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|Neuropsychopharmacology: The Fifth Generation of Progress|
Childhood Anxiety Disorders
Susan Jo Perlmutter, M.D.
Anxiety disorders are the most common form of psychopathology in children with an overall prevalence rate of 8–10% (60). Overanxious disorder (termed generalized anxiety disorder in DSM-IV), separation anxiety disorder, and simple phobia are among the most frequently diagnosed (3,24). Childhood anxiety disorders are often associated with other childhood anxiety disorders and with depression. It is extremely important for the clinician to be aware of these comorbid psychiatric diagnoses, as they impact on clinical course, prognosis, and treatment.
Over the past decade, considerable progress has been made in the understanding and treatment of separation anxiety disorder, selective mutism, panic disorder and obsessive-compulsive disorder in children and adolescents. This chapter reviews these childhood anxiety disorders and behavioral inhibition, a temperamental characteristic which appears to increase the risk of developing an anxiety disorder (12,13,72).
Behavioral inhibition is an early temperamental trait characterized by the tendency to withdraw when exposed to unfamiliar situations (42). Longitudinal studies of behaviorally inhibited children at the Harvard Infant Study Lab indicate that behavioral inhibition tends to be an enduring temperamental trait; children classified as behaviorally inhibited at age 21 months continued to be shy, timid, and fearful in unfamiliar settings at the ages of 4 and 7 (42). Kagan has suggested that children who are inhibited may have a lower threshold of responsivity in the limbic and hypothalamic circuits and, as a result, they react with greater sympathetic activation when exposed to novel situations (41).
Based on Kagan's work, Biederman and colleagues investigated behavioral inhibition as a risk factor for anxiety disorders (12,13). They found higher rates of behavioral inhibition in the offspring of parents with panic disorder with agoraphobia (PDAG) than in the offspring of parents without PDAG (72). They also found increased rates of multiple anxiety disorders among the children classified as behaviorally inhibited (12). Furthermore, on three-year follow-up, the authors discovered that inhibited children had markedly increased rates of anxiety disorders and also significantly higher rates of multiple anxiety disorders than the uninhibited children, supporting the view that behavioral inhibition is associated with an increased vulnerability for anxiety disorders (13). It has also been suggested that behavioral inhibition is linked to a familial predisposition to anxiety disorders, because behavioral inhibition in children is associated with increased rates anxiety disorders in their first-degree relatives (73).
SEPARATION ANXIETY DISORDER
Diagnosis and Epidemiology
One of the most common childhood anxiety disorders is separation anxiety disorder (SAD), with a reported prevalence ranging from 3.5% to 5.4% (14). The defining feature of SAD is developmentally inappropriate, excessive, and unrealistic anxiety regarding separation from home or from major attachment figures, usually a parent (2).
Symptoms and Comorbidity
Children with SAD become extremely distressed when separated from a parent; this distress can reach panic proportions, with accompanying autonomic symptoms of anxiety. Often these children actively resist or refuse to be separated from important attachment figures. For example, they may follow a parent around the house and refuse to sleep alone. Children with SAD worry excessively that their parents will die or suddenly disappear, or that they will be abducted, causing permanent separation. When these children are separated from their parents, even for a brief period of time, they spend much of this time worrying about the safety of their parents and anxiously await the parents' return (14).
Because these children avoid situations involving separation, school refusal frequently accompanies SAD. Separation anxiety disorder and "school refusal" or "school phobia" are terms that have been used interchangeably, even though they are not necessarily the same thing. For example, not all children with "school refusal" have SAD, and not all children with SAD have "school refusal". In fact, "school refusal" can be due to social phobia, anxiety about competence or performance in school, and other disorders, such as conduct disorder (truancy) or depression (social withdrawal). Furthermore, depression and overanxious disorder are frequent comorbid conditions of SAD (26).
Neurobiology and Etiology
Gittleman and Klein were the first to postulate a link between childhood SAD and adult panic disorder with agoraphobia (PDAG) and to suggest that SAD and PDAG may be different clinical manifestations of the same underlying disorder (33). This hypothesis has been supported by other studies, which have found that adults with PDAG report a significantly higher rate of childhood SAD than subjects with other anxiety disorders (20). Additionally, offspring of parents with panic disorder (PD) have been found to have an increased risk of SAD (20). However, several other studies do not support a specific association between childhood SAD and adult PDAG, but rather suggest that childhood SAD may be a risk factor for multiple anxiety disorders in adulthood (57,74). More long-term prospective studies of childhood SAD are needed to confirm the relationship between SAD and adult anxiety disorders.
Cognitive and behavioral techniques, including contingency management, modeling, relaxation, and exposure-based treatments are often used, but there have been no controlled studies of these treatments (14). Interestingly, in a study by Klein et al., imipramine treatment for SAD, 50% of the children with severe separation anxiety treated with a comprehensive behavioral program improved within four weeks, which precluded their entry into the drug treatment study (45). Because of this dramatic response, the authors suggested considering behavioral treatment before pharmacotherapy.
Controlled treatment studies have been done with imipramine, clomipramine, and alprazolam. Imipramine, a tricyclic antidepressant, was the first pharmacological agent tried for "school phobia" because it had been found to be strikingly effective in reducing panic attacks in adults with PDAG who had childhood histories of SAD (32). An initial controlled study with imipramine was promising, but later controlled studies failed to replicate the earlier findings (9,32,45). Of note, Klein's initial study was with "school phobic" children, only some of whom had SAD. Psychiatric comorbidity was not assessed, and imipramine treatment was combined with behaviorally-oriented therapy. However, in Klein's later study, only children with SAD were included, the presence of "school phobia" was not required, and only those children who did not respond to a one-month trial of behavior therapy were entered into the imipramine treatment study.
Bernstein et al. compared alprazolam (a triazolobenzodiazepine), imipramine, and placebo in a controlled study for "school refusal" (9). Although they found no significant differences among the three treatment groups, greater numbers of children improved with imipramine and alprazolam than with placebo. The lack of statistical significance may have been due to the small sample size. Moreover, only 14 of the 24 children completed the study. Clomipramine, another tricyclic antidepressant, has also been studied in controlled trials for "school refusal" and found to be ineffective (8).
Unfortunately, no firm conclusions about the usefulness of psychotropic medications for SAD can be drawn from these treatment studies because of problems with diagnostic heterogeneity, small sample size, and brief duration of treatment. Most of the studies had "school refusal" or "school phobia" as an inclusion criterion, rather than separation anxiety disorder. Additionally, some included cases of "school refusal" secondary to truancy or depression or cases of SAD which were comorbid with other psychiatric disorders. However, if pharmacotherapy is used, it should be in the context of a multimodal treatment plan that includes behavioral interventions.
Diagnosis and Epidemiology
The essential feature of panic disorder (PD) is the presence of recurrent and unexpected panic attacks characterized by a discrete period of intense fear or discomfort that is accompanied by somatic and/or cognitive symptoms (e.g., palpitations, sweating, dizziness, or fear of dying) . Individuals with PD often develop anticipatory anxiety and sometimes avoidance behavior or agoraphobia, which is a phobic avoidance of situations where help may not be available in the event of a panic attack.
Until recently, it was thought that PD did not occur in children. It is now known that PD does occur in children, but it is probably rare (although the prevalence of the disorder has been debated) . Numerous case reports provide further evidence that PD can occur prior to puberty, and that it presents with clinical symptoms similar to adult PD (4,15,21,83). It has been reported that children with PD have a high incidence of depression, similar to findings in adults with PD (14).
Although there are no pediatric studies of the pathophysiology of PD, most authors assume that it is similar to that seen in adults. Family genetic studies of PD have provided evidence for a genetic vulnerability, and it has been extensively reported in the adult literature that lactate infusion and carbon dioxide inhalation precipitate panic attacks in adults with PD (37,44,86). Additionally, noradrenergic dysfunction and abnormal cerebrospinal fluid (CSF) cholecystokinin concentrations are presumed to be involved in PD (23,59).
There appears to be increased vulnerability for the development of PD in the peripubertal period. Peak age of onset was between 15 and 19 years in the NIMH Epidemiologic Catchment Area Program—although it should be noted that this was based on patients' retrospective reports (85). Hayward et al. found a higher prevalence of panic attacks in sixth- and seventh-grade girls who were more physically mature, suggesting a link between puberty and PD (38).
Because of the similar symptom patterns of mitral valve prolapse (MVP) and panic attacks, there has been a question of increased prevalence of MVP in patients with PD. Symptoms of panic have been reported in adults and in a child with MVP (21), but systematic studies specifically examining the relationship between PD and MVP have been inconclusive (43).
Psychotherapy and Psychopharmacology
Although antidepressant medications (including tricyclic antidepressants, serotonin reuptake inhibitors, and monoamine oxidase inhibitors), high-potency benzodiazepines, and cognitive-behavioral therapies (CBTs) are effective in the treatment of adult PD, there have been no controlled studies of treatment for childhood PD (14). Several case reports suggested that the antidepressants desipramine and imipramine and the high-potency benzodiazepines alprazolam and clonazepam are useful for pediatric PD (4,11,15). Additionally, clinician experience and anecdotal evidence suggest that fluoxetine, a selective serotonin reuptake inhibitor, may be effective for PD in children and adolescents.
Optimal treatment may be a combination of pharmacotherapy and cognitive-behavioral therapy. Antidepressants usually are prescribed for prevention of panic attacks and benzodiazepines for the residual anticipatory anxiety and phobic avoidance (agoraphobia). Because of the potential for abuse and dependence, benzodiazepines should be given only for short periods, for instance in conjunction with early CBT or until an antidepressant takes full effect. Of note, alprazolam is to be avoided because its short duration of action causes interdose rebound anxiety and unpleasant withdrawal symptoms, making it especially susceptible to abuse and dependence.
Diagnosis and Epidemiology
Prior to DSM-IV, selective mutism had been known as "elective mutism" because it was assumed that these children were voluntarily refusing to talk in response to early trauma and dysfunctional family dynamics. However, more recent reports suggest that the disorder is not due to oppositional behavior or to early trauma, but is rather a manifestation of a shy and inhibited temperament and may be a variant of social phobia (16,17). In recognition of this, the new nomenclature "selective mutism" eliminates the oppositional component and reflects the component of social anxiety. The essential feature of selective mutism, as defined in DSM-IV, is the "consistent failure to speak in specific social situations despite speaking in other situations" (2). Prevalence of the disorder ranges from 0.08% to 0.7% (50).
Symptoms and Comorbidity
Typically, the child with selective mutism has no difficulty speaking at home with family members or to a best friend but will not speak in school or in unfamiliar social situations. They may not speak in public places like stores or restaurants. Usually, there is a distinct hierarchy of people to whom the child will speak. Most often, these children are not identified until they start preschool or kindergarten (50).
Studies of children with selective mutism reveal that these children have excessive social anxiety and behavioral inhibition and often meet DSM-III-R criteria for social phobia and avoidant disorder (18). They also have an increased incidence of comorbid elimination problems, obsessive-compulsive traits, depression, and school phobia; however, they only rarely have oppositional defiant behavior or aggression (29). Speech and language disorders may be more common among selectively mute children, but this has not been systematically assessed (29). Additionally, these children tend to have high familial rates of social phobia, avoidant disorder, and selective mutism (18). Although most cases of selective mutism resolve with age, the social anxiety and shyness may persist (50).
Psychotherapy and Psychopharmacology
Treatment for selective mutism includes behavioral therapies, psychosocial interventions, and more recently pharmacotherapy. Psychosocial interventions consist of school-based, multidisciplinary, individualized treatment plans and peer group activities (18). Several case reports have suggested the usefulness of phenelzine and fluoxetine for selective mutism; both of these antidepressants are established treatments for adult social phobia (16,34). Black and Uhde conducted the first controlled study of fluoxetine and found that the six subjects treated with fluoxetine were significantly more improved than the nine treated with placebo (17).
OBSESSIVE-COMPULSIVE DISORDER IN CHILDREN AND ADOLESCENTS
The essential feature of obsessive-compulsive disorder (OCD) is recurrent obsessions or compulsions that are time consuming or cause marked distress or impairment. Obsessions are recurrent, senseless, intrusive ideas, thoughts, impulses, or images that cause marked anxiety and distress. Compulsions are repetitive behaviors or mental acts that are done in a rigid fashion, according to certain rules, in order to prevent or to reduce anxiety (2). The diagnostic criteria for children are the same as for adults, except that children do not have to recognize the nonsensical nature of their symptoms.
Over the past decade, much has been discovered about childhood OCD. Until recently, childhood OCD was considered rare. However, epidemiologic studies have revealed that OCD in children and adolescents is not uncommon, with lifetime prevalence rates in community and clinical samples ranging from 0.2% to 1.2% (82). Moreover, over one-third of adults with OCD report onset of their symptoms during childhood (62). The underestimation of OCD may have been due, in part, to the nature of the disorder (40). Patients often recognize the irrationality of their symptoms and are reluctant to disclose them. Children in particular will attempt to hide their symptoms, at least initially, because of embarrassment and fear that they may be labeled as "crazy." They are reluctant to divulge their symptoms unless asked directly, and physicians often fail to ask. As a result, OCD often goes unrecognized and untreated.
The clinical symptoms of pediatric-onset OCD are essentially the same as those found in adult OCD. Swedo and colleagues reported the symptoms of 70 pediatric patients with OCD to be "strikingly similar" to those of adults with OCD (80). The most common obsessions were contamination fears; the most common compulsions were washing and cleaning, which occurred in over 85% of the cases at some time in their illness. Most subjects had both obsessions and compulsions; a few children had only compulsions, but obsessions in the absence of compulsions were rare. Similar findings were obtained by Last and Strauss (48) in their study of 20 children with OCD who presented to their outpatient clinic, and by Riddle et al. in their group of 21 clinically referred pediatric patients with OCD (70). Both of these latter studies found that contamination fears and washing rituals were the most common symptoms in childhood OCD, and that most children had both obsessions and compulsions.
Comorbidity is common in childhood OCD. In the NIMH cohort, only 26% of the subjects had OCD as their only psychiatric diagnosis. Comorbid depression was found in 35% of the subjects and other anxiety disorders in 40% (80). Similarly, Riddle et al. found 62% of their pediatric subjects had comorbid diagnoses, with 38% having one or more other anxiety disorder diagnoses and 29% a comorbid mood disorder (70). Additionally, Valleni-Basile et al. found high rates of comorbidity, particularly comorbid depression and other anxiety disorders, in their community sample of adolescents with OCD (82). These findings are consistent with the literature on adult OCD, where high rates of comorbidity, most frequently depression and other anxiety disorders, have been well documented (69).
Both Leonard et al. (51) and Riddle et al. (70) found a relatively high lifetime prevalence of tic disorders (57% and 24%, respectively), even though Tourette's syndrome (TS) was an exclusionary criteria for both of these studies. The association between OCD and TS is well documented, and there is extensive literature on the relationship between these two disorders (54,68).
Neurobiology and Etiology
Over the past decade, there has been an explosion of biological data implicating neurophysiological, neuroanatomical, neuroimmunological, and genetic factors in the etiology of childhood OCD.
The "serotonin hypothesis" was initially based on the efficacy of L-tryptophan therapy and the efficacy of controlled trials of serotonin reuptake inhibitors (SRIs) for adult OCD (22,35,39). Further, under double-blind, placebo-controlled conditions, patients with OCD were found to experience an acute exacerbation of their OC symptoms when challenged with meta-chlorophenylpiperazine (mCPP), a serotonergic agonist (88). After four months of treatment with clomipramine (a serotonin reuptake blocker), patients no longer experienced a worsening of their OCD symptoms when rechallenged with mCPP (87). These findings led Zohar and colleagues to conclude that there is an increased serotonergic responsiveness in OCD. The many controlled drug trials demonstrating the effectiveness of SRIs (e.g., clomipramine and fluvoxamine) in the treatment of adult OCD are the most persuasive evidence for the role of serotonergic dysregulation in OCD (35,39).
More recently, there has been speculation of dopamine dysregulation in OCD. This is based on the well known association between TS and OCD, the worsening of OC symptoms after the administration of stimulants (dextroamphetamine), and the use of dopamine-blocking agents (e.g., haloperidol) as successful augmenting agents in the treatment of OCD (19,36,64). The contradictory nature of the serotonin-dopamine findings suggests that the primary dysfunction may be "upstream" in a pathway that is as yet unidentified.
OCD has been reported to occur in association with numerous basal ganglia disorders, including Sydenham's chorea, post-encephalitic Parkinson's disease, Huntington's chorea, and Tourette's syndrome (25,68,75,84). Swedo (75) has proposed that Sydenham's chorea (an autoimmune inflammation of the basal ganglia triggered by group A b-hemolytic streptococcal infection) may be seen as a medical model for OCD on the basis of the frequency of OC symptoms reported by pediatric patients with Sydenham's chorea, as compared with nonchoreic rheumatic fever patients. Also implicating the basal ganglia and frontal lobes in the etiology of OCD are the 23 case reports to date of adults and an adolescent who developed OCD after traumatic brain damage to the frontal and temporal lobes and/or basal ganglia (10,28,63,65).
Neuroimaging studies implicate abnormalities in the orbitofrontal cortex, the anterior cingulate region, and the basal ganglia (the cortico-striatal-thalamo-cortical circuit). On computed tomography (CT), adults with OCD were found to have smaller caudate volumes and, with positron emission tomography (PET), significantly elevated metabolic rates in the heads of the caudate nuclei, cerebral hemispheres, and the orbital gyri (5,58). Others have found hypermetabolism in the orbital frontal region and alterations in the left anterior cingulate, compared with healthy controls. Also, a significant correlation between brain glucose metabolism and clinical measures of OCD severity has been seen (81). After one year of pharmacotherapy, repeat PET scans revealed normalization (decrease) of the orbitofrontal regional cerebral metabolism, which correlated with several measures of OCD improvement (79). In another study, it was found that glucose metabolic rate decreased in the head of the right caudate nucleus after successful treatment with either fluoxetine or behavioral therapy(6).
Family studies suggest that genetic factors play an important role in OCD. Several studies have demonstrated high rates of OCD in the first-degree relatives of pediatric and adult probands with OCD (49,66,70). Additionally, elevated rates of OCD have been found in the first-degree relatives of TS probands, regardless of whether the TS proband had OCD (67,68). Pauls et al. have hypothesized that OCD and TS are etiologically related and, in some cases, represent alternate expressions of the same gene(s) (67).
Post-streptococcal autoimmunity has been postulated as another etiologic factor for childhood-onset OCD. Recent investigations have identified a subgroup of children with OCD who appear to have symptom onset or exacerbations triggered by Group A b-hemolytic streptococcal (GABHS) infections via an autoimmune process (1). In a manner analogous to Sydenham's chorea, antibodies that arise in response to GABHS infection cross-react with neurons in the basal ganglia, causing inflammation and dysfunction, manifested as neuropsychiatric symptoms (tics and/or OCD) . Additionally, it was recently demonstrated that children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) have a trait marker associated with rheumatic fever, labeled D8/17 (a B-cell surface marker), suggesting similar post-streptococcal autoimmunity (77).
This subgroup of children with OCD are identified by the following: presence of OCD and/or tic disorder (DSM-III-R or DSM-IV); pediatric onset; episodic course of symptom severity; and association with GABHS infection (positive throat culture or elevated anti-GABHS antibody titers); and an association with neurological abnormalities (motor hyperactivity and adventitious movements, such as tics or choreiform movements) . In this subgroup of pediatric patients, there appears to be a close relationship between elevated anti-streptococcal antibody titers and/or antineuronal antibody titers and symptom exacerbations, and between seronegativity and symptom remissions (Swedo et al., unpublished data). Moreover, a recent case report demonstrated acute enlargement of the basal ganglia and severe worsening of OCD symptoms following a GABHS throat infection. After successful plasmapheresis, basal ganglia volume diminished as the OCD symptoms improved (31).
Cognitive-behavioral therapy is the psychotherapeutic treatment of choice for adults with OCD. According to March (61), there is abundant clinical and empirical evidence that CBT is an effective treatment for OCD in children and adolescents as well. CBT for OCD consists of exposure and response prevention with adjunctive anxiety management and cognitive therapy. Exposure involves exposing the child to the feared situation and is based on the principle that anxiety attenuates after sufficient duration of contact with a feared stimulus. Adequate exposure depends upon response prevention, which involves preventing rituals or avoidance behaviors until the anxiety attenuates. In pediatric patients, contact with feared situations is typically accomplished in a gradual fashion (graded exposure), with the therapist providing anxiety management strategies such as relaxation and breathing techniques. The cognitive therapy component involves thought blocking and cognitive restructuring.
Serotonin reuptake inhibitors (SRIs) have been clearly demonstrated to be effective in adults (35,39). SRIs include clomipramine hydrochloride (Anafranil¨), and the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (Prozac¨), fluvoxamine (Luvox¨), paroxetine (Paxil¨), and sertraline (Zoloft¨). Some of these have been systematically evaluated in children and adolescents with OCD and have been found effective.
The first controlled, double-blind trial that demonstrated the efficacy of clomipramine for childhood OCD was conducted by Flamant et al. and involved 19 children with OCD (30). A second, larger NIMH study involved 48 children with OCD and confirmed clomipramine's efficacy for childhood OCD by demonstrating the superiority of clomipramine over desipramine in a 10-week, double-blind crossover trial (52). A large multicenter trial confirmed the efficacy of clomipramine for childhood and adolescent OCD (27). Later, an eight-month, double-blind, desipramine substitution during long-term clomipramine treatment resulted in relapse in 89% of subjects, suggesting that long-term clomipramine treatment may be necessary (53).
Riddle et al. found fluoxetine effective for pediatric OCD in a placebo-controlled crossover trial (71). In a recent multicenter controlled trial involving 120 children and adolescents with OCD, fluvoxamine was found to be significantly more effective than placebo (Riddle et al. 1996, personal communication).
Augmentation strategies of clonazepam, neuroleptic and atypical neuroleptics have been found effective for adult and pediatric patients who have an inadequate response to the SRIs (56,64). Leonard et al. reported a case of a young man who experienced a 75% improvement of his OCD symptoms on a combination of fluoxetine and clonazepam (56). Interestingly, McDougle et al. found that patients with OCD and a comorbid chronic tic disorder may preferentially respond to a combination of haloperidol and fluvoxamine (64).
As in adults, childhood OCD tends to have a chronic waxing and waning course. The first prospective study of childhood OCD in a community-based sample of adolescents revealed that initial diagnosis of OCD predicted diagnosis of OCD at follow-up, suggesting that OCD is a chronic illness (7). In the largest systematic prospective study of childhood OCD, Leonard and colleagues found that only 6% were in complete remission, even though 70% of the children were taking psychoactive medication at the time of follow-up and the group as a whole had improved significantly (55). Children with OCD may need ongoing maintenance pharmacotherapy, CBT, or a combination of both to improve long-term outcome. Additional factors which may predict a better prognosis are a supportive family and lack of comorbid psychiatric disorders.
Much has been discovered about childhood anxiety disorders over the past decade, with increased understanding of the phenomenology and associated risk factors and the development of more effective psychotherapeutic and pharmacologic treatments. Identifying risk factors associated with childhood anxiety disorders, such as behavioral inhibition and genetic vulnerability, may lead to better prevention strategies.
Although there have been many exciting advances, there are still areas that need to be further investigated, including the neurobiological basis of these disorders, pharmacologic treatments, and long-term outcomes. To expand our understanding of childhood anxiety disorders, more longitudinal and controlled treatment studies need to be done.
The author thanks Dr. Susan E. Swedo for her assistance.