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Page 2 of 2 MEDICATION
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.
Drug Name
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.
Drug Name
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.
Drug Name
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.
Drug Name
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)
FOLLOW-UP
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.
Deterrence/Prevention:
* 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
* Psychoeducation
Complications:
* 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:
* 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.
Patient Education:
* 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.
MISCELLANEOUS
Medical/Legal Pitfalls:
* Failure to diagnose and, thus, failure to treat the disorder
BIBLIOGRAPHY
* AACAP: Practice parameters for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry 1998 Oct; 37(10 Suppl): 63S-83S[Medline].
* APA: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Elk Grove, Ill: APA; 1994.
* APA: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Elk Grove, Ill: APA; 1987.
* Barrett PM, Dadds MR, Rapee RM: Family treatment of childhood anxiety: a controlled trial. J Consult Clin Psychol 1996 Apr; 64(2): 333-42[Medline].
* Barrios BA, Hartmann DB: Fears and anxieties. In: Marsh EJ, Terdal LG, eds. Behavioral Assessment of Childhood Disorders. 2nd ed. New York, NY: Guilford; 1988:196-264.
* Beidel DC: Psychophysiological assessment of anxious emotional states in children. J Abnorm Psychol 1988 Feb; 97(1): 80-2[Medline].
* Birmaher B, Brent DA, Chiappetta L, et al: Psychometric properties of the Screen for Child Anxiety Related Emotional Disorders (SCARED): a replication study. J Am Acad Child Adolesc Psychiatry 1999 Oct; 38(10): 1230-6[Medline].
* Green WH: Child and Adolescent Clinical Psychopharmacology. 3rd ed. Lippincott Williams & Wilkins; 2001.
* Kagan J: Temperamental contributions to social behavior. Am Psychol 1989; 44: 668-74.
* Kendall PC: Childhood Disorders. London, England: Psychology Press; 2000.
* Kendall PC, Chu BC, Pimental SS: Treating anxiety disorders in youth. In: Kendall PC, ed. Child & Adolescent Therapy: Cognitive-Behavioral Procedures. 2nd ed. New York, NY: Guilford; 2000:235-287.
* Last CG, Hansen C, Franco N: Cognitive-behavioral treatment of school phobia. J Am Acad Child Adolesc Psychiatry 1998 Apr; 37(4): 404-11[Medline].
* Last CG, Perrin S, Hersen M, Kazdin AE: A prospective study of childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry 1996 Nov; 35(11): 1502-10[Medline].
* Manassis K: Keys to Parenting Your Anxious Child. Hauppage, NY: Barron's Educational Series; 1996.
* March JS, Parker JD, Sullivan K, et al: The Multidimensional Anxiety Scale for Children (MASC): factor structure, reliability, and validity. J Am Acad Child Adolesc Psychiatry 1997 Apr; 36(4): 554-65[Medline].
* Pohl RB, Feltner DE, Fieve RR, Pande AC: Efficacy of pregabalin in the treatment of generalized anxiety disorder: double-blind, placebo-controlled comparison of BID versus TID dosing. J Clin Psychopharmacol 2005 Apr; 25(2): 151-8[Medline].
* Reynolds CR, Richmond BO: What I think and feel: a revised measure of children's manifest anxiety. J Abnorm Child Psychol 1978 Jun; 6(2): 271-80[Medline].
* Shaffer D, Fisher P, Dulcan MK, et al: The NIMH Diagnostic Interview Schedule for Children Version 2.3 (DISC- 2.3): description, acceptability, prevalence rates, and performance in the MECA Study. Methods for the Epidemiology of Child and Adolescent Mental Disorders Study. J Am Acad Child Adolesc Psychiatry 1996 Jul; 35(7): 865-77[Medline].
* Silverman WK, Albano AM: The Anxiety Disorders Interview Schedule for Children (DSM-IV). San Antonio, Tex: The Psychological Corporation; 1997.
* Silverman WK, Kurtines WM, Ginsburg GS, et al: Treating anxiety disorders in children with group cognitive-behaviorial therapy: a randomized clinical trial. J Consult Clin Psychol 1999 Dec; 67(6): 995-1003[Medline].
* Simon GE, Savarino J, Operskalski B, Wang PS: Suicide risk during antidepressant treatment. Am J Psychiatry 2006 Jan; 163(1): 41-7[Medline][Full Text].
* Spence S: Helping Your Anxious Child: A Step-By-Step Guide for Parents. Oakland, Calif: New Harbinger Publications; 2000.
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Research 
