Pharmacologic treatment approaches for children and adolescents with posttraumatic stress disorder

Child Adolesc Psychiatric Clin N Am 12 (2003) 251 – 269

Pharmacologic treatment approaches for children and adolescents with posttraumatic stress disorder Craig L. Donnelly, MD Section of Child and Adolescent Psychiatry, Department of Psychiatry, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, USA

Exposure to extreme stress can exert profound and lasting changes on human cognition, emotion, and behavior. Historically, children’s responses to stress and trauma have been less well characterized and studied than have reactions in adults. It was not until the 1970s that researchers began systematically to examine trauma in childhood, and not until the late 1980s did the first sporadic reports of medication use in traumatized children begin to emerge. Systematic evaluation of traumatized children began to reveal that many of them had developed the syndrome of posttraumatic stress disorder (PTSD). PTSD is a syndrome in the family of anxiety disorders characterized by exposure to a serious or life-threatening trauma. After traumatic exposure, individuals with PTSD develop symptoms of reexperiencing the trauma, and they avoid stimuli associated with the trauma and display symptoms of increased arousal. These symptoms must be present for at least 1 month and be significantly distressing or debilitating in important areas of functioning. Surprisingly, to date no double-blind, randomized, placebo-controlled trials of medication treatments of PTSD in childhood have been conducted. Despite the early stages and limited scope of the scientific treatment literature for PTSD in childhood, there are indications that medication treatment has a role to play in the disorder in this age group. This article reviews pharmacologic treatment of PTSD in childhood and adolescence. An overview of the complexity of PTSD symptoms, psychiatric comorbidity, and the neurobiologic systems believed to mediate clinical expression of the disorder are presented as they pertain to medication choice and use. Specific medication classes that may be useful in childhood and adolescent PTSD are reviewed, and supportive literature is cited when available. The topics of when to use medications for childhood PTSD, what medications we can have confidence in, how to monitor clinical response to medication therapy, and the E-mail address: [email protected] 1056-4993/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S1056-4993(02)00102-5

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special considerations involved in psychopharmacologic treatment of children and adolescents are discussed.

Posttraumatic stress disorder symptom complexity and comorbidity Childhood and adolescent PTSD is a heterogeneous disorder typically characterized by complex symptom presentations. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [1] criteria set allows for at least 1750 possible symptom combinations in meeting the minimum criteria for a diagnosis of PTSD (ie, one in five B-criteria, plus three in five C-criteria, plus two in five D-criteria yields 1750 possible symptom combinations). There are at least 1750 ‘‘ways a child can look’’ symptomatically, using only the basic criteria to meet diagnostic threshold for the disorder. Establishing the diagnosis can be a complex task in the face of such symptom heterogeneity. Because of dependency needs and lack of experience in life, children are especially vulnerable to stress in the environment and in their caretakers and have less control over the events in their lives than do adults. This lack of control may account for some of the vulnerabilities to traumatic experiences that children exhibit. Given exposure to identical traumatic experiences, it seems that children are more sensitive to the effects of trauma than adults and consequently may exhibit higher rates of PTSD development. Conversely, like adults, children often present with multiple overlapping comorbid conditions, which add still further layers of complexity to their symptom presentation. Appropriate use of medication to treat children with PTSD entails segregating and specifying specific diagnoses and target symptoms. Traumatized children frequently have symptoms of disorders other than PTSD, and children with other disorders often have PTSD as a comorbid diagnosis [2 –7]. There is reason to believe that comorbidities become more complicated with time, because epidemiologic studies that sampled adults with child trauma histories indicated serious and multiple comorbid conditions that aggregate with PTSD [8 –10]. There may be advantages to intervening in PTSD symptoms early and aggressively to forestall the development of complicating comorbid conditions that may accrue over time as a result of the debilities caused by the primary disorder. The increased likelihood that at least one other psychiatric condition will be present along with PTSD [9] and the presence of associated comorbid symptoms along with the core features of PTSD often influences the choice of medication selected to treat PTSD. Comorbid conditions, such as depression or anxiety, or specific trauma-related symptoms, such as insomnia or flashbacks, may suggest different treatment strategies for medication intervention. Perhaps in no other disorder in psychiatry is the need for individual patient tailoring of medication treatment more important than in PTSD. Before moving to a discussion of specific medication treatments for childhood PTSD it is helpful to review the neurobiologic systems that presumably mediate clinical symptoms and are the likely targets for medication intervention. It is

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important to note, as Cohen [11] has pointed out, that we do not treat trauma in children; rather, we treat behavioral and emotional symptoms or symptom clusters that appear in some children exposed to traumatic life events.

Neurobiology The literature on the neurobiology of PTSD in childhood is in the early stages, and relatively little is known about the specific neurobiologic effects of early trauma on human growth and development [12 – 15]. DeBellis [16] reviewed the psychobiology of PTSD in childhood, and more general theories of the neurobiology of stress and trauma have been reviewed extensively elsewhere [17,18]. A body of literature is emerging, based on a synthesis of clinical and animal experimental research, to guide treatment decisions in child and adult PTSD [11,19– 23]. Early life trauma seems to affect various central nervous system functions, anatomic development, and neuroendocrine and immunologic system regulation [16,23 –26]. Theoretical models, largely based on dysregulation in these systems that mediate the stress response, are gradually becoming more sophisticated [27,28], although the child and adolescent literature remains unsystematic and lags considerably behind adult research. Specific neurotransmitters implicated in traumatic stress in childhood include norepinephrine, serotonin, dopamine, g-aminobutyric acid (GABA), excitatory amino acids, corticosteroids and their modulators, and endogenous opioids [12,13]. Not surprisingly, these neurotransmitter systems ramify through various neuroanatomic regions implicated in PTSD, including brain stem arousal mechanisms, diencephalic modulatory centers of sensory and emotional information, and cortical and limbic structures of memory and motivation, including areas that mediate selective appraisal of threat. In an elegant study that examined brain anatomy and development, DeBellis [16,29] showed that compared with control children, maltreated children were found to have smaller intracranial and cerebral (but not hippocampal) volumes when tracked over 2 years of development. These children also were shown to exhibit more suicidal ideation and behavior, greater depression, increased overall rates of psychopathology (based on parent reports), and increased frequency of dissociation. Dysregulation in the hypothalamic-pituitary axis and cortisol (a ‘‘stress’’ hormone) secretion are known to be present in adults and children with PTSD [22,30], although the specific abnormality tends to vary. Studies in adults, especially studies that involve individuals with rape trauma or early childhood sexual abuse, have shown low cortisol levels, and unlike in depression, in which there is a failure to suppress to dexamethasone challenge, these individuals may be super-suppressors of cortisol secretion when challenged with dexamethasone. King et al [31] demonstrated that girls aged 5 to 7 years who were exposed to recent sexual abuse exhibited significantly lower salivary cortisol levels than agematched controls. Although these findings are intriguing, the precise devel-

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opmental implications for early life dysregulation in hypothalamic-pituitary axis function have yet to be worked out. Of the three symptom clusters in PTSD (ie, reexperiencing, avoidance, and hyperarousal), the symptoms of hyperarousal may be the most amenable to pharmacologic intervention in terms of the typical symptoms that are the focus of clinical attention in childhood. Sleep disturbances, irritability, difficulty concentrating, hypervigilance, exaggerated startle responses, and outbursts of aggression represent states of increased physiologic arousal [14,15] and may reflect neurobiologic sequela of trauma. Somatic symptoms of autonomic hyperactivity or increased arousal may represent tonic and phasic physiologic activity and tend to reinforce other symptoms of the disorder. Phasic symptoms occur more often when the child encounters traumatic reminders. The child is seen as ‘‘on alert,’’ hypervigilant, scanning and ready to respond to any environmental threat [27]. Especially in school-aged children, physiologic reactivity may include somatic symptoms as a form of hyperarousal. Sleep disturbance may be severe and persistent; changes seen in sleep architecture have been noted in adult studies [32]. Difficulty falling asleep, sleepwalking, and night terrors are not uncommon in children with PTSD. These sleep problems and general tonic hyperarousal symptoms can decrease further a child’s ability to concentrate and attend to important tasks and may adversely affect mood states, learning, and behavior in school. Hypervigilance and exaggerated startle responses may lead to chronic efforts to ensure personal security or the safety of others [27]. These recurrent episodes of fear may seriously change a child’s sense of competence and negatively alter self-concept and self-confidence. Incident-specific fears commonly occur in children and often generalize to other situations. Fears are particularly evident during times of vulnerability (eg, in the bathroom, at bedtime, when alone) or in response to specific reminders. Finally, hyperarousal that leads to temporary or chronic difficulty in modulating aggression can make children act more irritable, oppositional, and explosive. Hyperarousal can result in a reduced tolerance to the normal behaviors, demands, and slights of peers and family members and in unusual acts of aggression or social withdrawal [33]. Often, externalizing behaviors, such as hyperactivity, hyperreactivity, and irritability, can be the most obvious and disabling of the symptom triad in children and adolescents with PTSD and may further complicate the diagnosis by masking other less obvious symptoms. Future studies of the neurobiology of PTSD in children and adolescents must be more systematic in cross-correlating clinical symptoms of reexperiencing, avoidance and hyperarousal with functional and anatomic neuroimaging, relevant neuroendocrine findings, neuropsychiatric assessment, and response to specific medications.

Special considerations in child and adolescent populations Pharmacotherapy treatment approaches to childhood PTSD must be embedded in a broad context of assessment and treatment. Certainly the initial step in the

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treatment of PTSD is psychoeducation of the child, parents, and adult caregivers. This initial didactic explanation is an important but often neglected element of all types of therapy for childhood PTSD. It involves providing an explanation of the symptoms of the disorder, its natural course left untreated, and the specific rationale and expectable goals for therapy—a process collectively referred to as psychoeducation. Treatment never should be a mysterious process. Psychoeducation provides the opportunity to discuss explicitly with the child and adult caregiver the components of treatment and define specific treatment targets, reasonable goals, and a clear rationale for all interventions. Children and adolescents must understand the nature of their disorder and how their therapy relates to the bad things that have happened to them. Parents especially must understand the rationale and basic behavioral principles of cognitive behavioral therapy, because by its very nature it requires some amount of discomfort during the course of treatment. Parents and children also must understand the role of medication in treatment, the treatment target symptoms for medication versus psychotherapy, and the realistic goals that are desired and obtainable. Without a clear understanding of the connection between therapeutic tactics and the expected timing of symptom relief, parents and children are more likely to withdraw from treatment or fail to adhere to pharmacotherapy. Reviews of the empirical evidence on the effectiveness of pharmacotherapeutic agents in children with PTSD [19,34] and textbooks of pediatric psychopharmacology [35 – 37] clearly lag behind the adult literature, in which recently published PTSD practice guidelines [20] provide substantial information and multiple levels of evidence to support medication use. Of the 16 publications on medication treatment of pediatric PTSD between 1980 and 2002, no randomized, double-blind, placebo-controlled clinical trials were covered. Child clinicians who use pharmacotherapy must proceed without the benefit of controlled empirical research. In the absence of such efficacy-based research evidence, a rational approach to the pharmacologic treatment of childhood PTSD symptoms can be informed by understanding medication effects on the neurobiologic stress systems. Data from the adult literature also may inform clinical decision making. It should be borne in mind, however, that when it comes to pharmacology, children are not simply small adults [38]. Differences in efficacy, dosage, and tolerability between adults and children make simple downward extrapolation from the adult literature an undependable guide. As a general principal, clinicians are advised to ‘‘start low and go slow’’ regarding medication dosages and titration schedules. Table 1 provides a list of pharmacologic actions, agents, and dosing guidelines for PTSD and related symptoms for use in pediatric populations. Because of the lack of empirical studies in childhood PTSD, it is difficult to recommend a clear treatment hierarchy. Cognitive-behavioral therapy in schoolaged and older children and adolescents is likely to be the treatment of first choice because it is probably less risky and has supporting data [31,39,40]. In the recent past outpatient psychotherapy generally has been considered the preferred initial treatment, with pharmacology used as an adjunct [35]. Many experts recommend a

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Table 1 Pharmacologic actions associated with posttraumatic stress disorder and related symptoms Pharmacologic activity Specific agent

Dose range

PTSD symptom cluster remark

a and b adrenergic

Clonidine Guanfacine Propranolol Quetiapine Risperidone Olanzapine Imipramine Amytriptyline Venlafaxine XR Mirtazapine Phenelzine

0.05 – 0.6 mg/d 0.5 – 6 mg/d 20 – 160 mg/d 24 – 400 mg/d 0.5 mg – 6 mg/d 2.5 – 10 mg/d 25 – 300 mg/d 25 – 300 mg/d 37.5 – 375 mg/d 7.5 – 60 mg/d 15 – 75 mg/d

Cluster B, C, D symptoms

Buproprion SR

50 – 200 mg bid

Clomipramine Fluoxetine Fluvoxamine Paroxetine a Sertraline a Citalopram Escitalopram Cyproheptadine Trazadone Nefazadone Buspirone Alprazolam Clonazepam Carbemazepine Valproic acid Lithium carbonate Naltrexone

25 – 200 mg/d 5 – 80 mg/d 50 – 300 mg/d 5 – 60 mg/d 25 – 200 mg/d 5 – 60 mg/d 10 – 30 mg/d 2 – 28 mg/d 25 – 600 mg/d 50 – 600 mg/d 15 – 60 mg/d 0.25 – 6 mg/d 0.5 – 6 mg/d 200 – 1000 mg/d 125 – 1750 mg/d 300 – 1500 mg/d 25 – 50 mg/d

Dopaminergic

Noradrenergic/ serotonergic

Monoamine oxidase inhibitor Noradrenergic/ dopaminergic Serotonergic

Benzodiazepine Anticonvulsant Antimanic Opioid antagonist

Cluster B and D symptoms

Cluster B and D symptoms

More effective than tricyclic antidepressants C Cluster D (mood and ADHD Sx’s) Cluster B, C, D symptoms

Sleep onset, traumatic night

Cluster B and D symptoms Reduces anxiety, insomnia, on core PTSD symptom cluster Cluster B and C symptoms Cluster B and D symptoms Limited to Cluster D Symptom Cluster symptoms self injurious behaviors

Dose ranges for agents in this table are guidelines. The maximum dosage listed for each based on use in late adolescence/young adulthood. Also, most of the agents listed in this table used in childhood are ‘‘off label’’ (ie, sufficient information is lacking for a label indication regarding their use in pediatric PTSD and effective doses have not been established for this use in childhood). Abbreviations: Cluster B Symptoms, reexperiencing, intrusive recollections, traumatic nightmares, flashbacks; Cluster C Symptoms, avoidant behavior, numbing, dissociation; Cluster D Symptoms, hyperarousal, insomnia, irritability, hypervigilance, hyperstartle. a Indicates FDA label indication for PTSD.

blend of cognitive, behavioral, dynamic, and family-based interventions for childhood PTSD. In these modalities children can confront and work through disturbing elements of trauma experiences in a safe and supporting environment. There is admittedly scant empirical support in the childhood treatment literature for any treatment strategy for PTSD. Severity or acuity of symptoms and partial or no response to psychotherapeutic interventions are the chief reasons for pharmacologic treatment.

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Pharmacology plays two central roles in childhood PTSD treatment. First, it targets disabling symptoms so that the traumatized child may pursue a normal growth and developmental trajectory. Second, it helps traumatized children tolerate emotionally distressing material and work through the distress in psychotherapy and improves functioning in life. Given the complex pathophysiology of PTSD, effective pharmacotherapy may require a multisystemic approach in which several agents are used to target separate clusters of symptoms of PTSD and the accompanying comorbidities. Pharmacotherapy may be an early treatment consideration in the face of severe agitation, aggressiveness, self-mutilation behaviors, and disorganization or debilitating symptoms of insomnia, depression, or anxiety. Once a sufficient response is achieved, the question of how long to maintain medication treatment is unclear. Evidence from treatment research for other disorders indicates that long-term medication use prevents relapse of several psychiatric disorders. A recent report on continuation treatment for adult PTSD with the selective serotonin reuptake inhibitor (SSRI) sertraline suggested that this also may be the case for PTSD [41].

Medication use in child and adolescent posttraumatic stress disorder This section reviews classes of medication related to their function and their effects in relation to target PTSD symptoms. Despite the lack of data, medication use in children with PTSD has become a standard of care. In a large sampling of treatment providers, Cohen et al [11] found that 95% of medical practitioners who treat pediatric PTSD use pharmacotherapy in combination with psychodynamic and cognitive-behavioral therapies. Whether to use medication for PTSD can be a deceptively complex question. There is no simple rule that determines the choice to use medication in PTSD. Rather, medication should be one consideration among various potential therapeutic interventions, including psychoeducation, supportive therapy, family therapy, and cognitive behavioral therapy. Decisions to use medications are tailored to individual patient needs and influenced by patient concerns and preferences. The acceptability of pharmacotherapy and alternative treatment modalities to the patient is one criterion on which to base decisions to prescribe medication. Another criterion might be the presence of significantly severe comorbid psychiatric conditions that respond to medications that also treat PTSD. Medication also might be favored as a first-line choice when the intensity of PTSD or comorbid depression or anxiety symptoms interferes with a patient’s ability to engage in or tolerate a psychotherapeutic intervention. Finally, medication treatment also may be indicated when there is not access to competent PTSDfocused psychotherapy and when symptoms persist beyond a reasonable course of treatment. Medication use in children and adolescents with PTSD should be based on a stepwise approach in which broad-spectrum agents are considered first followed by attention to comorbid diagnoses likely to be amenable to pharmacologic interven-

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tion. Medication algorithms have been developed for such a stepwise approach in adults and children [19,21,42,43]. Ideally, medications should decrease intrusions, avoidance, and anxious arousal, minimize impulsivity, improve sleep, treat secondary disorders, facilitate cognitive-behavioral psychotherapies, and improve functioning in daily life. One should remember that effective treatment of even one symptom in children who suffer with PTSD (eg, improvement of a sleep-onset disturbance) can have a positive effect that enhances multiple domains of functioning. In adults, many case reports, uncontrolled trials, and newly emerging randomized controlled trials suggest that the benefits of conventional drug treatments in PTSD are modest to significant [13,21,44]. Two SSRIs, paroxetine and sertraline, recently have received Food and Drug Administration (FDA) approval for the treatment of PTSD in adults [45,46], although much more limited, clinical experience is similar for children and adolescents. Important considerations in the use of medication are the types of target symptoms present that are likely to be medication responsive (both core PTSD and comorbid condition symptoms), their severity, and the degree of disability that they cause. Although no medication currently has an FDA label indication for the treatment of PTSD in childhood, data from adult studies and clinical experience with other disorders in childhood provide guidance in selecting pharmacologic agents. Pharmacotherapy may be an important component in the multimodal treatment of PTSD because it may offer relief from highly debilitating symptoms and buffer children against intense symptoms, which allows for easier confrontation of traumatic material in therapy. Because there is a high probability that another psychiatric condition will be present along with PTSD [9], the associated comorbid disorders and symptoms often influence the choice of medication selected to treat PTSD. Depressed mood, anxiety, or specific trauma-related symptoms, such as insomnia or flashbacks, may suggest different treatment options for clinicians.

Specific medications for use in posttraumatic stress disorder Table 1 provides a listing of the specific medications, dose ranges, and clinical action of the agents used in the treatment of PTSD. Adrenergic agents The catecholamines norepinephrine, epinephrine, and dopamine are involved in sympathetic arousal, anxiety, frontal lobe activation, mood regulation, reward dependence, working memory, thinking, and perception. Adrenergic agents, such as the a-2 agonists clonidine and guanfacine and the b-antagonist propranolol, reduce sympathetic tone and may be effective in the symptoms of hyperarousal, impulsivity, activation, sleep problems, and nightmares observed in PTSD [13,47,48]. Clonidine in particular has been shown to decrease startle

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responses and may target other symptoms of physiologic lability as measured by autonomic arousal [27]. In an open label trial that involved 17 children with PTSD, Perry et al [14] found significant improvement in anxiety arousal, concentration, mood, and behavioral impulsivity using relatively low doses of clonidine. Harmon and Riggs [49] reported the effectiveness of the transdermal clonidine patch in reducing PTSD symptoms in all seven patients in their openlabel trial. In a single case study, Horrigan [47] reported the effectiveness of guanfacine in reducing PTSD-associated nightmares in a 7-year-old patient. Evidence exists that if tolerance develops to one agent, (eg, clonidine), replacement with guanfacine can provide renewed symptomatic response [50]. In one of the first studies of medication treatment in childhood PTSD, propranolol was shown to reduce arousal symptoms in survivors of childhood sexual abuse, presumably by blocking sympathetic nervous system hyperreactivity, although central effects also may play a role [51]. In an uncontrolled A-B-A design study of children with PTSD, Famularo et al [51] found that propranolol significantly reduced PTSD symptoms over the 5 weeks of treatment (2.5 mg/kg/day) in 8 of 11 abused children. Intrusion and arousal symptoms seemed to respond the best to treatment in this study. Adrenergic agents may be helpful in managing the hyperarousal, activation, motor hyperactivity, and sleep-onset problems often associated with PTSD in childhood. By reducing central nervous system adrenergic tone to target reexperiencing and hyperarousal symptoms, use of adrenergic agents are a rational treatment strategy in PTSD. The a-2 adrenergic agents also may be more effective than the psychostimulants for attention deficit hyperactivity disorder (ADHD) symptoms in maltreated or sexually abused children with PTSD [12,13]. Dopaminergic agents The only current study that used a dopamine blocking agent to treat PTSD in childhood was that by Horrigan and Barnhill [52]. In an uncontrolled design, risperidone was used to treat 18 children with PTSD who had high rates of comorbid psychiatric disorders (eg, 83% with comorbid ADHD and 35% with comorbid bipolar disorder). Thirteen of the 18 subjects in this study experienced remission of their PTSD symptoms. With scant evidence as to their use in PTSD symptoms per se, the atypical neuroleptic agents currently are reserved for patients with refractory PTSD or persons who exhibit paranoid behavior, parahallucinatory phenomena or intense flashbacks, self-destructive behavior, explosive or overwhelming anger, or psychotic symptoms. Consistent with adult treatment practices, there has been a shift in child psychiatry toward the use of the newer atypical neuroleptic agents, such as risperidone, olanzapine, and quetiapine, because of their apparent lower risk of side effects, such as extrapyramidal symptoms and tardive dyskinesia. These agents currently do not have an FDA label indication for use in childhood, however. The atypical neuroleptic agents may have a limited role to play in childhood PTSD but should be reserved for severe cases in which

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psychotic symptoms, severe aggression, or self-injurious behaviors complicate management and first-line treatments do not contain these symptoms. Serotonergic agents The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is widely distributed in the central nervous system and subsumes various functions, including drive satiety, mood, aggression, anxiety, and compulsive and impulsive behaviors. It may be an important neurotransmitter in psychiatric symptoms commonly associated with PTSD, such as aggression, obsessive and intrusive thoughts, alcohol and substance abuse, and suicidal behavior [42,43]. Suicidal behavior is known to be associated with childhood maltreatment and low 5-HT functioning [53,54]. Panic attacks, dissociative episodes, and flashbacks seem to be related to serotonin function [55]. There are significant phenomenologic overlaps between PTSD symptoms and their comorbid conditions, which share mediation by serotonergic systems. Currently, two medications—the SSRIs sertraline and paroxetine—have received approval from the FDA as indicated treatments for PTSD. Favorable results with other SSRIs, such as fluoxetine, fluvoxamine, and citalopram, also have been reported in the treatment of adult PTSD [44]. Surprisingly, there are no controlled reports of the use of SSRIs in childhood PTSD. SSRIs may be useful in children with PTSD because of the various symptoms associated with serotonergic dysregulation, including anxiety, depressed mood, obsessive thinking, compulsive behaviors, affective impulsivity, rage, and alcohol or substance abuse. The SSRIs have received the most clinical attention and are likely first-line choices in childhood because of their broad-spectrum activity in anxiety, mood, and obsessive-compulsive spectrum disorders. They also have demonstrated effectiveness in adult populations [44 – 46]. These agents are being actively investigated for use in children. For example, in a recent study, Seedat et al [56] report the effectiveness of citalopram in a 12-week open label trial in eight adolescents with moderate to severe PTSD. Subjects in their trial exhibited a 38% reduction in PTSD symptoms at the end of treatment, although self-reported depressive symptoms failed to improve. The SSRIs can be effective in reducing trauma-associated reexperiencing, anxiety, and collateral mood symptoms, although they may be less effective in avoidance or numbing symptoms. The SSRIs may be useful in children with PTSD and persons with associated symptoms of depression or panic symptoms [57].They are generally safe and well tolerated and tend to be the agents of first choice. Nefazadone, a serotonergic antagonist antidepressant, has been reported to be helpful in PTSD and associated irritability and disruptive behavior in adolescents in an uncontrolled case series reported by Domon and Anderson [58]. They reported an average effective dose of 200 mg twice per day. Nefazadone was well tolerated in doses up to 600 mg/day. It should be noted that nefazadone has received an FDA mandated ‘‘black box’’ warning because of problems with hepatic toxicity. Mirtazapine, a serotonin and norepinephrine active antidepressant, has

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shown promise, either alone or in combination with an SSRI for the treatment of PTSD [59,60]. Treatment nonresponse to serotonergic agents would be indicated if target symptoms did not exhibit a 25% to 50% reduction after 8 to 12 weeks at maximum doses. One must apply common sense, however, and if more circumscribed symptoms (eg, insomnia, agitation) do not exhibit a response after shorter intervals, use of alternative strategies that target more specific symptoms should be considered. Buspirone is a nonbenzodiazepine anxiolytic serotonin 5-HT1A partial agonist that may play a role in reducing anxiety, flashbacks, and insomnia [61], although no controlled studies of this agent have been published in childhood populations. Cyproheptadine is an antihistaminic 5-HT antagonist that has shown limited use in reducing traumatic nightmares [62]. Because of its sedative action and generally safe side effect profile, it may be a useful agent in sleep-onset problems and nightmares in children with PTSD. Agents such as nefazadone, trazadone, and cyproheptadine, used alone or in conjunction with the SSRIs, may be particularly useful in sleep dysregulation and trauma-related nightmares that occur frequently in patients with PTSD. Medication tolerability affects adherence to pharmacotherapy over the course of treatment. Favorable tolerability findings from the recent large-scale studies that led to FDA approval for sertraline and paroxetine are not surprising in view of the well-established safety and side effect profile of the SSRI medication class. Multicenter studies have shown variable rates of side effects, such as asthenia, diarrhea, abnormal ejaculation, impotence, nausea, dry mouth, insomnia, and somnolence [41,45,46]. These side effects are often mild and transient and do not typically necessitate discontinuation of treatment.

Adrenergic and serotonergic agents: tricyclic antidepressants, venlafaxine Tricyclic antidpressants, such as imipramine and desipramine, largely have been supplanted in child and adolescent psychiatry by the newer antidepressant agents because of unwanted side effects and potential cardiotoxicity. These agents may have second-line use in childhood PTSD when comorbid conditions such as ADHD, enuresis, or sleep disorders are present. Three randomized clinical trials have been conducted, and multiple case reports and open label trials with tricyclic antidepressants in PTSD have been published, although only one study has been reported in childhood. Robert et al [63] reported the use of low-dose imipramine (1 mg/kg) to treat symptoms of acute stress disorder in children with burn injuries. In this study, 25 children aged 2 to 19 years were randomized to receive either chloral hydrate or imipramine for 7 days. Ten of 12 subjects who received imipramine experienced from half to full remission of acute stress disorder symptoms, whereas 5 of 13 subjects responded to chloral hydrate. Sleep-related flashbacks and insomnia seemed to respond well to treatment.

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Because of their safety and side effect profile and the apparent lack of effectiveness in childhood depression, the tricyclic antidepressants have been supplanted by the SSRIs as first-line pharmacotherapy in the treatment of depression and anxiety in childhood. As such, these agents should be reserved for second- or third-line treatment in pediatric PTSD. Venlafaxine, which exhibits noradrenergic and serotonergic properties, seems to be a safe and effective medication for the treatment of depression and generalized anxiety symptoms. Although no treatment studies exist in children and adolescents, it does have strong consensus support in the adult treatment guidelines. As such, it should be considered as an alternate class agent when firstline treatment with the SSRIs has been ineffective or suboptimal.

Gamma-aminobutyric acid and benzodiazepine agents Benzodiazepine receptors are functionally linked to receptors for the inhibitory neurotransmitter gamma-aminobutyric acid. This system is clearly involved in the neurobiology of anxiety and stress. The benzodiazepines have been used to treat anxiety disorders in children and adults, although there are few, if any, data to support their effectiveness in the core symptoms of PTSD [42]. Adult studies indicate that they have little effect on core PTSD symptoms of reexperiencing, avoidance, and numbing and pose the risk of rebound effects such as anxiety, sleep disturbance, and prominent rage reactions. Clinicians who treat children should be aware of the troublesome and sometimes serious side effects of disinhibition, sedation, and irritability when using these agents and the difficulty in withdrawing patients from established benzodiazepine treatment. These agents (eg, clonazepam, lorazepam) may play a minor role in reducing acute and intense symptoms of anxiety or agitation or may be used as short-term adjunctive treatment to facilitate exposure tasks in psychotherapy. They should be used with caution in children and adolescents, however, because of their propensity to cause paradoxical disinhibition and their abuse potential. The benzodiazepines cannot be recommended as first- or second-line therapy currently.

Opioid antagonists Opioid antagonists have been used with mixed results in adults with PTSD. No clinical trials with these agents have been published in children and adolescents with PTSD. Naltrexone has been used to prevent hypothesized hyperrelease in endogenous opioids as a means of blunting the tendency to self-mutilate and reducing rates of relapse in alcoholic patients who have achieved sobriety. The opioid antagonists may have limited use in treating debilitating self-mutilative behavior and perhaps reducing substance abuse comorbidity in adolescent patients with PTSD.

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Miscellaneous agents and agents that affect multiple neurotransmitters: anticonvulsants, bupropion, psychostimulants Trauma exposure may induce sensitization or kindling phenomena in limbic nuclei in the human central nervous system. Several successful open label trials have been conducted with antikindling and anticonvulsive agents with adult patients with PTSD. The mood stabilizers may play a role in the treatment of childhood PTSD, especially in cases of severe affective instability. Lithium, valproate, and carbamazepine may reduce extreme mood lability and anger dyscontrol. Carbamazepine has received the most attention and has been shown to markedly reduce flashbacks, traumatic nightmares, intrusive recollections, and sleep disturbance in adults [64]. Loof et al [65] reported the use of carbamazepine (300 –1200 mg/day, serum levels 10 –11.5 mg/mL) in 28 children and adolescents with sexual abuse histories. By treatment end, 22 of 28 patients were asymptomatic regarding PTSD symptoms. The remaining 6 significantly improved in all PTSD symptoms, except for continued abuse-related nightmares. Half of this cohort was comorbid for ADHD, depression, oppositional defiant disorders (ODD), or polysubstance abuse and was treated with concomitant medications (eg, methylphenidate, clonidine, sertraline, fluoxetine, or imipramine). In patients who cannot tolerate carbamazepine, valproic acid may be a useful alternative because it has demonstrated success in reducing avoidant and hyperarousal symptoms in adults [66]. There have been no published controlled trials of anticonvulsants in the treatment of pediatric PTSD. These agents are commonly used in children and adolescents with seizure disorders, and they may be a useful intervention for debilitating avoidance and numbing, hyperarousal, and sleep dysregulation in children with PTSD or cases in which overwhelming anger and aggressiveness or explosiveness predominate. The same brain areas that are involved in the stress response also mediate motor behavior and affect regulation, arousal, sleep, startle response, attention, and cardiovascular function. It is not unusual for traumatized children, particularly children exposed to chronic trauma such as maltreatment, to exhibit a constellation of anxiety plus ADHD and other disruptive behavior symptoms. Some clinicians consider the use of a-agonists in these situations, hoping to avoid stimulantinduced exacerbation of anxiety and PTSD. Many traumatized children have favorable responses in reduction of hyperactivity, impulse dyscontrol, and attention impairment, with the psychostimulant agents such as methylphenidate or dextroamphetamine and their various formulations. Similarly, bupropion is often considered a second-line agent for ADHD symptoms and may be a useful agent when affect dysregulation or depressed mood co-occurs with ADHD symptoms [67].

Assessment and symptom monitoring As in all psychiatric disorders, the first step in establishing a treatment program is a careful, thorough assessment that is stressor focused, as in the case of PTSD

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[68,69]. Although semistructured interviews are useful for assessing psychiatric problems in children and adolescents, reliability or validity data for PTSD instruments have been slow to emerge [70], and no structured instrument can replace a well-conducted series of clinical interviews in this most complex disorder [82]. Clinical response to medication is best monitored with instruments that measure PTSD symptom severity. A wide choice of self-rating scales and structured clinical interviews may be used with adults and children. Selection of a given instrument depends on the balance among time available, patient compliance, clinical concerns, and scientific necessity. For rigorous research protocols, more labor-intensive structured interviews may be used, such as the Clinician Administered PTSD Scale (CAPS) [71] for adults or CAPS for Children (CAPS-C) [72], which was developed with the support of the National Center for PTSD. The CAPS-C allows for current and lifetime diagnoses and dimensional assessment of DSM-IV PTSD symptoms and collateral psychopathology. The interview is time consuming and demanding for the clinician to conduct and is probably best reserved for clinical research settings. It provides greater accuracy and completeness in exchange for the extra effort. Several reliable and valid self-rating questionnaires for measuring PTSD symptom severity have good psychometric properties [68,73]. Because PTSD is usually associated with comorbid diagnoses and impaired functional status, it is not uncommon to monitor other psychopathologic features along with PTSD per se. It has become ‘‘state-of-the-art’’ for treatment trials for PTSD to define optimal outcomes in terms of reduced severity of anxiety and depression in addition to PTSD per se and global improvement scales, which also may include measurement of general function and quality of life. The most commonly used instrument to date in childhood—the Pynoos-Nader version of the Stress-Reaction Index—shows modest empirical support as a semistructured interview (R. Pynoos, MD, personal communication, September 1995). It has been used as a self-report measure [70,74] but neither adequately captures the DSM-IV criteria nor yields a DSM-IV diagnosis. With the caveat that parents are generally better at evaluating children’s externalizing rather than internalizing symptoms [75], a multimethod, multimodal evaluation is preferable, including information from multiple sources [76]. In children younger than 48 months, the most important trauma variable predictor seems to be whether a caregiver was threatened; thus, caregiver reports are crucial sources of clinical information [77]. Parent-teacher measures, such as the Conners Parent and Teacher Rating Scales [78] and the SNAP IV [79], are efficient adjuncts for assessing collateral externalizing symptoms. Self-report measures, such as the Children’s Depression Inventory [80] or the Multidimensional Anxiety Scale for Children [81], can be used to assess internalizing comorbidities. Finally, because the DSM-IV nosology is less sensitive to early life trauma evaluation and because it underemphasizes developmental differences and social contextual factors, it is less than adequate for evaluating childhood-onset PTSD. For example, some aspects of the PTSD symptom complex may best be reported by the affected child, others by parents, and still others by teachers or other

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observers. Because the child’s social context—neighborhood, family, peer, and school environments—may affect strongly the risk of PTSD and corollary symptoms, it is important to consider variables such as loss, secondary adversities, family dysfunction, and attachment-related symptoms when monitoring a child with PTSD. Because posttraumatic symptoms vary with the nature of the stressor (eg, chronic abuse versus sudden trauma), the ability to consider symptoms in a developmental framework depends on a precise characterization of the stressor, associated adversities (eg, placement in a foster home after removal from parents), and comorbid conditions identified in a thorough diagnostic evaluation and monitored with scales that are sensitive to these variables. Clinicians should not hesitate to modify existing scales to include individually tailored target symptoms with four point (0 –3) Likert scale ratings. Such modification allows tracking of response to treatment on symptoms that are clinically relevant to particular patients but that may not be included in the standard scales.

Summary Posttraumatic stress disorder is a common cause of morbidity in children and adolescents. The disorder in youth is similar to that in adults, with high rates of psychiatric comorbidity. Children seem to be more sensitive to the effects of trauma, and early life trauma exposure may induce a complex sequence of events that leads to the development of multiple psychiatric disorders in adulthood. The state of knowledge regarding medication treatments for children and adolescents is in the earliest stages of development. There are no well-conducted, randomized clinical trials to guide practitioners. Medication may play an important role in reducing debilitating symptoms of PTSD and providing a buffer for children while they confront difficult material in therapy and may help to improve their general functioning in day-to-day life. Given the various medications with potential usefulness in PTSD, it is helpful to use a stepwise approach to treatment. As a general principal, broad-spectrum agents, such as the SSRIs, are a good first choice. The SSRIs have efficacy in treating the core symptoms of PTSD and conditions such as the anxiety disorders and depression that commonly co-occur with PTSD. These agents also improve social and occupational functioning and an individual’s perception of improved quality of life [41,45,46]. Although the SSRIs are generally effective for a broad spectrum of problems, clinicians should systematically monitor for the persistence of symptoms that do not respond to these agents. For example, despite significant improvements in core PTSD symptoms in one study that used sertraline, little improvement was seen in patients’ comorbid anxiety and depressive symptoms [41]. This finding demonstrates the value of continuous symptom monitoring and shows that residual or comorbid symptoms may require a different medication to augment effective SSRI treatment for PTSD. A reasonable approach is to begin with a broad-spectrum agent, such as an SSRI, which should target anxiety, mood, and reexperiencing symptoms. Adre-

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nergic agents, such as clonidine, used either alone or in combination with an SSRI may be useful when symptoms of hyperarousal and impulsivity are problematic. Supplementing with a mood stabilizer may be necessary in severe affective dyscontrol. Similarly, introduction of an atypical neuroleptic agent may be necessary in cases of severe self-injurious behavior, dissociation, psychosis, or aggression. Comorbid conditions such as ADHD should be targeted with pharmacotherapy known to be effective, such as psychostimulants or newer agents such as atomoxetine. Pharmacologic treatment of PTSD in childhood is one approach to alleviating the acute and chronic symptoms of the disorder. Despite the lack of well-designed, randomized, controlled trials that support efficacy, medication can be used in a rational and safe manner. Reduction in even one disabling symptom, such as insomnia or hyperarousal, may have a positive ripple effect on a child’s overall functioning. Pharmacotherapy is typically used as one component of a more comprehensive multiple modality treatment package, including psychoeducation of the parent and child, focused exposure-based psychotherapy with adjunctive family therapy when indicated, and long-term booster interventions that use an admixture of psychodynamic, cognitive-behavioral, and pharmacologic interventions.

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