Author: Dennis A Nutter, Jr, MD, Consulting Staff, Department of Psychiatry, Northeast Georgia Medical Center
Coauthor(s): Lene Holm Larsen, PhD, Instructor, Department of Child and Adolescent Psychiatry, Children's Memorial Hospital of Chicago; Carrie Sylvester, MD, MPH, Director of Education in Child and Adolescent Psychiatry, Professor, Departments of Psychiatry and Pediatrics, Northwestern University Medical School
Dennis A Nutter, Jr, MD, is a member of the following medical societies: American Academy of Child and Adolescent Psychiatry, American Psychiatric Association, North Carolina Medical Society, and Society for Research in Child Development
Editor(s): Chet Johnson, MD, Medical Director, Child Development Unit, Professor, Department of Pediatrics, University of Kansas Medical Center; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Caroly Pataki, MD, Associate Program Director, Clinical Associate Professor, Department of Psychiatry and Biobehavioral Sciences, Division of Child and Adolescent Psychiatry, Neuropsychiatric Institute and Hospital, UCLA; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Murray M Kappelman, MD, Professor, Departments of Pediatrics and Psychiatry, University of Maryland School of Medicine
Background: Generalized anxiety disorder (GAD) was introduced in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), replacing overanxious disorder of childhood (Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition [DSM-III-R]). GAD is associated with persistent, excessive, and unrealistic worry that is not focused on a specific object or situation.
Children with GAD worry more often and more intensely than other children in the same circumstances. They may worry excessively about their performance and competence at school or in sporting events, about personal safety and the safety of family members, or about natural disasters and future events.
The focus of worry may shift, but the inability to control the worry persists. Because children with GAD have a hard time “turning off” the worrying, their ability to concentrate, process information, and engage successfully in various activities may be impaired. In addition, problems with insecurity that often result in frequent seeking of reassurance may interfere with their personal growth and social relationships. Further, children with GAD often seem overly conforming, perfectionistic, and self-critical. They may insist on redoing even fairly insignificant tasks several times to get them “just right.” This excessive structuring of one's life is used as a defense against the generalized anxiety related to the concern about the individual's overall and specific performance.
Pathophysiology: Little empiric data are available regarding the physiologic indicators of anxiety in children (Barrios, 1988; Beidel, 1988). The high cost, lack of normative data, idiosyncratic patterns, and high sensitivity of cardiovascular and electrodermal measures in children contribute to the difficulties in physiologic assessment of anxiety in children (Kendall, 2000).
* In the US: Prevalence for children and adolescents ranges from 2.9-4.6%. GAD is more common in adolescents (aged 12-19 y) than in children (aged 5-11 y).
* Internationally: Worldwide prevalence of GAD is unknown.
* Deaths related to GAD in childhood and adolescence are related more to comorbid conditions such as depression than to GAD. Children and adolescents with both depression and an anxiety disorder tend to have more severe forms of depression; therefore, GAD should be viewed as a risk factor for morbidity and mortality.
* Anxiety disorders have a high rate of comorbidity. Children with GAD are also likely to meet criteria for other anxiety disorders and, to a lesser degree, for a depressive or disruptive behavior disorder.
* Anxiety disorders tend to be unstable over time. That is, a child may struggle with anxiety for a long period, but it may not necessarily be a result of the same specific anxiety disorder.
* Anxiety is a serious problem in children and adolescents. We now understand that, in addition to deleteriously affecting the child's social and academic functioning (Pine, 1997), anxiety can cause serious long-term consequences. Many children with one of the anxiety disorders suffer intermittently for the rest of their lives. Other serious psychiatric conditions, such as major depressive disorder and substance misuse; these are closely associated with pediatric anxiety if not treated in a timely and effective manner.
* GAD also may co-occur with conditions associated with stress, such as irritable bowel syndrome and headaches. The long-term physiologic effects of stress are more likely to cause nonpsychiatric gastrointestinal, cardiovascular, or other sequelae later in life.
Race: Specific racial or cultural group prevalence rates are not available.
Sex: In childhood, the sex distribution tends to be equal for females and males. In adolescence, a female-to-male ratio of 6:1 has been suggested; however, epidemiologic study results vary.
Age: The age of onset varies. GAD is more common in adolescents and older children than in young children. In addition, affected adolescents and older children tend to have more symptoms than affected younger children.
History: An evaluation for GAD should include data gathering through diagnostic interviews with the child and parent, direct observation, and questionnaires. Family history of anxiety and mood disorders, the child's early temperament and adjustment to school, and life stressors or disruptions are among important factors to consider in GAD.
* Structured interviews yielding DSM-IV diagnoses, such as the Diagnostic Interview Schedule for Children (DISC) and the Anxiety Disorders Interview Schedule for DSM-IV Child and Parent Versions (ADIS-C/P), can be employed.
* Questionnaires such as the Revised Children's Manifest Anxiety Scale (RCMAS), the Multidimensional Anxiety Scale for Children (MASC), and the Screen for Child Anxiety Related Emotional Disorders (SCARED) child and parent versions can be used to further assess anxiety symptoms.
* The DSM-IV requires the following to satisfy a diagnosis of GAD:
o Excessive anxiety and worry, occurring more days than not for at least 6 months, about a number of events or activities
o Difficulty controlling the worry
o One of the following symptoms in association with the worry: restlessness, fatigue, poor concentration, irritability, muscle tension, or sleep disturbance
o Focus of worry that is not confined to features of another Axis I diagnosis, eg, worry about having a panic attack, social embarrassment, or separation from caregiver
o Clinically significant distress or impairment experienced in social, school, or other important areas
o Disturbance not due to a substance or general medical condition and does not occur exclusively during a mood disorder, a psychotic disorder, or associated with a pervasive developmental disorder
Physical: Children with GAD may experience somatic symptoms such as shortness of breath, rapid heart beat, sweating, nausea or diarrhea, frequent urination, cold and clammy hands, dry mouth, trouble swallowing, or a “lump in the throat.” Problems with muscle tension also can occur, including trembling, twitching, a shaky feeling, and muscle soreness or aches. Patients often complain of stomachaches and headaches. Despite these symptoms, few findings are noted on physical examination.
Excessive laboratory exclusion of somatic complaints is to be avoided; however, careful interview and physical examination assessment of stress-related symptoms should be repeated if the psychological diagnostic picture is unclear.
Causes: Multiple factors are thought to contribute to the development of GAD and to the broad category of anxiety disorders. Biological, familial, and environmental factors are considered important. Behavioral inhibition (Kagan, 1989), an early temperament associated with aversion to novel situations, has been found to be associated with later development of anxiety disorders.
Research has demonstrated an association between parents with anxiety disorders and children with behavioral inhibition. The tendency of anxiety to occur in families also has been established. Anxious parents may genetically predispose their children to anxiety, model anxious behavior, and behave and/or parent in ways that encourage and maintain anxious behavior in the child. Environmental factors, such as other parental emotional problems, disrupted attachment, stressful life events, and traumatic experiences, also may place the child at risk for developing GAD. The role of the family in understanding child anxiety is important, particularly in situations in which the needs of younger children who are developmentally limited in their ability to benefit from direct individual intervention are considered.
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography
Anxiety Disorder: Obsessive-Compulsive Disorder
Anxiety Disorder: Panic Disorder
Anxiety Disorder: Separation Anxiety and School Refusal
Anxiety Disorder: Social Phobia and Selective Mutism
Anxiety Disorder: Specific Phobia
Anxiety Disorder: Trichotillomania
Attention Deficit Hyperactivity Disorder
Child Abuse & Neglect: Posttraumatic Stress Disorder
Eating Disorder: Anorexia
Mood Disorder: Bipolar Disorder
Mood Disorder: Depression
Mood Disorder: Dysthymic Disorder
Obstructive Sleep Apnea Syndrome
Oppositional Defiant Disorder
Peptic Ulcer Disease
Personality Disorder: Avoidant Personality
Somatoform Disorder: Hypochondriasis
Somatoform Disorder: Somatization
Other Problems to be Considered:
Substance-induced anxiety disorder, anxiety disorder due to a general medical condition, an adjustment disorder, or psychotic disorder also should be considered.
Distinguishing anxiety from developmentally appropriate fears is important. Throughout childhood and early adolescence, children experience various transitory fears occurring concurrently with their ability to recognize and understand potential dangers in their environment. A progression occurs from immediate, tangible fears (eg, separation from caregiver, strangers) to anticipatory, less tangible fears (eg, bad dreams, getting hurt, school failure). Children are expected to overcome and resolve these fears as part of the developmental process.
Distinguishing anxiety from realistic worry is also imperative. Worry can be thought of as feeling uneasy or concerned about something. It represents an internal representation of a realistic threat. For example, a child with a learning disability may worry about an upcoming examination, or a child with a medical condition may worry about an upcoming surgery. This kind of worry is expected to be specific to a situation, and it is expected to subside once the situation has passed; thus, the temporal requirement for GAD diagnosis (6 mo) is not met.
* Consider urine drug screening, thyroid-stimulating hormone level assessment, and less common laboratory tests based on history and physical findings.
Medical Care: Behavioral and cognitive-behavioral therapies are among the most researched and promising treatments for childhood anxieties. Behavioral techniques (eg, relaxation training, modeling, imagining and visualizing, in vivo exposure) and cognitive techniques (eg, identifying and modifying self-talk, challenging irrational beliefs) often are used in combination with psychoeducation and contingency maintenance. Typically, children are taught to recognize early physiologic and cognitive signs of anxiety and to develop and implement coping techniques. The importance of parental participation in the treatment process recently has received attention. Adding a family component focused on techniques such as contingency management, communication, and problem solving to individual child cognitive-behavioral therapy has produced favorable long-term treatment benefits in several clinical trials (eg, Barrett, 1996; Last, 1998; Silverman, 1999).
For a more detailed review of current integrated cognitive-behavioral therapies for children with anxiety disorders, see Kendall et al (2000). Practically speaking, less successful real-world treatments are frequently encountered because of a dearth of qualified child therapists and a failure to recognize the importance of directly or indirectly (family component) treating parental anxiety. Several cognitive-behavioral therapy books, such as Helping Your Anxious Child: A Step-By-Step Guide for Parents by Sue Spence and Keys to Parenting Your Anxious Child (Barron's Parenting Keys) by Katharina Manassis, MD, are readily available for parents and their children to work with at home and at school.
Surgical Care: Children with an anxiety disorder are particularly likely to benefit from age-appropriate preoperative preparation including relaxation practice for elective procedures.
Consultations: Early referral to a psychologist, psychiatrist, or behavioral-developmental pediatrician for evaluation and treatment can alleviate symptoms and stress that may be the early manifestations of a more severe disorder. Family therapy referral also may be indicated, but that may be best managed by the mental health professional or the developmental and behavioral pediatrician who performs the consultative evaluation.
Diet: Limiting caffeine intake is appropriate.
Activity: Regular exercise promotes a sense of well-being that is particularly beneficial in individuals with anxiety and mood disorders.
Medication is ideally adjunctive to psychological treatment of GAD. Unfortunately, lack of experienced and qualified therapists may preclude an adequate trial of cognitive-behavioral therapy. Selective serotonin reuptake inhibitor (SSRI) antidepressants are currently first-line medications in the pharmacotherapy of anxiety disorders in children. These antidepressants are powerful anxiolytics with a broader spectrum that may improve comorbid affective disorders and symptoms of anxiety.
Benzodiazepines have a relatively favorable adverse effect profile but are generally not chosen as first-line treatments for anxiety in children and adolescents. These agents may cause behavioral disinhibition in young children. They also have street value as drugs of abuse. Buspirone (BuSpar) is an anxiolytic agent whose efficacy in the treatment of anxiety disorders in children and adolescents has not yet been demonstrated. BuSpar is slow to work in adults but does not cause habituation or disinhibition. Antihistamines and antipsychotics are not recommended for treatment of childhood-onset anxiety disorders.
Drug Category: Selective serotonin reuptake inhibitors -- Antidepressant agents chemically unrelated to the tricyclic, tetracyclic, or other available antidepressants. Inhibit neuronal reuptake of serotonin, thus potentiating serotonergic activity in the brain, with the regulation of hypervigilance and other aspects of anxiety. These changes also may have a weak effect on norepinephrine and dopamine neuronal reuptake. Fluoxetine is presented as the example. Several SSRIs are now available.
SSRIs are greatly preferred over the other classes of antidepressants. Because the adverse effect profile of SSRIs is less prominent, improved compliance is promoted. SSRIs do not have the cardiac arrhythmia risk associated with tricyclic antidepressants. Arrhythmia risk is especially pertinent in overdose, and suicide risk must always be considered when treating a child or adolescent with mood disorder.
Physicians are advised to be aware of the following information and use appropriate caution when considering treatment with SSRIs in the pediatric population.
In December 2003, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory that most SSRIs are not suitable for use by persons younger than 18 years for treatment of “depressive illness.” After review, this agency decided that the risks to pediatric patients outweigh the benefits of treatment with SSRIs, except fluoxetine (Prozac), which appears to have a positive risk-benefit ratio in the treatment of depressive illness in patients younger than 18 years.
In October 2003, the US Food and Drug Administration (FDA) issued a public health advisory regarding reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder. This advisory reported suicidality (both ideation and attempts) in clinical trials of various antidepressant drugs in pediatric patients. The FDA has asked that additional studies be performed because suicidality occurred in both treated and untreated patients with major depression and thus could not be definitively linked to drug treatment.
However, a recent study of more than 65,000 children and adults treated for depression between 1992 and 2002 by the Group Health Cooperative in Seattle found that suicide risk declines, not rises, with the use of antidepressants. This is the largest study to date to address this issue.
Currently, evidence does not exist to associate obsessive-compulsive disorder (OCD) and other anxiety disorders treated with SSRIs with an increased risk of suicide.
Fluoxetine (Prozac) -- Longest history of use in children and adolescents. Now available in generic preparations. Long half-life is both an advantage and a drawback. If it works well, an occasional missed dose is not a problem; if problems occur, eliminating all active metabolites takes a long time. Adverse effects of SSRIs seem to be quite idiosyncratic; thus, relatively few reasons exist to prefer one to another at this point if dosing is started at a conservative level and advanced as tolerated.
Adult Dose 5 mg/d PO initially; may advance by 5-mg increments q3-5d to 20 mg/d
Then, advance in this manner again after about 6 wk; for GAD, higher doses commonly used for other anxiety disorders or depressive disorders usually are not required
Pediatric Dose <18 years: Not approved
2 mg/d in young children or extremely anxious adolescents initially; may benefit from doses of 5-10 mg/d; rate of dosage advance should be more conservative than in adults
Contraindications Documented hypersensitivity; MAOIs concurrently or within last 2 wk
Interactions Increases toxicity of diazepam and trazodone by decreasing clearance; interacts with many drugs because of inhibition of CYP450, CYP2C9, CYP2C19, CYP2D6, and CYP3A4; also increases toxicity of MAOIs and highly protein-bound drugs; serotonin syndrome (ie, myoclonus, rigidity, confusion, nausea, hyperthermia, autonomic instability, coma, eventual death) occurs with simultaneous use of other serotonergic agents (eg, anorectic agents, tramadol, buspirone, trazodone, clomipramine, nefazodone, tryptophan); discontinue other serotonergic agents at least 2 wk before beginning SSRIs
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions May cause agitation in children and adolescents; may cause bipolar switch in vulnerable individuals (as with all antidepressants); use with caution in individuals with compromised hepatic function or history of seizures; can cause movement problems, GI upset, weight change, and insomnia; anxious adults experience increased sensitivity to mild adverse effects
Caution with comorbid eating disorder, although is useful adjunct to treatment of eating disorders
Drug Category: Benzodiazepines -- Depress all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Also increase the frequency of chlorine channel opening in response to GABA binding. GABA receptors are chlorine channels that mediate postsynaptic inhibition, resulting in postsynaptic neuron hyperpolarization. The final result is a sedative-hypnotic and anxiolytic effect.
Benzodiazepines have been used in children for a variety of indications, including the reduction of anticipatory or acute situational anxiety. Note the importance of using caution, and use only in conjunction with psychotherapy aimed at reducing the length of time on benzodiazepines.
Many pediatricians are most familiar with diazepam (Valium), and no particular reason exists to prefer another benzodiazepine in children because diazepam is available as a generic preparation and has a smooth longer action that may be advantageous. Lorazepam (Ativan) has the advantage of being quite short acting in the event of disinhibition, but it is not as useful for treatment of GAD because of the frequent dosing. Clonazepam (Klonopin) has been studied in severe anxiety disorders but has been anecdotally (incorrectly) noted to have some increased risk of behavioral disinhibition. Alprazolam (Xanax) has been most studied in anxiety disorders in children.
Diazepam (Valium) -- Individualize dosage, and increase cautiously to avoid adverse effects. Necessary to use for shortest time possible when abrupt discontinuation is not a risk. Further, should not be continued if patient discontinues psychotherapy.
Adult Dose 2-10 mg PO q3-4h, repeat q2-4h prn; not to exceed 30 mg in 8 h
Pediatric Dose Infants and young children: 0.1-0.3 mg/kg/d PO
Older children and adolescents: 1-2.5 mg PO tid/qid
Contraindications Documented hypersensitivity; narrow-angle glaucoma; pregnancy; avoid in individuals at risk of becoming pregnant
Interactions Phenothiazines, barbiturates, alcohol, and MAOIs increase CNS toxicity when administered concurrently
Pregnancy D - Unsafe in pregnancy
Precautions Caution with other CNS depressants, low albumin levels, or hepatic disease (may increase toxicity)
Drug Category: Azaspirodecanediones -- Buspirone is the anxiolytic in this category. It has high affinity for serotonin receptors, has a moderate affinity for dopamine receptors, and does not have cross-tolerance with benzodiazepines. No reports of dependence exist. One drawback is that it takes 1-4 weeks to become effective.
Buspirone hydrochloride (BuSpar) -- 5-HT1 agonist with serotonergic neurotransmission and some dopaminergic effects in CNS. Has anxiolytic effect but may take up to 2-3 wk for full efficacy. Relative disadvantage is lack of official approval for use in individuals <18 y.
Adult Dose 15 mg/d PO divided tid initially; may increase by 5 mg/d q2-4d; not to exceed 60 mg/d
Pediatric Dose <18 years: Not approved; not established; suggested dose based on limited data
Children: 2.5 mg/d PO; may increase by 2.5 mg q3-4d, adding doses to achieve tid dosing with a total daily dose of 20 mg/d
Adolescents: Titrate as for children with eventual adult dose
Note that younger individuals and developmentally delayed individuals may respond to lower doses than adults, thus conservative advancing is prudent
Contraindications Documented hypersensitivity; MAOIs concurrently or within last 2 wk
Interactions Toxicity is increased with MAOIs, phenothiazines, and CNS depressants; increases toxicity of digoxin and haloperidol
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Caution in hepatic or renal impairment
Drug Category: Anticonvulsants -- Pregabalin (Lyrica; Pfizer, Inc, New York, NY) has been approved for use in adults by the European Commission (EC) and the US Food and Drug Administration (FDA) for the management of diabetic peripheral neuropathy, postherpetic neuralgia, and adjunctive treatment of partial-onset seizures. On March 27, 2006, the EC approved a new indication for pregabalin, allowing its use in adults for the treatment of GAD in the European Union.
Pregabalin (Lyrica) -- Not FDA approved for treating adult or pediatric GAD in the United States. EC approval was based on a review of data from 5 randomized, double-blind clinical trials in more than 2000 patients, which showed that pregabalin provided rapid and sustained efficacy in treating GAD, yielding significant relief from psychic and somatic symptoms within the first week of treatment.
Most adverse events were mild to moderate in intensity and generally dose-related. Dizziness and drowsiness were most frequently reported.
Structural derivative of GABA. Mechanism of action is unknown. Binds with high affinity to alpha2-delta site (a calcium channel subunit). In vitro, reduces calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. FDA approved for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures.
Adult Dose 50-100 mg PO bid
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions May cause additive effects on cognitive and gross motor functioning when coadministered with drugs that cause dizziness or somnolence
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Discontinue gradually (over a minimum of 1 wk) to minimize increased seizure frequency in patients with seizure disorders; may cause insomnia, nausea, headache, or diarrhea upon abrupt withdrawal; common adverse effects include dizziness, somnolence, blurred vision, weight gain, and peripheral edema; may elevate creatinine kinase level, decrease platelet count, and increase PR interval; doses >300 mg/d associated with higher rate of adverse effects and treatment discontinuation; decrease dose with renal impairment (ie, CrCl <60 mL/min)
Further Outpatient Care:
* Weekly outpatient therapy for 3-4 months with less frequent follow-up booster sessions may be sufficient.
* A cognitive-behavioral approach is likely to be most beneficial. Treatment should consist of individual sessions with family involvement to support the treatment process. Cognitive therapy features may be incorporated into an eclectic approach by highly skilled and experienced therapists.
* Psychodynamic therapies, including play therapy, are time-honored modalities, but most outcomes research has focused on the brief or intermediate therapies, which are more structured.
In/Out Patient Meds:
* For patients for whom medication is prescribed, regular appointments with a child and adolescent psychiatrist or developmental-behavioral pediatrician are necessary for the duration of treatment. Parents and patients must be warned of the possible risks of activation and disinhibition and what to do in such circumstances.
* Consistent, stable, supportive home environment
* Parenting practices that promote self-confidence, self-esteem, and effective coping skills
* Minimal number of psychosocial stressors or traumatic events
* Adaptive problem solving and coping skills modeled by parents and other significant people in the child's life
* Comorbid depression and other comorbid conditions
* School truancy and withdrawal from other age-appropriate activities
* Strained family relationships when the child's anxiety contributes to irritability, noncompliance, demanding behavior, and/or chronic reassurance seeking
* “Self-medication” leading to substance abuse by adolescents
* Parents' inability to help in the child's treatment or to model adaptive coping/anxiety management because of their own untreated anxiety (or other psychiatric condition)
* Prognosis is thought to be relatively good when treatment is implemented early and effectively. However, the child remains at risk of developing GAD or other anxiety disorders. For example, Last and colleagues in 1996 reported an 80% recovery rate from overanxious disorder during a 3- to 4-year follow-up period. However, 35% of the children developed a new psychiatric disorder in the same interval.
* Psychoeducation should be part of the treatment process. Patients and parents should have a good understanding of the contributing and maintaining factors of anxiety. Also, they should be clear regarding treatment goals, processes, and expectations.
* Failure to diagnose and, thus, failure to treat the disorder
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