Don’t worry, you’ve got this! Treatment of anxiety disorders in children and adolescents

Research examining the impact of COVID-19 on the mental health of children and adolescents indicates that depression and anxiety are prevalent, due in part to factors such as changes to routine, virtual online schooling, forced increase in time with parents and families, social isolation and loneliness.(1-3) In addition, children with a pre-existing mental health diagnosis are experiencing higher rates of clinical deterioration.(4) While a sharp decline in referrals for child and adolescent mental health services was observed initially, with the pandemic dragging on into a second year, mental health services are experiencing a rebound increase in referrals, and a so-called “echo pandemic” of mental illness looms.(5,6) With possible backlogs in access to mental health services, pharmacists may be fielding more inquiries from patients and families for advice on managing pediatric anxiety during the pandemic. Anxiety disorders are cognitive disorders characterized by excessive worrying, fear and rumination.(7) They are the most frequently occurring psychiatric disorders in children, with an estimated lifetime prevalence of 31%, of which simple phobias are the most common.(8) Anxiety disorders are more frequent in females; parental history of anxiety disorder and traumatic childhood events increase the risk for anxiety disorders in adolescence and adulthood.(7) Anxiety disorders: types, features and identification Anxiety disorders are heterogeneous, and include separation anxiety, specific phobias, selective mutism, social anxiety disorder, generalized anxiety disorder (GAD), panic disorder (with or without agoraphobia) and substance-induced anxiety disorder.(9) Table 1 lists the main features of each disorder.(7,9,10) Obsessive-compulsive and related disorders (OCD) and post-traumatic stress disorder (PTSD) share many features with anxiety disorders. They were categorized as anxiety disorders in older versions of the Diagnostic and Statistical Manual of Mental Disorders (DSM), but are now listed as separate DSM-5 categories.(9) Anxiety disorders are associated with increased risk of suicide attempt and comorbid major depressive disorder, substantial impairments in function and quality of life, increased healthcare utilization and decreased productivity.(8) More than one anxiety disorder may be present at any given time. Common comorbidities include major depressive disorder, bipolar disorder, attention deficit/hyperactivity disorder (ADHD), OCD, tic disorders, eating disorders and substance use disorders.(10) Separation anxiety, specific phobias and selective mutism typically begin in childhood, while social anxiety disorder, GAD and panic disorder typically start later in adolescence or adulthood.(8) OCD and PTSD may start in childhood, or any time thereafter.(8) Anxiety disorders are frequently undetected and therefore untreated. Early identification and starting effective treatment may reduce impairment in social and academic functioning, and reduce persistence of the anxiety disorder into adulthood.(10) Children may be unable to identify their emotional state as anxious, and instead may display avoidant, aggressive or regressive behaviours or somatic symptoms (e.g., frequent stomach aches) or experiment with alcohol and substance use.(7)Children also may not possess awareness or insight into the unreasonableness of their worries or level of functional impairment caused by the anxiety disorder.(7) Pathophysiology Neurotransmitters that mediate the symptoms of anxiety disorders appear to be the monoamines—norepinephrine, serotonin and dopamine—and the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). Other neurotransmitters and peptides, such as corticotropin-releasing factor may be involved. Peripherally, the autonomic nervous system, especially the sympathetic nervous system, mediates many of the symptoms.(11) Treatment The goals of treatment for the various pediatric anxiety disorder include: reducing the frequency, intensity and duration of anxiety symptoms; reducing the impact of anxiety symptoms on daily functioning; improving coping ability; preventing mortality (i.e., from suicide); and preventing or minimizing adverse drug reactions if pharmacotherapy is used. Choice of treatment depends on patient age, severity of illness, comorbidities (if present), availability or patient ability and motivation to access and participate in psychological treatments, and patient preference. Other factors to consider include patient insight and acceptance of their diagnosis, time to onset of symptom reduction, time requirement for psychological therapy, costs of psychological therapy and/or medications, potential for enduring benefits of psychological therapy, and risk of medication adverse effects.(8) Psychological treatments Psychological treatments such as behavioural therapy (BT) or cognitive-behavioural therapy (CBT) tailored to the specific disorder and individualized for each patient, are often the first intervention in most pediatric anxiety disorders of mild to moderate severity. For severe anxiety disorders, they should be employed whenever possible in combination with pharmacotherapy.(8,10) While there are often waitlists for accessing one-on-one or group CBT services, many youths with anxiety disorders can benefit from free resources available online (see Box 1). BOX 1: Anxiety Resources for Pharmacists and Families Antidepressant (and Anti-Anxiety) Medication Monitoring Form, Kelty Mental Health Resource Centre: Family-friendly monitoring form to track symptoms of anxiety and depression and treatment adverse effects http://bit.ly/KMH-monitor Anxiety in Children, Anxiety Canada: Anxiety resources and information for parents and youth, including symptom descriptions, videos and case vignettes, with link to free online CBT-based course (My Anxiety Plan) to help parents/caregivers “coach” anxious children. https://www.anxietycanada.com/learn-about-anxiety/anxiety-in-children/ Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders: BMC Psychiatry 2014 www.ncbi.nlm.nih.gov/pmc/articles/pmid/25081580/ COVID-19 Youth Mental Health Resource Hub: Educational support resources for youth including posters, pdf files and videos to help deal with mental health concerns during the pandemic. www.jack.org/COVID DrugCocktails.ca: Facts about the risks of mixing prescription medication (e.g., anti-anxiety meds such as SSRIs and SNRIs) with substances of abuse. Youth-friendly and professional versions. www.drugcocktails.ca Helping Anxious Children, HereToHelp: Quality information on mental health, mental illness and substance use problems.www.heretohelp.bc.ca/visions/anxiety-disorders-in-children-and-youth-n14/helping-anxious-children MindShift CBT App, Anxiety Canada: Free evidence-based anxiety relief using scientifically proven CBT-based strategies (for Android and iOS phones). https://www.anxietycanada.com/resources/mindshift-cbt/ Screen for Childhood Anxiety Related Disorders (SCARED) Tool, Child Version: Screening tool that covers more than 40 of the most common anxiety-related symptoms experienced by children and adolescents. www.shared-care.ca/files/SCARED_Child_Updated_June_2015.pdf Taming Worry Dragons, 4th ed (2009) and Worry Taming for Teens (2002): A creative and developmentally appropriate approach to CBT, designed to help anxious children learn how to cope with their worries. Available from: Odin Books www.odinbooks.com Pharmacological treatments SSRIs and SNRIs: With the exception of specific phobias, and to a limited extent, selective mutism, substantial evidence supports treatment of most pediatric anxiety disorders with selective serotonin reuptake inhibitors (SSRIs) and some serotonin–norepinephrine reuptake inhibitors (SNRIs).(10) Despite this evidence base, none of the available SSRIs or SNRIs are approved by Health Canada for treatment of pediatric anxiety disorders. For many children with anxiety disorders, pharmacological treatments are prescribed only for severe illness, or when BT/CBT is inaccessible or ineffective. Based on a meta-analysis of randomized controlled trials (RCTs) of SSRIs and SNRIs in pediatric anxiety disorders, evidence supports the use of fluoxetine for school refusal or mixed anxiety (i.e., the trial included patients with one of several possible forms of anxiety), sertraline for mixed anxiety or GAD, paroxetine for social anxiety, fluvoxamine for mixed anxiety, venlafaxine for social anxiety or GAD, and duloxetine for GAD.(12) The forest plot from this meta-analysis can be viewed online (http://bit.ly/anxietyMA).(12) Overall, SSRIs have a moderate to large effect size (magnitude of difference between treatment groups [usually active treatment vs. placebo]) and SNRIs have a small to moderate effect size for anxiety symptoms in short-term efficacy trials.(12) At present, no published positive RCT evidence exists for bupropion, citalopram, desvenlafaxine, escitalopram, levomilnacipran, mirtazapine, vilazodone or vortioxetine for the treatment of any pediatric anxiety disorder. Dosing of SSRIs/SNRIs is generally based on doses or dose ranges used in RCTs for pediatric anxiety disorders. Some trials enrolled patients as young as age seven, up to age 18. Many trials allowed flexible dosing based on clinician judgment. Dosing for children under age 12 is typically cautious and at the low end of the available dosing range, with gradual increases as tolerated. However, many adolescents will be titrated to doses that are comparable to those used in adults. Typically, weight-based dosing (mg/kg/day) is not used for SSRIs/SNRIs. For adolescents (like with adults), target doses of SSRIs/SNRIs for anxiety symptoms tend to be in the mid to higher end of the dosage range; this is in contrast to the approach used for treating depressive disorders, where SSRIs/SNRIs are typically prescribed in the lower end of the dosage range. Randomized controlled pharmacotherapy trials for child and adolescent anxiety disorders have typically examined benefits and risks over a six- to eight-week timeframe. The combination of CBT and pharmacotherapy has been shown to improve treatment response rates over either modality used alone.(13) Unfortunately, anxiety symptoms frequently recur following medication discontinuation, especially if patients are unable to effectively engage in CBT-based treatments. This may result in long-term medication use. For many children, anxiety disorders persist into adulthood, necessitating long-term treatment planning.(14) Benzodiazepines provide rapid-onset anxiolytic effects and may be useful for “as needed” or short-term management of acute anxiety symptoms not responsive to nondrug relaxation techniques, such as deep breathing, progressive muscle relaxation and guided imagery.(10) Caution should be exercised as benzodiazepines may cause paradoxical disinhibition reactions characterized by acute excitement and hostility in younger children or in patients with impulse control problems, neurological disorders (e.g., autism spectrum disorder) or learning disabilities.(15) Benzodiazepines for management of anxiety disorders in children and adolescents were not found to be effective in several small RCTs.(8) Alprazolam should be avoided due to pharmacokinetic and pharmacodynamic properties, which result in more severe withdrawal symptoms upon discontinuation, and because of documented concerns of substance misuse.(16) Lorazepam and clonazepam are the most common benzodiazepine choices for children and adolescents, although prescription patterns vary among prescribers and practice settings. When a benzodiazepine is prescribed for a child or adolescent, it should be for a limited duration (e.g., 2–4 weeks), and in conjunction with a plan for how and when the benzodiazepine will be safely discontinued. Possible benzodiazepine tapering schedules for adolescents are available from the 2013 Nova Scotia Adolescent Withdrawal Management Guidelines (http://bit.ly/NSAWMG-2013). Atomoxetine and guanfacine: The norepinephrine reuptake inhibitor and nonstimulant ADHD medication, atomoxetine, has been shown to significantly reduce symptoms of GAD, separation anxiety and social anxiety disorder in patients with comorbid ADHD in a 12-week RCT.(17) In a small pilot RCT, guanfacine extended-release modestly reduced symptoms of GAD, separation anxiety and social anxiety disorder in patients with comorbid ADHD, although results did not reach statistical significance.(18) Tricyclics: An older RCT of the tricyclic agent, imipramine, showed benefit over placebo when combined with CBT in the treatment of school refusal, while a trial of amitriptyline was not superior to placebo for treatment of functional abdominal pain in children and adolescents.(19,20) Due to risk for serious toxicity following intentional overdose and poor tolerance of adverse effects, prescription of tricyclic agents for treatment of anxiety in children and adolescents is uncommon in contemporary practice. One exception is clomipramine when prescribed in the setting of treatment-resistant OCD.(21) Other medications used for treatment of anxiety disorders in adults, which lack supporting evidence for use in children and adolescents, include buspirone (a 5-HT1A receptor agonist), gabapentin and pregabalin (alpha2-delta ligands of voltage-dependent calcium channels) and quetiapine (a second-generation antipsychotic agent).(8) Metabolic adverse effects of second-generation antipsychotics such as quetiapine may occur even with doses below those used to treat bipolar disorder or schizophrenia; routine use of quetiapine for treatment of anxiety disorders in children and adolescents is not recommended.(22,23) Suicidality and other adverse effects Warnings regarding treatment-emergent suicidality (which encompasses suicidal ideation, suicide attempt, preparatory actions toward suicide attempt and completed suicide) in children and adolescents are present in manufacturers’ product labelling for all current antidepressant/antianxiety treatments. In a meta-analysis of suicidality rates in RCTs of pediatric depression and anxiety, the observed net absolute increase in treatment-emergent suicidality rate with active treatment compared to placebo was lower in non-OCD anxiety disorders (0.88%) compared to major depressive disorder (1.27%).(24) Many of the common adverse effects experienced by children and adolescents during SSRI initiation and dose titration are similar to those experienced by adults, including headache, nausea, dyspepsia and increased sweating. However, close monitoring and follow up is required for symptoms of behavioural changes and activation following SSRI/SNRI initiation, especially in younger children or in those with comorbid illnesses (e.g., autism spectrum disorder); emergence of these symptoms during treatment may require drug tapering and discontinuation.(25) Pharmacist’s role Pharmacists may contribute to improving the health of children and adolescents with anxiety disorders by screening patients for the presence of anxiety disorders using the SCARED tool (Box 1). Development of adequate rapport with children and adolescents to ask these screening questions can sometimes be challenging, but even reviewing the screening tool with a parent or caregiver can validate that the symptoms the young person is experiencing are in keeping with a possible anxiety disorder and are worthy of clinical followup. Making youth and caregivers aware of the freely available online resources that can help ameliorate anxiety is important, given the current increase in demand for and wait time to access nonemergency psychiatric services. Pharmacists can greatly assist prescribers with selection and dose titration of pharmacotherapy to treat pediatric anxiety disorders that are either unresponsive to psychological therapy, or in situations where a child or adolescent is unwilling or unable to access psychological therapies. Pharmacists can also contribute by raising awareness of which therapies are safe, effective and appropriate choices for treatment of anxiety in children and adolescents. For patients starting treatment, pharmacists can suggest that parents and caregivers track both change in symptoms and possible side effects over time using an antidepressant/antianxiety monitoring form (Box 1). This form can be taken to follow-up visits with the prescriber to inform decisions regarding continuance of therapy, further dose adjustments or the need to discontinue or switch medications. Pharmacists are well placed to counsel patients and families about safe and effective use of pharmacologic treatments for pediatric anxiety disorders; important counselling points are presented in Table 2.(8,24,26,27) Summary Pharmacists may contribute to improving the health of children and adolescents with anxiety disorders via screening and referral to freely accessible resources, and by assisting prescribers with evidence-based selection, dosing and monitoring of pharmacotherapy when indicated. They also can have a positive impact by counselling patients and families regarding drug administration, expectations for medication onset, duration of treatment and management of adverse effects. Dean Elbe (delbe@cw.bc.ca) is a Board-Certified Psychiatric Pharmacist, a Clinical Pharmacy Specialist at the Healthy Minds Centre at BC Children’s Hospital (since 2007), an author and international speaker. He is the associate editor for psychopharmacology for the Journal of the Canadian Academy of Child and Adolescent Psychiatry, lead editor of the Clinical Handbook of Psychotropic Drugs for Children & Adolescents, 4th ed and was the project leader on the development of the www.DrugCocktails.ca website. References 1. Wagner KD. New findings about children’s mental health during COVID-19. Psychiatr Times 2020. https://www.psychiatrictimes.com/view/new-findings-children-mental-health-covid-19 (accessed March 18, 2021). 2. Loades ME, Chatburn E, Higson-Sweeney N, et al. Rapid systematic review: the impact of social isolation and loneliness on the mental health of children and adolescents in the context of COVID-19. J Am Acad Child Adolesc Psychiatry 2020;59:1218-39.e3. 3. Verlenden JV, Pampati S, Rasberry CN, et al. Association of children’s mode of school instruction with child and parent experiences and well-being during the COVID-19 pandemic — COVID Experiences Survey, United States, October 8–November 13, 2020. MMWR Morb Mortal Wkly Rep 2021;70:369-76. 4. Cost KT, Crosbie J, Anagnostou E, et al. Mostly worse, occasionally better: impact of COVID-19 pandemic on the mental health of Canadian children and adolescents. Eur Child Adolesc Psychiatry 2021;26:1-14. 5. Newlove-Delgado T, McManus S, Sadler K, et al; Mental Health of Children and Young People group. Child mental health in England before and during the COVID-19 lockdown. Lancet Psychiatry 2021:S2215-0366(20)30570-8. 6. Deolmi M, Pisani F. Psychological and psychiatric impact of COVID-19 pandemic among children and adolescents. Acta Biomed 2020;91(4):e2020149. 7. Elbe D, Black TR, McGrane IR, et al. Clinical handbook of psychotropic drugs for children and adolescents, 4th ed. Boston, MA: Hogrefe, 2018. 8. Katzman MA, Bleau P, Blier P, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry 2014;14(Suppl 1):S1. 9. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th edition, 2013. 10. Walter HJ, Bukstein OG, Abright R, et al. Clinical practice guideline for the assessment and treatment of children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry 2020;59:1107-24. 11. Bhatt NV. Anxiety disorders. Medscape. https://emedicine.medscape.com/article/286227-overview (accessed March 18, 2021). 12. Locher C, Koechlin H, Zion SR, et al. Efficacy and safety of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and placebo for common psychiatric disorders among children and adolescents. A systematic review and meta-analysis. JAMA Psychiatry 2017;74:1011-20. 13. Walkup JT, Albano AM, Piacentini J, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med 2008;359:2753-66. 14. Patel DR, Feucht C, Brown K, et al. Pharmacological treatment of anxiety disorders in children and adolescents: a review for practitioners. Transl Pediatr 2018;7:23-35. 15. Paton C. Benzodiazepines and disinhibition: a review. Psychiatric Bull 2002;26:460-2. 16. Alt-Daoud N, Hamby AS, Sharma S, et al. A review of alprazolam use, misuse and withdrawal. J Addict Med 2018;12:4-10. 17. Geller D, Donnelly C, Lopez F, et al. Atomoxetine treatment for pediatric patients with attention-deficit/hyperactivity disorder with comorbid anxiety disorder. J Am Acad Child Adolesc Psychiatry 2008;46:1119-27. 18. Strawn JR, Compton SN, Robertson B. Extended release guanfacine in pediatric anxiety disorders: a pilot, randomized, placebo-controlled trial. J Child Adolesc Psychopharmacol 2017;27:29-37. 19. Bernstein GA, Borchardt CM, Perwien AR, et al. Imipramine plus cognitive-behavioral therapy in the treatment of school refusal. J Am Acad Child Adolesc Psychiatry 2000;39:276-83. 20. Saps M, Youssef N, Miranda A, et al. Multicenter, randomized, placebo-controlled trial of amitriptyline in children with functional gastrointestinal disorders. Gastroenterology 2009;137:1261-9. 21. Geller DA, March J; AACAP Committee on Quality Issues (CQI). Practice parameter for the assessment and treatment of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 2012;51:98-113. 22. Pringsheim T, Panagiotopoulos C, Davidson J, et al. Evidence-based recommendations for monitoring safety of second-generation antipsychotics in children and youth. Paediatr Child Health 2011;16:581-9. 23. American Psychiatric Association. Choosing wisely: five things physicians and patients should question. https://www.choosingwisely.org/wp-content/uploads/2015/02/APA-Choosing-Wisely-List.pdf (accessed February 2, 2021). 24. Bridge JA, Iyengar S, Salary C, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment. A meta-analysis of randomized controlled trials. JAMA 2007;297:1683-96. 25. Luft MJ, Lamy M, DelBello MP, et al. Antidepressant-induced activation in children and adolescents: risk, recognition and management. Curr Probl Pediatr Adolesc Health Care 2018;48:50-62. 26. Gabriel M, Sharma V. Antidepressant discontinuation syndrome. CMAJ 2017;189:E747. 27. Lexi-Comp Online. Lexi-Comp online interaction analysis, Hudson, Ohio: Lexi-Comp; 2021; March 19, 2021.

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