 1.1% for adolescents 12-15 y/o (Merikangas et al. 2010); 8.6% for 8 y/o and 17.1% for 17 y/o (Kashaniand Orvaschel, 1990). • The onset of GAD may be gradual or sudden and, unsurprisingly, symptoms are often exacerbated by stress (Rapoport & Ismond, 1996) • Early GAD onset is associated with greater excessiveness and uncontrollability of worry, as well as a more chronic course with more severe life impairment (Ruscioet al. 2005 ).

31. Gender • Gender differences in the prevalence of GAD in children and adolescents are inconsistent. • Merikangas et al. (2010) reported no gender differences in a sample of 8–15-year-olds, using the DSM-IV • In another study, girls (of all ages) were found to have higher rates than boys (15 % of girls and 9 % of boys (Kashaniet al., 1990). • Clinical samples have reported no gender differences in GAD in children 9–13 years of age (Last et al., 1992). • With respect to symptoms of GAD and/or worry, females report more GAD symptoms than males.

32. Course • GAD, phobias, panic disorder, and depressive disorders predicted each other over time, and early-onset GAD was a stronger predictor of later anxiety rather than depressive disorders. • Predictors of GAD onset over time - Parental GAD and depression, childhood behavioral inhibition, childhood separation events, and parental overprotection. • GAD was associated with the personality trait “reward • dependence” (based on self-reported personality) and dysfunctional family functioning. • Community sample; N= 3,021; • 14–24 years at time 1) for 10 years. Bessdo et al., 2010

33. Race/Ethnicity • Lower lifetime rates of anxiety disorders among immigrants than among US-born natives of the same national origins (Vega et al. 1998 , Grant et al. 2004). • Early age at immigration and longer duration residing in the USA are both associated with increased risk for mental dis-orders among immigrants relative to natives (Breslau et al. 2007). • A epidemiological survey conducted in South Africa revealed that rates of GAD were significantly higher in men than women (Bhagwanjee et al. 1998).

34. Suicidality • Any single anxiety disorder (phobia, GAD, panic disorder) increased the odds of suicidal ideation by 7.96 times [95% confidence interval (CI) 5.69–11.13] and increased the rate of suicide attempts by 5·85 times (95% CI 3.66–9.32). • Rates of suicidal behavior increased with the number of anxiety disorders. • Estimates of the population attributable risk suggested that anxiety disorders accounted for 7–10% of the suicidality in the cohort. • Christchurch Health and Development Study (CHDS). • 25-year longitudinal study; over 1000 participants. • Subjects aged 16–18, 18–21 and 21–25 years. Boden et al., 2007

35. Temperament and Genes • Genetic correlations between GAD and neuroticism were high 0.80 (95% confidence interval=0.52–1.00), with no significant difference between men and women (1.00 and 0.58, respectively) (Hettema et al, 2004). Bivariate Twin Model for Neuroticism and Generalized Anxiety Disorder aThephenotypic correlation is decomposed into the additive genetic correlation (rg) between additive genetic factors (AN and AG), the common environmental correlation (rc) between common familial environmental factors (CN and CG), and the individual-specific environmental correlation (re) between individual-specific environmental factors (EN and EG) for neuroticism and generalized anxiety disorder, respectively.

36. Temperamental Trait and GAD Distribution of harm avoidant scores and presence/absence of current DSM-IV GAD in children and adolescents.

37. Genes and Anxious Brains (Monkeys)

38. Genes and Anxious Temperament (AT)

39. Neurological Pathways • Contradictory research findings - Youth with GAD exhibited greater amygdala volumes (De Bellis, et al., 2000), whereas reduced amygdala volume was identified in adolescents with GAD, SAD, or SoPh(Milham et al., 2005). • Patients with GAD fail to engage regulatory regions in response to heightened displays of amygdala activity resulting from emotional stimuli (Etkin et al., 2010). • Compared to healthy controls, adolescents with GAD displayed a relatively weaker negative task-dependent functional connectivity (TDFC) between the lateral prefrontal cortices and the amygdala during an emotional attention orienting task (Thomas et al., 2001). • This is consistent with the notion that individuals with anxiety are less able to regulate neural responses to emotion, even prior to adulthood.

40. Schematic Framework Pine, et al 2008

41. Areas of the Brain Affected by GAD

42. The noradrenaline pathways in GAD Noradrenaline Pathways GABAergic pathways Serotenergic Pathways

43. The Septohippocampal Circuit

44. Fear and Anxiety in the Brain Networks that Support Negative Reactivity and Regulation Etkin, A. & Wager, T. D. (2010)

45. Genes • A meta-analysis of family and twin studies of anxiety disorder estimated GAD heritability to be 32% (Hettemaet al. 2001).

46. Cognitive Symptoms • Worry and the disturbance of mental processes (e.g., thinking, planning, abstract reasoning, problem solving, and recall) encompass the cognitive features of anxiety (Kendall et al., 2004). • With GAD, there is an overall attitude of apprehension. Children and adolescents with GAD are often described as self-conscious, perfectionistic “worriers” (Beidel, Turner, 2005; Eisen& Kearney, 1995).

47. Cognitive Factors • Youth with GAD display problematic cognitive processes (Ginsburg & Affrunti, 2013). • Youth with GAD are: • more likely to overestimate the negative consequences of their actions, • expect negative consequences to occur with greater frequency, • overestimate the likelihood of threatening situations, • interpret ambiguity as threatening, and • have impaired problem-solving skills Albano et al., 1996; Bögelset al., 2003; Léger et al., 2003

48. Attentional Bias • Youth with GAD are more likely to interpret ambiguous information as threatening and have an attentional bias toward threatening stimuli. • Waters et al. (2008) examined the attentional bias for angry and happy faces in 7-12 y/o with GAD (N= 23) and nonanxious controls ( N= 25). • Found that GAD severity was associated with greater attentionalbias toward angry faces. Mean attention bias scores (+SE) for angry and happy faces as a function of group (CON = control; LCA = low clinical anxiety; HCA = high clinical anxiety).

49. Attention Orienting • A process that involves focusing one’s attention on salient stimuli. • Recent RCTs have demonstrated that training anxious children to modify their attentional threat biases can facilitate disengagement of attention to threat, which in turn can reduce anxiety symptoms (Bar-Haim et al.,2011; Eldar et al., 2012). • These findings suggest that attention biases might emerge over time through reinforcement or as a means to reconcile ambiguous situations (Field et al., 2010).

50. Dot-probe paradigm