Anxiety is a ubiquitous affect in childhood and adolescence. A primary task of emotional and psychological life for the child is to master the anxieties and fears that occur with the vicissitudes of normal development. Intensified states of anxiety occur with such regularity at nodal points in each child's development that a predictable pattern of key tasks emerges. Mastery of each epigenetic stages challenges resets the child's "developmental thermostat," serves to decrease anxiety, and brings the opportunity for increased competence and the unfolding of new, more highly adaptive defenses.
In addition, anxiety can serve as a signal of prolonged or intense conflict, and it can be seen to varying degrees as a symptom in all categories of child and adolescent psychopathology. Clinical manifestations of anxiety are multiple and include motoric overactivity, decreased concentration, impulsivity, dissociative phenomena, and aggressive behavior.
Intense, prolonged anxiety is a central component of a constellation of clinical features that converge to form anxiety disorders, as described by DSM-III-R. Severe symptomatic anxiety and disorders of anxiety, relatively common forms of psychopathology in the child and adolescent age group, are challenging to diagnose and even more challenging to treat.
In child and adolescent psychiatric settings, treatment intervention is typically multimodal, and includes individual therapy or behavior treatment, parent guidance and/or family therapy, and psychopharmacology. Pharmacotherapy for child and adolescent anxiety disorders has, over the years, included antihistamines, benzodiazepines, tricyclic antidepressants, and more recently, beta blockers, serotonin reuptake inhibitors, and buspirone.1,2
Benzodiazepines, the focus of this article, have been used in clinical practice with children and adolescents since shortly after their introduction for use with adults. Until recently, there has been very little methodologically rigorous investigation of their psychiatric use in the child and adolescent population. Unfortunately, preDSM-III criteria for diagnoses were not empirically based nor were they operati onalized, so diagnostic categories were inconsistent, heterogeneous, and imprecise, making studies difficult to generalize.
BENZODIAZEPINE USE AND DIAGNOSIS
The DSM-III and DSM-III-R era brought empiric, phenomenologically oriented classification systems with multiaxial classification. This has led to a more sophisticated and precise categorization of disorders and more homogeneous diagnostic groups.3
Anxiety disorders in children and adolescents are now understood to be a diverse group of clinical entities broadly encompassing such subcategories with phenomenological differences as obsessive compulsive disorder, posttraumatic stress disorder, panic disorder, and overanxious disorder. In some cases, such as obsessive compulsive disorder, unmodified adult criteria can be used to diagnose the condition in children and adolescents.
Greater diagnostic precision has paralleled developments in the understanding of epidemiology, natural history, genetic risks, pathophysiology, and treatment options. As with mood disorders, continuity or lack of continuity with adult disorders must be investigated. Early biological markers, such as behavioral inhibition, may identify children at risk. Longitudinal studies of these children and studies of children of parents with panicdisorder with or without agoraphobia, for example, can contribute a body of data on the developmental psychopathology of anxiety disorders. Better understanding of the developmental psychopathology of anxiety disorders will ultimately improve treatment options.
In adults, established indications for benzodiazepines include generalized anxiety disorder, panic disorder, and alcohol withdrawal. Established indications in childhood and adolescence include seizures, night terrors, somnambulism, sleep induction, and muscle relaxation.
Probable indications for children and adolescents include overanxious disorder, avoidant disorder, separation anxietydisorder, and panic disorder. Posttraumatic stress disorder and simple phobias may potentially respond to benzodiazepines. In addition, severe anticipatory anxiety such as return to school following absence may be ameliorated by benzodiazepine use. Hospitalized children and adolescents undergoing noxious procedures may be candidates for short-term benzodiazepine use. Children with severe, unremitting anxiety that has not responded to other pharmacologic agents or nonpharmacologic agents are candidates. Finally, children with severe agitation and activation on inpatient settings with or without psychotic symptoms may be candidates.4
Unfortunately, systematic data regarding efficacy for specific disorders and target symptoms, and risks such as abuse, dependence, and cognitive dysfunction are not available in this population. The decision to use benzodiazepines in children and adolescents should be made carefully, weighing potential risks against likely benefits. Pharmacotherapy should only be used in conjunction with other forms of treatment including individual, behavioral, and/or family therapy. In general, benzodiazepine use in children and adolescents should be considered when nonpharmacologie treatment has failed, when response to other medications has been limited, and/or when anxiety or sleep symptoms are so disruptive as to interfere with adaptive functioning at school or home. Medication trials should be shortterm, not lasting more than several months. The benzodiazepine should be tapered slowly when it is discontinued, so as to avoid withdrawal or discontinuation symptoms.
MECHANISM OF ACTION
Benzodiazepines enhance and facilitate the transmission of gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the brain. This occurs through binding at benzodiazepine/ GABA receptor membrane, complexes involving chloride channels. These complexes are found primarily in the neocortex and limbic systems. Benzodiazepines may also decrease serotonin turnover, decrease noradrenergic activity in the locus coeruleus, and decrease dopaminergic function. The facilitation of GABAergic transmission and inhibition of CNS functions are thought to produce the anxiolytic, sedative, hypnotic, anticonvulsant, and muscle relaxant properties.4,15
Experimental data on the pharmacokinetics of benzodiazepines in children are remarkably limited, and even more limited in adolescents. The very few studies that compare the metabolic capacity of children and adults indicate an increased ability to metabolize and eliminate diazepam in children, consistent with the typical findings of faster hepatic biotransformation and renal clearance in children. There are essentially no data in adolescents, but the usual pharmacokinetic principles would suggest that adolescents probably have slower metabolism and clearance than younger children, and that adult pharmacokinetic patterns are seen by late adolescence.
Interestingly, there are more data on benzodiazepine metabolism in infants, based on maternal use during pregnancy Though maternal metabolism and the role of maternal-fetal transfer can be complicating factors, it appears that newborn and premature infants have a limited capacity for metabolism and elimination of diazepam. Compared with older children and adults, infants show longer halflives of parent compounds and lower rates of drug biotransformation, particularly in glucuronide conjugation.6
Suggested dosages are listed in the Table. However, these are only guidelines because there are little data available in the literature.
The following adverse effects are likely to be seen with use of benzodiazepines in young patients. The effects usually respond to dosage reduction or to a switch to another benzodiazepine or medication.
Sedation. Fatigue and drowsiness are common, but usually diminish over time. Dosage reduction may be necessary. Medications with longer half lives may be associated with more sedation.
Cognitive and performance decrements. Psychomotor impairments, including short-term memory, are not well studied in children, but are potentially most problematic in adolescents and children. However, decrements in cognitive performance have not been documented to date; one study showed that no impairments occurred.
Abuse. These medications are potentially abusable by adolescents with a history of substance abuse. Optimally, these patients should not be candidates for this medication.
Oral Dosage and Regimen for Treatment of Anxiety and Sleep Disorders
Dependence. Patients with a history of substance abuse or alcohol abuse are at high risk for physical and psychological dependence and should not be candidates.
Below are some less common but potentially serious effects.
Behavioral disinhibition. There are no systematic studies to date, and it is difficult to predict which children are at risk. Overexcitement, hyperactivity, aggressive outbursts, perceptual disorganization, and spells of rage can occur as manifestations of disinhibition, particularly in prepubertal children.
Discontinuation syndromes. Rebound anxiety, reoccurrence of primary anxiety, and withdrawal reactions can occur in children and adolescents, as is the case with adults. Detailed studies of this phenomenon are lacking in this population. Withdrawal reactions are more likely to occur when medication is abruptly discontinued, or with shorter acting agents. Insomnia, muscle tension, and even seizures can occur; gradual tapering is recommended to avoid this.
Teratogenicity is possible, although there arc no data to substantiate older claims of an association between diazepam and oral cleft abnormalities. Sexually active female adolescents should probably be counseled accordingly.
BENZODIAZEPINE STUDIES/SPECIFIC INDICATIONS FOR USE
Unlike in adult populations, very few studies of benzodiazepines in children have been conducted with rigorous methodology. Problems in most of the studies done to date have included lack of diagnostic homogeneity, small sample size, significant comorbidity, and lack of reliable rating scales or quantification.5 Optimal dosing in this age group, particularly with prepubertal children, has not been systematically established. Adverse effects known to occur in adults, such as dependence, withdrawal reactions, cognitive and memory dysfunction, and disinhibition, have not been systematically studied in children and adolescents. The role of pharmacodynamic and pharmacokinetic factors in this age group is likely to be complex, with only limited data available.
Early studies of chlordiazepoxide (CLDX) in two heterogeneous populations of young patients showed that medication could play a useful role in treatment. In 1962, Breitner studied the effects of CLDX 20 mg to 50 mg per day in juvenile delinquents ages 8 to 24; patients reportedly felt better and were able to engage in psychotherapy on the medication.' Nine children ages 8 to 11 with "school phobia" were treated by D'Amatos with 10 mg to 30 mg daily of CLDX over one to four weeks. Children were also receiving psychotherapy. All but one were attending school regularly by the third week of treatment. These children were compared with another group of patients receiving psychotherapy only. In the latter group, only two returned to school.8
A study of the effects of CLDX on 51 psychiatrically disturbed children and adolescents was conducted by Krakowski in 1963. 9 Diagnostic groups were heterogeneous, but symptoms for inclusion in the study were anxiety, hostility, insomnia, and impulsivity. Doses of CLDX ranged from 15 mg to 40 mg daily over periods of up to 10 months. About 239/ of patients were reported to have improved markedly and 43% improved moderately. Side effects were relatively infrequent and included fatigue, sedation, muscle weakness, and depression.
Kraft10 treated 130 children ages 7 to 17 with doses of CDLX from 30 mg to 60 mg daily. This was a diagnostically heterogeneous group; 53 patients were reported to improve.10
Kline11 studied the effects of diazepam (DZP) or placebo in a double-blind design in 50 children and adolescents ages 3 to 15 with enuresis. Doses of up to 25 mg nightly were used. At four weeks the group of 28 on DZP were significantly drier than the group on placebo; 22 were completely dry, and 22 were wet two or fewer nights per week. Of 22 on placebo, only one child was dry. When the remaining group on placebo were switched to DZP, 12 became dry11
Glick, in an open study,12 reported on three children with sleepwalking and night terrors and four with insomnia treated with diazepam (DZP) 2 mg to 5 mg at bedtime. Mechanism of action is likely related to Stage IV sleep reduction. All of the patients improved in this study
Lucas and Pasley13 studied the effects of diazepam compared with placebo on 12 patients ages 7 to 17. Diagnostic groups were heterogeneous and included "psychoneurotic" or schizophrenic patients. Target symptoms for medication included anxiety, aggressive behavior, and oppositionality. Dosages were titrated upward to a maximum of 20 mg per day; total length of the study was 16 weeks. Eleven of the 12 children who completed the initial part of the study were globally assessed. Five children were reported to show no change, and six were either slightly more anxious or worse. When scores on 10 different target symptoms were combined in the nine children who eventually completed the study, those on diazepam scored significantly higher than placebo. Side effects included drowsiness and disinhibition.13
Pettis team (1982) studied the effects of CLDX on a heterogeneous group of nine boys ages 7 to 11. Diagnostic categories included personality disorder, conduct disorder, and schizophrenia. Target symptoms of intervention included anxiety, aggressivity, depression, and lack of impulse control. Dosages ranged from 15 mg to 20 mg per day. Moderate to marked improvement was observed in six subjects and no change or deterioration in three. The child with schizophrenia worsened and the children who were more anxious, withdrawn, inhibited, or depressed had the most improvement.14
Unfortunately, all of these studies suffer from methodological difficulty including small sample size, heterogeneous diagnostic groups and ages, lack of systematic standardized ratings of symptoms, lack of controls, lack of systematic ratings of side effects, inadequate followup of symptoms, and lack of prospective and blinded placebo-controlled design.
In recent years, alprazolam (ALPZ) has been studied in childhood and adolescence. A 10-year-old with severe pavor nocturnus (night terrors) was treated by Cameron and Thyer15 with ALPZ up to 0.75 mg nightly. Her symptoms reportedly diminished immediately and had not recurred on follow-up at nine months.
Biederman10 described three children (ages 8-11) with anxiety disorders and possible panic attacks who were treated with clonazepam. Dosages ranged from 0.5 mg to 3 mg daily. AU children were reported to improve and side effects were minimal.
Pfefferbaum and co-workers17 gave ALPZ to 13 school-aged patients with cancer who had anxiety reactions to stressful and noxious procedures, such as bone marrow aspirations. Dosages ranged from 0.375 mg to 3 mg daily. Improvement was noted on three rating scales.17
Simeon and associates18 conducted an open trial of ALPZ in 12 children and adolescents ages 8 to 16 with overanxious and avoidant disorders, following a placebo washout. ALPZ was titrated upward over two weeks and the study lasted an additional four weeks. Dosages ranged from 0.5 mg to 1.5 mg daily. Seven of the subjects showed at least some improvement and no subject's condition deteriorated. Side effects were minimal; cognitive effects as measured by paired associate learning showed improvement.
A second study19 by the same team of 30 patients ages 8 to 16 with overanxious (/2=21) and avoidant disorders (n=9) used a double-blind placebo-controlled design. Mean daily dose of ALPZ was 1.57 mg. Clinical global impression showed a trend in favor of medication, but this was not statistically significant. The medication was well tolerated with no clinically significant side effects. There was no deterioration in cognitive function.
Kutcher and MacKenzie20 gave clonazepam to adolescents ages 16 to 19 with panic disorder. Dosages were 1 mg to 2 mg daily and panic attack frequency and ratings on the Hamilton Anxiety Rating Scale fell during treatment. Side effects were infrequent. No cognitive deterioration or disinhibition was noted.
In summary, although a variety of studies have been conducted since the 1960s, it is difficult to draw conclusions because of various methodological difficulties including small sample size, diagnostic heterogeneity, and lack of controls. More recent studies show promise and point toward the need for further investigation of these medications.
There are a variety of nonpharmacologic and pharmacologic treatment alternatives for patients who are refractory to or cannot tolerate treatment with benzodiazepines for psychiatric indications. Nonpharmacologic treatment alternatives include behavior therapy, individual psychotherapy, and family therapy. Other medications with anxiolytic properties such as tricyclic antidepressants, serotonin reuptake inhibitors, beta blockers, and buspirone are available as well.
Standard nonpharmacologic alternatives for treatment should be considered, although these options are not the focus of this article. (For a good review see Gittelman R, Anxiety Disorders of Childhood, New York, NY: Guilford Press; 1985, and Bernstein G, Borehardt C, Anxiety disorders of childhood and adolescence: a critical review, J Am Acad Child Adolesc Psychiatry, 1991; 30:519-530.)
Behavior therapy can be useful in separation anxiety disorder, simple phobias including school refusal based on separation anxiety, panic disorder with phobic avoidance, and obsessive compulsive disorder, individual therapy and family therapy can be helpful in overanxious and avoidant disorder, posttraumatic stress disorder, separation anxiety disorder, and obsessive compulsive disorder. Family therapy and/or parent guidance can have a role in all childhood and adolescent anxiety disorders.
Children with separation anxiety disorder can be treated with Imipramine or desipramine, although cardiovascular risk issues must be taken into account, given several recent reports of sudden death in prepubertal children receiving tricyclic antidepressants.21 Adolescents or younger children can also be treated with tricyclic antidepressants for panic disorder or posttraumatic stress disorder. Young patients with avoidant disorder and/or overanxious disorder might be offered buspirone as a pharmacologic alternative, since it seems to have a favorable side effect profile. Posttraumatic stress disorder in children has been treated with propranolol in one study; while the role of benzodiazepines has not been systematically assessed, beta blockers may be useful in this disorder.22
Anxiety disorders that occur comorbidly in association with attention deficit hyperactivity disorder might be treated with Clonidine or bupropion.23-24
Obsessive compulsive disorder in childhood and adolescence should be treated with serotonin reuptake inhibitors, as with adults, such as clomipramine or fluoxetine.25,26
It appears then, that certain kinds of young patients would be candidates for benzodiazepine treatment. Sleep disorders such as night terrors and sleepwalking (which are not particularly associated with psychopathology) can be ameliorated. Severe anxiety in the psychologically healthy child associated with noxious procedures such as bone marrow aspirations can be reduced by benzodiazepine treatment, particularly when behavioral and other measures have failed. Finally, benzodiazepines may have a role in specific forms of childhood psychopathology such as overanxious disorder, avoidant disorder, and separation anxiety disorder.
In summary, anxiety disorders are among the most frequently diagnosed forms of psychopathology in childhood and adolescence. An accumulating data base regarding classification, natural history, comorbidity, genetics, pathophysiology, and treatment studies is beginning to emerge. A body of psychopharmacologic literature on the treatment of "anxiety" in childhood and adolescence has existed for nearly 30 years; however, it has only been in recent years, as phénoménologie diagnosis and empiric classification has evolved, that "anxiety" as affect has been differentiated from anxiety as syndrome or disorder. Several recent studies are beginning to suggest that benzodiazepines have a role in the treatment of carefully diagnosed anxiety disorders in childhood and adolescence, including school refusal based on separation anxiety disorder, overanxious and avoidant disorders, and panic disorders in adolescence.
Current studies hold promise, but further investigation is needed.
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Oral Dosage and Regimen for Treatment of Anxiety and Sleep Disorders