Psychiatric Annals

Review Article 

Psychopharmacological Treatment of Pediatric PTSD

Sadiq Naveed, MD; Sabeeha Naazneen Shaik, MBBS; Amber Ehsan Faquih, MD; Vinod Kumar, MBBS; Fatima Motiwala, MD

Abstract

Early recognition and treatment of posttraumatic stress disorder (PTSD) in youth are critical. This article provides a comprehensive overview of the up-to-date evidence for pharmacological options for children with PTSD. Eight electronic databases were searched and a manual search of the full text of included articles was performed. Two independent reviewers performed screening of the articles using the predetermined eligibility criteria. The data were extracted by two independent reviewers. The search generated 32 articles with a total patient population of 833. The pharmacological options were antidepressants, antipsychotics, mood stabilizers, alpha-adrenergic agents, beta-blockers, serotonin and histamine antagonists, and opioid agonists. The mood stabilizers and second-generation antipsychotics should be reserved for patients with significant safety concerns or aggressive behaviors because of their side-effect profile. Alpha-adrenergic agonists can be used in patients who are re-experiencing symptoms of PTSD and without safety concerns. [Psychiatr Ann. 2020;50(5):209–228.]

Abstract

Early recognition and treatment of posttraumatic stress disorder (PTSD) in youth are critical. This article provides a comprehensive overview of the up-to-date evidence for pharmacological options for children with PTSD. Eight electronic databases were searched and a manual search of the full text of included articles was performed. Two independent reviewers performed screening of the articles using the predetermined eligibility criteria. The data were extracted by two independent reviewers. The search generated 32 articles with a total patient population of 833. The pharmacological options were antidepressants, antipsychotics, mood stabilizers, alpha-adrenergic agents, beta-blockers, serotonin and histamine antagonists, and opioid agonists. The mood stabilizers and second-generation antipsychotics should be reserved for patients with significant safety concerns or aggressive behaviors because of their side-effect profile. Alpha-adrenergic agonists can be used in patients who are re-experiencing symptoms of PTSD and without safety concerns. [Psychiatr Ann. 2020;50(5):209–228.]

Childhood maltreatment poses a significant public health concern, resulting in adverse life consequences ranging from minor disruptions to severe and debilitating impacts on functioning as adults.1 The World Health Organization estimates that about 25% of adults were abused as children.2 The Adverse Childhood Experience (ACE) study reported child maltreatment in three categories: (1) abuse, (2) household challenges, and (3) neglect. Physical abuse was the most common (28%), followed by sexual abuse (21%), emotional neglect (15%), emotional abuse (11%), and physical neglect (10%).3 Household challenges included substance abuse, parental separation or divorce, mental illness, domestic violence, and incarcerated household members.3

The prevalence of ACEs ranges from 12.5% of respondents having more than four ACEs to 64% with one or more ACEs.4 A study conducted in Wales reported that 46.5% of respondents had at least one ACE and 13.6% experienced four or more ACEs before age 18 years.5 Children and adolescents go through different developmental stages including infancy and toddlerhood, early and middle childhood, and early and middle/late adolescence. The impact of trauma and stress reactions can vary depending on the development stage of the child.6 Trauma and adverse experiences can adversely impact various domains including dissociation, cognition, attachment, biology, self-concept, behaviors, and affective regulation.6 Early childhood trauma is associated with structural and functional changes in the brain at many levels, resulting in changes in neurotransmitters, neuroanatomy, and hypothalamic-pituitary-adrenal axis.7 Early exposure to trauma results in volume reduction in the hippocampus, corpus callosum, prefrontal cortex, alteration in the symmetry of frontal lobe, and reduced neuronal density.7 Trauma also activates the adrenergic system in the body, which explains the efficacy of adrenergic agents in patients with posttraumatic stress disorder (PTSD).7

Childhood maltreatment is associated with an increased risk of several chronic physical and mental health conditions. These people are at a higher risk of chronic disease, including type 2 diabetes and heart and respiratory diseases.8 Childhood abuse has a dose-dependent relationship with an increased risk of psychological consequences including depression, anxiety disorders, PTSD, personality disorders, and substance use disorders.8 A study by Banducci et al.9 suggested that adults with alcohol, cocaine, cannabis, or opioid dependence were 4.5 to 9.79 times more likely to have psychiatric disorders if they had been abused as children.9 Trauma increases the risk of substance use disorders that can lead to other psychiatric disorders, including mood and anxiety disorders. In a recently conducted study, the prevalence of acute stress disorder and PTSD was reported to be 14.2% at week 2 and 9.6% at week 9, respectively.10 Patients with the negative alterations in cognition and mood at week 2 were reported to be at a higher risk for progression to PTSD in the future.10

Fang et al.5 estimated the annual cost of confirmed cases of childhood maltreatment to be around $124 billion. Childhood maltreatment costs around $210,012 per victim, which is comparable to other chronic health conditions.5 This cost covers the cost related to health care, educational, child welfare, and juvenile justice systems of the United States.5 Moreover, childhood maltreatment adversely affects health status, socioeconomic status, emotional functioning, and productivity.5 Early recognition and treatment of PTSD in children and adolescents are critical to the developmental trajectory and functioning of a person, as well as prognosis of the illness.

Psychotherapeutic interventions are the first-line treatment for PTSD in children and adolescents.11 The psychotherapeutic options include trauma-focused cognitive-behavioral therapy (TF-CBT), child-parent psychotherapy, and cognitive-behavioral interventions for trauma in schools.11 In recent years, there has been an increase in the use of pharmacological agents, but most of the evidence stems from studies of PTSD in adults.11 This narrative review provides an updated summary of the existing evidence for the use of pharmacological agents in youth.

Methods

Although this article is a narrative review, the robust search strategy of a systematic review was used to screen and include relevant studies and reduce the risk of publication bias.

Eligibility Criteria

Our inclusion criteria included studies focused on the psychopharmacology of PTSD in patients younger than age 18 years. This review article included case reports, case series, open-label trials, and randomized controlled trials (RCTs). All books, conference papers, theses, editorials, review articles, meta-analyses, in vitro studies, laboratory studies, animal studies, studies including healthy participants, and abstract-only articles were excluded. No restrictions on language, country, publication year, gender, and ethnicity of patients were applied.

Search Strategy

The review was performed using electronic databases including PubMed, Scopus, Web of Science, POPLINE, New York Academy of Medicine Grey Literature Report, PsycINFO, PsycArticles, and CINAHL by using the following search strategy: (“post traumatic stress disorder” or PTSD or “acute stress disorder” or psychological trauma) and (pharmacology or medications or treatment) and (“antidepressants” or “SSRIs” or “SNRIs” or “sertraline” or “fluoxetine” or “fluvoxamine” or “paroxetine” or “citalopram” or “escitalopram” or “SNRIs” or “duloxetine” or “venlafaxine” or “desvenlafaxine” or “tricyclic antidepressants” or “Imipramine” or “other antidepressants” or “trazodone” or “nefazodone” or “antiadrenergic medications” or “clonidine” or “guanfacine” or “propranolol” or “prazosin” or “antipsychotics” or “aripiprazole” or “risperidone” or “quetiapine” or “ziprasidone” or “olanzapine” or “mood stabilizers” or “lamotrigine” or “divalproex” or “topiramate” or “tiagabine” or “carbamazepine” or “phenytoin” or “levetiracetam” or “gabapentin” or “pregabalin” or “oxcarbazepine” or “benzodiazepine” or “cyproheptadine”) and (children or adolescents or pediatric population or youth).

Study Selection

Search results from the electronic databases were imported to Endnote X7 and duplicates were removed. Two independent reviewers performed title and abstract screening (when available) and then full-text screening of the included articles by using the predetermined eligibility criteria. The manual search of included articles by full-text screening was performed. The discrepancy among reviewers was resolved by discussion and guidance from a third reviewer (S.N.).

Data Extraction

The data were extracted independently by the authors and were cross-checked by discussion among the two reviewers. The data were extracted for author name, name of pharmacological agents, study design, sample size, duration, age range, dose ranges, measurement scales for primary outcome, clinical outcomes, and common side effects.

Results

The search of electronic databases and manual search generated 316 and 17 results, respectively. After the removal of duplicates and the title and abstract screening, the full-text screening was performed for 52 articles. After full-text screening, 32 articles were included. Of the 32 articles, there were eight RCTs, six open-label trials, two chart reviews, four case series, and 12 case reports, with a total patient population of 833. The medication groups included antidepressants, mood stabilizers, antipsychotics, alpha-adrenergic agents, and other pharmacologic agents such as beta-blockers, serotonin and histamine antagonists, and opioid agonists.

Antidepressants

Among the antidepressants, the efficacy of sertraline, fluoxetine, citalopram, and mirtazapine was assessed and is summarized in Table 1. The effectiveness of sertraline was evaluated in three RCTs. One RCT compared the effectiveness of the combination of sertraline and TF-CBT with TF-CBT and placebo.12 This study reported an improvement in PTSD symptoms in both groups with no significant difference between the combination group, TF-CBT, and placebo group. In two other RCTs, there was also no difference between sertraline and placebo for improvement in PTSD symptoms13,14 except that the parents reported improvement in PTSD symptoms in one of these RCTs.14

Summary of Studies Assessing for Use of Antidepressants for Pediatric PTSDSummary of Studies Assessing for Use of Antidepressants for Pediatric PTSDSummary of Studies Assessing for Use of Antidepressants for Pediatric PTSD

Table 1:

Summary of Studies Assessing for Use of Antidepressants for Pediatric PTSD

Fluoxetine was effective for PTSD symptoms in one RCT,15 but it failed to show greater effectiveness than TF-CBT in a long-term RCT.16 However, both fluoxetine and TF-CBT showed improvement in PTSD symptoms when compared with placebo.16 Two open-label trials assessed for the effectiveness of citalopram.17,18 In an open-label trial of citalopram, about 67% of patients were reported as responders, and a reduction in hyperarousal symptoms was observed.17 Another open-label trial also showed significant improvement in PTSD symptoms with citalopram.18 A case report suggested therapeutic benefits of mirtazapine in combination with fluvoxamine.19 Mirtazapine was effective in improving appetite, sleep, and anxiety.

Mood Stabilizers

Table 2 summarizes the evidence for mood stabilizers including lamotrigine, gabapentin, carbamezapine, divalproex, and lithium. Divalproex was effective for PTSD symptoms in patients with comorbid conduct disorder according to a secondary analysis of one RCT.20 High doses of divalproex resulted in a significant improvement of intrusion, avoidance, and hyperarousal symptoms compared to the low doses of divalproex.20 One retrospective chart review of 28 patients reported beneficial effects of carbamazepine in reducing symptoms of PTSD (79% of patients). These patients were using other psychotropic medications for comorbid psychiatric conditions.21 In a 15-year-old patient, the combination of gabapentin, lamotrigine, flunitrazepam, and fluvoxamine was effective for nightmares, flashbacks, and other core symptoms of PTSD.22 In a case series assessing efficacy of several psychotropic agents, lithium was beneficial for PTSD symptoms in combination with other antipsychotics.23

Summary of Studies Assessing for Use of Antipsycotics and Mood Stabilizers for Pediatric PTSDSummary of Studies Assessing for Use of Antipsycotics and Mood Stabilizers for Pediatric PTSDSummary of Studies Assessing for Use of Antipsycotics and Mood Stabilizers for Pediatric PTSDSummary of Studies Assessing for Use of Antipsycotics and Mood Stabilizers for Pediatric PTSD

Table 2:

Summary of Studies Assessing for Use of Antipsycotics and Mood Stabilizers for Pediatric PTSD

Antipsychotics

In a case series of five patients with comorbid bipolar disorder and PTSD, aripiprazole (n = 2) and olanzapine (n = 2) were reported to be effective in combination with lithium.23 In one patient with bipolar disorder and PTSD, aripiprazole was effective as a monotherapy.23 Due to ongoing aggressive behaviors, monthly injectable zuclopenthixol was added in addition to lithium and aripiprazole.23 Quetiapine and clozapine were effective for core symptoms of PTSD in a case series and retrospective chart review, respectively.24,25 In two case reports, risperidone26 and aripiprazole27 were efficacious for behavioral issues and intrusive symptoms of PTSD. Eye movement desensitization and reprocessing therapy was used in addition to aripiprazole in a case report of a patient with Asperger's syndrome and selective mutism by Ipci et al.27Table 2 summarizes evidence for antipsychotics for PTSD in children and adolescents.

Alpha-Adrenergic Agents

The evidence for alpha-adrenergic agents in children with PTSD is summarized in Table 3. In an open-label trial, guanfacine not only showed improvement in PTSD symptoms but also showed improvement in inattention and hyperactivity in patients with comorbidity with attention-deficit/hyperactivity disorder.28 Guanfacine improved nightmares in a case report without any side effects.29 The efficacy of prazosin was reported in a retrospective chart review,30 one case series,31 and four case reports.32–35 Prazosin resulted in improvement of PTSD symptoms, particularly sleep problems,30–35 avoidance symptoms,30,34 alteration in cognition and mood,30 hyperarousal,30,32,34 and nightmares.31–35 Clonidine was studied in an open-label trial36 and two case reports.37,38 The open-label trial of clonidine suggested favorable evidence for aggression, interaction with staff and peers, impulse control, emotional outbursts, mood lability, hyperarousal, hypervigilance, anxiety, oppositionality, insomnia, nightmares, dissociative symptoms, and repetitive play.36 Similar evidence for clonidine was replicated in two case reports.37,38

Summary of Studies Assessing the Use of Alpha-Adrenergic Agonists for Pediatric PTSDSummary of Studies Assessing the Use of Alpha-Adrenergic Agonists for Pediatric PTSDSummary of Studies Assessing the Use of Alpha-Adrenergic Agonists for Pediatric PTSDSummary of Studies Assessing the Use of Alpha-Adrenergic Agonists for Pediatric PTSDSummary of Studies Assessing the Use of Alpha-Adrenergic Agonists for Pediatric PTSD

Table 3:

Summary of Studies Assessing the Use of Alpha-Adrenergic Agonists for Pediatric PTSD

Other Pharmacological Agents

The evidence for opioid agonists (morphine), beta-blockers (propranolol), and the serotonin-histamine antagonist is summarized in Table 4. In an open-label study focused on prevention of PTSD, the correlation of morphine dose with the improvement in arousal symptoms was reported, but it was nonsignificant for other symptoms of PTSD.39 Our search found one RCT,40 one open-label trial,41 and one case series.42 There was no significant difference between patients taking propranolol and a control group in terms of remission of PTSD symptoms in an open-label RCT.40,41 The open-label trial assessed for efficacy of propranolol for prevention of PTSD in children with burns.41 A case series of 11 patients reported improvement in PTSD symptoms, which was reflected by the mean scores on the PTSD inventory scale.42 One case report showed beneficial effects of cyproheptadine at a dose of 4 mg in reducing nightmares within 1 month of its use.43

Summary of Studies Assessing the Use of Miscellaneous Pharmacological Agents for Pediatric PTSDSummary of Studies Assessing the Use of Miscellaneous Pharmacological Agents for Pediatric PTSD

Table 4:

Summary of Studies Assessing the Use of Miscellaneous Pharmacological Agents for Pediatric PTSD

Discussion

This review article reports the evidence for the use of pharmacological agents in children and adolescents with PTSD. These pharmacological agents include selective serotonin reuptake inhibitors (SSRIs), mirtazapine, antipsychotics, mood stabilizers, morphine, propranolol, and cyproheptadine in case reports, case series, chart reviews, open-label trials, and RCTs.

In children and adolescents, the reactions to trauma can vary from patient to patient depending on the presence of different factors like the age of the child, gender, proximity to trauma, different types and severity of the trauma, family history, and support system.44 The reactions to trauma are attributed to prefrontal dysfunction and activated noradrenergic system.44 There is evidence of a higher concentration of norepinephrine in the cerebrospinal fluid (CSF) of patients with PTSD.44 It is consistent with increases in urine, plasma, and CSF catecholamines.44 This underlying pathology explains the reasons for the efficacy of numerous pharmacological agents with an effect on the adrenergic system and can help in selecting appropriate pharmacological agents for children and adolescents.

Among SSRIs, there is mixed evidence for sertraline, fluoxetine, citalopram, and mirtazapine. The review of the evidence suggests that SSRIs were comparable to TF-CBT in efficacy for PTSD in some studies, with favorable evidence for citalopram in an open-label trial18 and positive parental feedback for sertraline in an RCT.14 However, this response can be attributed to a possible improvement in depressive symptoms, suggesting use in patients with comorbid depressive or anxiety disorders. This limited evidence is important in the context of possible activation (eg, agitation, anxiety), increased irritability, poor sleep, and inattention due to SSRIs. The current recommendations of the American Academy of Child and Adolescent Psychiatry suggest insufficient evidence for the use of SSRIs alone for pediatric PTSD.45 Mirtazapine, a non-activating antidepressant, was found to be effective for insomnia and nightmares at lower doses.19 This can be attributed to presynaptic alpha-adrenergic activity.

The effectiveness of anti-adrenergic agents including clonidine, guanfacine, and prazosin is suggested to be due to underlying heightened noradrenergic activity in patients with PTSD. These pharmacological agents were well tolerated in these studies. However, this evidence is limited to open-label trials, chart review, and case reports, indicating a need for well-designed RCTs. Cyproheptadine was effective for nightmares and insomnia, which is consistent with the conclusion from a previously conducted systematic review.46 The effectiveness of anti-adrenergic agents can be explained by the heightened stress response and noradrenergic systems in the body. This increased nor-adrenergic tone has increased the interest of clinicians and researchers for the use of these pharmacological agents.

The antipsychotic drugs risperidone, aripiprazole, quetiapine, clozapine, and olanzapine were effective in patients with PTSD for aggression, intrusive thoughts, and hyperarousal symptoms. Lithium, divalproex, carbamazepine, lamotrigine, and gabapentin were effective for patients with PTSD. These patients were diagnosed with a comorbid disorder in addition to PTSD. The effectiveness of risperidone and quetiapine can be attributed to a higher alpha-adrenergic activity of these agents.47 The positive response with mood stabilizers can be attributed to a higher comorbidity of bipolar disorder, conduct disorder, and autism spectrum disorder. The choice for an appropriate pharmacological agent should account for the presence of another comorbid mood disorder and should weigh the benefits against undesired effects.

The proposed algorithm by Gilman et al.48 suggests the use of adrenergic agents, antiepileptic agents, and second-generation antipsychotics in patients with no or partial response to psychological treatments. Given the side-effect profile of mood stabilizers and second-generation antipsychotics, these pharmacological agents should be reserved for patients with significant safety concerns or aggressive behaviors.48 In patients with treatment-resistant PTSD, the argumentation with a different class of medications should be considered in addition to individual therapy and family therapy. Patients should be assessed frequently for the effectiveness of these pharmacological agents.48 SSRIs should be used cautiously in patients with comorbid anxiety disorders or major depressive disorder.

The authors emphasize the need for well-designed RCTs in children and adolescents with PTSD. The available evidence (18 studies) only reaches the threshold of level of evidence IV.49

Study Limitations

There were only four case series and 12 case reports mentioned in this review article. Another limitation of this review was the lack of the quantitative analysis to provide objective insight into the effectiveness of these pharmacological agents. Publication bias is a potential limitation of the case reports, as the case reports with negative findings are unlikely to be published.50 This review has a higher risk of publication bias due to a higher number of case reports and case series. We recommend clinicians consider these limitations when choosing a pharmacological agent for their patients.

Conclusion

The existing literature has favorable evidence for the use of adrenergic agents, mood stabilizers, and second-generation antipsychotics in youth with PTSD. When prescribing appropriate pharmacological agents, the side-effect profile of antipsychotics and mood stabilizers should be kept in mind. SSRIs should be used cautiously in patients with comorbid anxiety disorders or major depressive disorder due to limited evidence.

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Summary of Studies Assessing for Use of Antidepressants for Pediatric PTSD

Study (year)Pharmacologic AgentDesignParticipants, nDuration, weeksAge Range, yDose Range, mgScale Used for Primary Outcome MeasureClinical OutcomeCommon Side Effects
Cohen et al.12 (2007)SertralineRCT24 TF-CBT + Sertraline = 12 TF-CBT + Placebo = 121210–1750–200 (mean dose = 150 mg/d)CPSSThere was no significant difference between both groups considering the remission of PTSD symptoms The only statistically significant difference was in CGAS scores among TF-CBT and sertraline group between week 3 and 5 The improvement between week 3 and 5 points towards onset of therapeutic effect of sertraline. Both groups observed significant improvement in their PTSD symptoms, depression, anxiety, and behaviorsOne child with previous history of ODD was admit-ted overnight during week 12 for running away No other side effects were reported
Robb et al.13 (2010)SertralineDB-RCTSertraline = 67Placebo = 62106–1750–200 Mean dose:Children = 96.2 ± 48.8 mg) Adolescents = 114.8 ± 52.1 mgUCLA PTSD-IThere was no difference between sertraline and placebo at any timepoint in study At week 10, the least-squares mean change was significant in placebo group compared to sertraline The post-hoc analysis suggested no correlation between end point improvement in the UCLA-PTSD-I total score and age or gender Younger patients were more likely to be males, and were treated with higher doses of sertraline A greater improvement was observed in non-white patients on UCLA-PTSD-1 scaleHeadache, nausea, vomiting, diarrhea
Stoddard et al.14 (2011)SertralineDB-RCT26 Sertraline = 17 Placebo = 9246–2025–150 (mean dose not mentioned)CPTSDI DICAThis study assessed for efficacy of sertraline in prevention of PTSD compared to placebo The mean change in child-reported DICA PTSD symptoms was not significantly different among both groups from baseline to study endpoint At follow-up, parents reported a greater improvement in sertraline group compared to placebo on DICA PTSD scaleNot reported
Martsenkovsky et al.15 (2015)FluoxetineDB-RCT1101212–1820–40 (mean dose not mentioned)CAPS-2The reduction in CAP-2 scores among patients taking fluoxetine was significantly greater compared to placebo at week 12 A greater percentage of patients were described as treatment-responders as measured by CGI scores in fluoxetine-treated patients compared to placeboSomnolence, headache, irritability
Martsenkovskyi et al.16 (2017)FluoxetineRCT11612 monthsChildrenN/ACAPS-5-CAThere was no significant difference among both groups (sertraline and TF-CBT) for PTSD symptom severity in this long-term study Both TF-CBT and sertraline were better than placebo This study suggested that the response to antidepressant in PTSD was related to future development of depressionNot reported
Seedat et al.17 (2002)CitalopramOpen-label trial8 (7 participants were analyzed)1212–1820CAPS-CAThere was a significant improvement in all participants from baseline to study end points on CAPS scores and CGI scores A mean reduction of 50 points (38%) in total CAPS scores from start to the endpoint of the study was notedSweating, nausea, headache, akathisia, tiredness
Seedat et al.18 (2001)CitalopramOpen-label trial24810–1820–40 (mean dose = 20.0 ± 3.53 mg)CAPSIn children and adolescent group, about 67% were classified as responders as measured by CGI scores and 5 participants minimally improved Among youth, a mean reduction of 42.9 points (54%) in CAPS total scores between baseline and endpoint was reported The children and adolescents reported an improvement in hyperarousal symptoms with a greater improvement at week 8 Among youth, there was significant reduction in CAPS at study endpointDrowsiness, headache, nausea, increased sweating, yawning, dizziness, insomnia, tremors, increased appetite
Good and Petersen9 (2001)Fluvoxamine and mirtazapineCase report1Last follow-up at 4 weeks8Mirtazapine = 7.5 mg Fluvoxamine dose amount was not mentionedNo scales were usedA favorable response to mirtazapine followed by partial response to fluvoxamine in a child suffering from PTSD An improvement in anxiety, sleep, and appetite was reportedNot reported

Summary of Studies Assessing for Use of Antipsycotics and Mood Stabilizers for Pediatric PTSD

Study (year)Pharmacologic AgentDesignParticipants, nDuration, weeksAge Range, yDose Range, mgScale Used for Primary Outcome MeasureClinical OutcomeCommon Side Effects
Steiner et al.20 (2007)DivalproexSecondary analysis of previous RCT71 (12 male participants had PTSD)7Age range not mentioned (mean age = 16)High dose= 500–1,500 mg/day (plasma level = 50–120 mcg/mL) Low dose = 250 mg/dayCGI-SPatient had comorbid conduct disorder and PTSD With divalproex, 42% of participants (n = 5) reported very much improvement, 34% much improvement (n = 4), and 25% (n = 3) minimal improvement The mean blood level was 71.5 mcg/mL and 15.6 mcg/mL in high-dose and low-dose group, respectively There was a significant improvement in core symptoms of PTSD (intrusion, avoidance, and hyperarousal) among high-dose group compared to low-dose groupGastrointestinal upset, sleepiness
Loof et al.21 (1995)CarbamazepineRetrospective chart review28 (12 girls, 16 boys)18 months8–17Carbamazepine (weight-based) = 300–1,200 mg/day Target blood level = 10–11.5 mcg/mLNo scale was usedAbout 50% of patients were diagnosed with comorbid ADHD, depressive disorder, ODD, or polysubstance use These patients were taking methylphenidate (n = 3), clonidine (n = 1), sertraline (n = 2), fluoxetine (n = 1), imipramine (n = 1) along with carbamazepine 22 out of 28 (79%) patients reported complete remission of their symptoms 6 participants reported significant improvement in their symptoms, with rare residual abuse-related nightmaresNot reported
Celik et al.23 (2012)Olanazapine, lithium, and aripiprazole (and zuclopenthixol administered monthly in one pateint)Case series56–8 months14–17Cases 1 and 2 = olanzapine 20 mg/d, and lithium 900 mg/day Case 3 = aripiprazole 20 mg/day Case 4 = lithium 900 mg/day, and aripiprazole 20 mg/day Case 5 = lithium 900 mg/day and aripiprazole 30 mg/day. Monthly zuclopenthixol was added due to aggressive behaviorsNo scale was used for PTSD symtpoms2 patients were diagnosed with comorbid bipolar disorder and PTSD 2 patients had SSRI-induced manic episode with one experiencing a manic episode later on, and one patient had family history of bipolar disorder All patients improved with the medications with an improvement in symptoms of PTSD and bipolar disorder In case 1, quetiapine 300 mg/day was found to be effective until it was discontinued by the patientNot reported
Kishimoto et al.22 (2014)Lamotrigine, gabapentinCase report1Unable to determine the duration Patient graduated from junior high school15Lamotrigine = 50 Gabapentin = 400No scale was used to measure PTSD symtpomsPatient was taking flunitrazepam 2 mg for hypnotic and analgesic effects at first She was started on gabapentin 400 mg for PTSD symptoms which disappeared after 3 days of medication initiation These symptoms re-emerged after she was questioned by the police (4 months after start of treatment) Patient was started on lamotrigine 25 mg/day due to re-experiencing symptoms, so lamotrigine was increased to 50 mg. Symptoms of PTSD resolved by week 3Not reported
Kant et al.25 (2004)ClozapineRetrospective chart review39Not mentioned12–1625–250 mg Mean dose = 102 ± 57 mg/dayNo scale was usedThere was significant reduction in the use of other medications while they were transitioned to clozapine Hallucinations, flashbacks, aggressive behaviors, and self-mutilation in patients with PTSD improved with clozapineWeight gain, sedation, hyper-salivation, constipation
Stathis et al.24 (2005)QuietapineCase series6615–1750–200TSCCQuetiapine resulted in an improvement in dissociative symptoms, anxiety, aggression, and depression No improvement in sexual concern symptoms was reportedMean increase in weight of 3.9 kg, transient daytime sedation
Keeshin and Strawn26 (2009)RisperidoneCase report110 months130.5 mg twice a day (one dose in morning and one dose at night)No scale was usedPatient was also taking divalproex 24 mg/kg twice a day and clonidine 0.15 mg at night. The serum concentration of divalproex was 112 mg/dL Risperidone was started at 0.5 mg twice a day, which resulted in improvement in intrusive symptoms Due to residual hallucinations and paranoia, risperidone was increased to 0.5 mg in morning and 1 mg at night However, the dose of risperidone was decreased to 0.5 mg twice a day due to unilateral breast tenderness and high prolactin level The breast tenderness resolved in 2 days after dose reduction Patient continued to report remission of symptoms with no hospitalization for a period of 10 monthsMild unilateral breast tenderness and increase in serum prolactin levels was 44 ng/mL
Ipci et al.27 (2017)AripiprazoleCase report1Unable to determine the duration6Dose not mentionedNo scale was usedPatient had a history of Asperger syndrome and PTSD and was started on aripiprazole and EMDR Treatment combination resulted in a decrease in compulsive behaviors and improvement in speech and behaviors Fluoxetine and risperidone were previously discontinued due to lack of effficacyNot reported

Summary of Studies Assessing the Use of Alpha-Adrenergic Agonists for Pediatric PTSD

Study (year)Pharmacologic AgentDesignParticipants, nDuration, weeksAge Range, yDose Range, mgScale Used for Primary Outcome MeasureClinical OutcomeCommon Side Effects
Harmon and Riggs36 (1996)ClonidineOpen-label trial7 preschool children2 years3–60.1–0.2 mg 0.1 mg at night (n = 2) to 0.05 mg twice a day and 0.1 mg at night Patch was used every 5 days in children to avoid initial sedative effectNo scale was usedClonidine was effective for aggression (n = 7), better relationship with staff and peers (n = 7), impulsivity (n = 5), emotional outbursts, mood lability (n = 5), hyper-arousal (n = 5), hypervigilance (n = 5), generalized anxiety (n = 5), oppositionality (n = 5), insomnia and nightmares (n = 5) It helped in decreasing repetitive play (n = 1) and dissociative symptoms (n = 1)Early sedation with oral clonidine Mild irritation and erythema (n = 2) with clonidine patch Post streptococcal glomerulonephritis with hypertension (n = 1)
Connor et al.28 (2013)Guanfacine extended-releaseOpen-label trial19 (but only 17 included for analysis)816–18Dose range = 1–4 mg Mean daily dose = 1.19 mg ± 0.35mg The weight adjusted dailly dose = 0.03 ± 0.01 mg/kgUCLA PTSD-RIA high percentage of patients had comorbid ADHD and PTSD About 82.4% of participants reported >30% reduced traumatic stress from the baseline as measured by the UCLA PTSD-RI 70.6% of participants had both >30% reduction of UCLA PTSD-RI scores and a CGI-I of 1 or 2 from baseline to study endpoint There was also improvement in inattention and hyperactivity domainsSedation, headache, dry mouth, dizziness/faintness A decrease in diastolic blood pressure
Keeshin et al.30 (2017)PrazosinRetrospective chart review342–305–181–15 mg, where n = 12 received >5 mg About 24% were treated with >0.1 (0.1–0.3) mg/kg of body weightUCLA-PTSD RIPrazosin was effective for PTSD symptoms with improvement on UCLA-PTSD RI from baseline to endpoint Prazosin also resulted in a significant improvement on sleep sub-scale with a similar improvement for PTSD symptom clusters including intrusion, avoidance, cognition and mood alteration, and arousal symptoms 14 patients were taking SSRIs and 2 were taking psychostimulants for comorbid diagnosis including depressive disorder (n = 11), anxiety disorder (n = 17), and ADHD (n = 3)
Oluwabusi et al.31 (2012)PrazosinCase series2Case 1 = 16 weeks Case 2 = 8 weeks16 and 15Case 1 took 1 mg in morning and 2 mg at night. Bupropion extended-release 300 mg was used in addition to prazosin Case 2 took 3 mg of prazosin and sertraline 100 mg was used in addition to prazosinNo scale was usedCase 1 Bupropion extended-release was helpful for core symptoms of PTSD Trazodone 150 mg was ineffective for insomnia and nightmares Insomnia and nightmares subsided within 3 weeks of initiation of prazosin The dose of prazosin was titrated to 1 mg in morning and 2 mg at night Case 2 This patient responded to sertraline 100 mg for core symptoms of PTSD The dose optimization of prazosin to 3 mg at night was helpful for nightmares and insomniaTransient dizziness during first week of treatment in second patient
Horrigan29 (1996)GuanfacineCase report1770.5 mgNo scale was usedClonidine was switched to guanfacine Guanfacine resulted in improvement in nightmaresNot reported
Porter and Bell37 (1999)ClonidineCase report12 years110.05–0.1 mg three times dailyNo scale was usedClonidine was successfully used in treating aggressive and sexualized behavior in a child with extensive abuse; also showed increased expression of emotional issues and decreased nightmares During follow-up visits, medications were stopped, which resulted in relapse of symptoms Behavioral symptoms improved with re-initiation of medicationsNot reported
De Bellis et al.38 (2001)ClonidineCase report1Indefinite period (>6 months)70.05 mg for 2 weeks, then 0.1 mg at night for rest of the periodCGASClonidine was effective in improvement of insomnia, intrusion, nightmares, decreased sleep latency, night awakenings, and increased sleep efficiency N-acetylaspartate/creatine ratios increased, a marker of neuronal integrityNot reported
Fraleigh et al.33 (2009)PrazosinCase report11.5 months; restarted with follow-up after 1 month1 mg initially then increased gradually to 1.5 mg16No scale was usedPrazosin was effective in decreasing the intensity and frequency of PTSD-associated nightmares and led to improvement in sleepNot reported
Brkanac et al.35 (2003)PrazosinCase report18151 mg and then gradually increased dose to 4 mg over 10 days in 1-mg incrementsNo scale was usedPatient previously took nefazodone 200 mg, trazodone 50 mg, and zolpidem 5 mg as needed at night, which were discontinued at admission Patient was started on mirtazapine which was increased to 45 mg Prazosin was started at 1 mg due to sleep disturbances and lack of improvement, and was gradually increased in 1-mg increments to 4 mg every night at bedtime Prazosin resulted in improvement in global functioning, sleep duration, and complete resolution of nightmares Mirtazapine was discontinued due to daytime sedation Patient also received psychotherapy in addition to medications
Strawn et al.32 (2009)PrazosinCase report11 month161 mg for first week then dose was increased to 2 mgCAPSAt the 1-mg dose of prazosin nightmares occurred less frequently and completely resolved at 2 mg Patient's sleep was restored to normal sleep latency and attenuation of hyperarousal symptoms without any effect on avoidant symptoms CAPS score decreased from 67 to 40Not reported
Strawn and Keeshin34 (2011)PrazosinCase report111 months71CGI-I and CGI-SPatient was diagnosed with ADHD and was taking dex-methylphenidate extended-release 10 mg Prazosin was very effective in reducing nightmare frequency and severity in less than 1 month from start of treatment Patient also reported a decrease in hyperarousal symptoms with restored normal sleep latency and decreased avoidant symptoms Patient had relapse of symptoms after 4 to 5 months without prazosin, which improved with re-initiation of treatmentWeight gain, increase in body mass index

Summary of Studies Assessing the Use of Miscellaneous Pharmacological Agents for Pediatric PTSD

Study (year)Pharmacologic AgentDesignParticipants, nDuration, weeksAge Range, yDose Range, mgScale Used for Primary Outcome MeasureClinical OutcomeCommon Side Effects
Nugent et al.40 (2010)PropranololRCT pilot29 (14 propranolol, 15 placebo10 days (follow-up at 6 weeks)10–182.5mg/kg/day (maximum dose = 40 mg twice daily)CAPS-CAAt follow-up visits, there was a nonsignificant decrease in PTSD symptoms among boys in propranolol group as compared to the placebo group However, girls in the propranolol group had higher PTSD symptoms than the placebo groupNot reported
Stoddard et al.39 (2009)MorphineOpen-label trial for prevention of PTSD70 (only 11 children were included in analysis)6 months was the maximum duration1–40.1–0.7 mg/kg/day Mean dose for whole sample = 0.63 mg/kg/day Mean dose of children included in analysis = 0.41 mg/kg/dayCSDC-BThe relationship between the average morphine dose and PTSD symptoms was not statistically significant; however, the correlation between morphine dose and reduction in arousal symptoms was statistically significantNot reported
Rosenberg et al.41 (2018)PropranololOpen-label trial for prevention of PTSD202 (89 propranolol, 113 non-propranolol)The mean duration of treatment was 26.5 ± 19.8 days Data were collected over 2 years6–17Dose range = 0.36 ± 12.12 mg/kg/day Mean dose = 3.64 ± 3.19 mg/kgMAGICThere was no significant difference in prevalence of PTSD among participants in the propranolol and control groupsNot reported
Famularo et al.42 (1988)PropranololCase series114-week trial with medication followed by 3 weeks without medication6–120.6–2.2 mg/kg/dayChildhood PTSD inventory scoreThere was a significant difference in mean scores on PTSD inventory scale over the three time periods Post hoc tests results suggested a noticeable improvement with medication from baseline to study endpoint and a significant decrement after treatment when compared with during treatmentMild decrease in blood pressure and pulse (n = 2), sedation (n = 1)
Gupta et al.43 (1998)CyproheptadineCase report16 months follow-up after starting treatment94No scale was usedResolution of nightmares was noticed at 4 mg of cyproheptadine within a month. This improvement was observed for the duration of follow-up. Patient was also successfully treated for ADHD with methylphenidate Diphenhydramine and trazodone were ineffective for this patientNot reported
Authors

Sadiq Naveed, MD, is an Assistant Professor of Psychiatry and Behavioral Sciences, University of Kansas Medical Center. Sabeeha Naazneen Shaik, MBBS, is a Medical Student, Kurnool Medical College. Amber Ehsan Faquih, MD, is a Research Assistant, Emory University. Vinod Kumar, MBBS, is an Associate Staff Physician, Cleveland Clinic Pakistan. Fatima Motiwala, MD, is a Resident Physician, Texas Tech University Health Sciences Center.

Disclosure: The authors have no relevant financial relationships to disclose.

Address correspondence to Sadiq Naveed, MD, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160; email: snaveed@kumc.edu.

10.3928/00485713-20200330-01

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