CHAPTER 22

Anxiety disorders are a group of disorders categorized by excessive fear that results in behavioral disturbances and impairment in activities of daily living. Mood disorders are diagnoses of which a disturbance in mood, either depression or mania, is the underlying disorder that causes functional impairment as well as cognitive and somatic changes. Among youth aged 13 to 17 years, there is an estimated lifetime prevalence of 31.9% for anxiety disorders and 14.3% for mood disorders,1 as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).² In total, approximately 11% to 20% of children in the United States will have a behavioral or emotional disorder at any given time.³ These statistics indicate that behavior and emotional problems are common throughout childhood and begin early in life. Among all children meeting criteria for a behavioral or emotional disorder, anxiety and mood disorders are some of the most prevalent psychiatric conditions seen in children and adolescents.⁴ Anxiety and depressive symptoms at low levels, however, have been shown to have an evolutionary benefit.⁵ The absence of anxiety may lead to injury or death, as anxiety symptoms increase alertness and reduce the probability of missing potential threats. Withdrawing motivation and decreasing activity may allow a person to conserve his or her efforts in situations in which that energy would be wasted or worsen the situation.⁵ The challenge for busy primary pediatric health care professionals is to know when symptoms are transient, developmentally appropriate, or suggestive of a more significant anxiety and mood problem that is maladaptive and causing impairment in functioning across settings.

Primary pediatric health care professionals play an important role in promoting the social-emotional health of children (see Chapter 12, Social and Emotional Development), and they often serve as an entry point to behavioral health services and treatment. Because of frequent contact with families and the opportunity to see children and adolescents before symptoms have become frank disorders, primary pediatric health care professionals are well-positioned to assess the severity of a child’s problem, offer brief intervention and treatment, and assess the need for more intensive services. Ideally, primary care clinicians should feel competent to identify, manage, and advocate for children with anxiety and mood disorders and to know when to refer to developmental-behavioral pediatrics, child psychiatry, or other behavioral health professionals; however, this is not always the case. The reasons are multifactorial and include time limitations, reimbursement constraints, and lack of behavioral health professionals to whom patients can be referred to once identified.6 In a study survey of 832 pediatric primary care providers, 77% felt that the greatest barrier to treating mental/behavioral health problems was the lack of time.⁷ Nearly half of surveyed pediatricians reported lack of confidence in their ability to treat child mental/behavioral health problems due to lack of training in identifying such problems.⁶ To address this, there are increasing numbers of resources available to promote mental/behavioral health competencies.^8,9

The American Academy of Pediatrics (AAP) Task Force on Mental Health and the Bright Futures Periodicity Schedule recommends that mental/behavioral health surveillance questions be asked at all health care visits, including topics such as school performance and sleep hygiene.¹⁰ Standardized behavior rating scales can aid clinical judgment and often can be incorporated into pediatric primary care settings. These scales are not designed to make a diagnosis but to help the primary care clinician determine whether there is a problem requiring further exploration.

History and key questions are often the most useful way to begin to assess the severity of a behavioral problem. Although caregivers may be able to report accurately on behaviors that are observed, children should be directly interviewed, as they are most qualified to describe mood and/or anxiety symptoms, and sometimes these feelings have not been previously disclosed. In addition, input from people actively involved in the child’s life outside of the home environment, such as teachers, is extremely useful in allowing the primary pediatric health care professional to have a better understanding of the impact of these symptoms on a child’s daily functioning.

Parents and children may be reluctant to bring their anxiety and depressive symptoms to the attention of a medical professional due to concerns of being “labeled” with a mental health disorder or fear of being treated with medication; however, adolescents report an increased willingness to disclose mental health information if their confidentiality is assured.¹¹ Low emotional competence in the adolescent or child, which is defined as the ability to manage and express emotions and negative attitudes related to seeking professional help, is also another barrier to a person’s willingness to disclose information about mental health problems.¹² Additionally, parents have decreased recognition of the significance of the child’s distress and the impact it is having on the child, especially as these are internalizing symptoms.¹³ Family dysfunction and parental psychopathology, such as maternal depression, may also influence the presentation of the child’s symptoms more negatively. Therefore, primary pediatric health care professionals must convey an interested and nonjudgmental attitude toward their families in order to encourage the child or adolescent and parent to share their concerns.¹⁴

Anxiety Disorders

Anxiety disorders are a group of disorders categorized by excessive fear resulting in behavioral disturbances and impairment in activities of daily living. Fear is defined as an emotional response to a real or perceived imminent threat. Anxiety is the anticipation of a future threat.2 While it is common for children to experience fear or anxiety transiently, children with anxiety disorders overestimate and misperceive the danger of situations they fear, and these fears persist in an excessive way beyond developmentally appropriate periods.¹⁵ Age-typical anxiety and fear in childhood tends to follow a developmental sequence. Young children develop attachment to their caregivers early in life and experience normative fears at separation, such as at bedtime or when being dropped off at child care or preschool. As children begin to explore the environment around them, fear of animals or objects in their environment develops as a protective response.¹⁶ When children enter school and engage in more complex peer interactions, performance and social fears emerge. While children with age-typical fears will try to avoid or escape triggers that provoke their anxiety, children with anxiety disorders often go to extreme lengths.

The presentation of anxiety disorders can vary, and children may present in less expected ways. For example, they may present with somatic complaints, such as stomachaches, headaches, and nausea, or they may present with irritability, oppositionality, or anger, particularly when they are confronted with their fear trigger. Children, particularly younger children, do not always recognize that their fear and worry are excessive, which can make detection of an anxiety problem more difficult.¹⁷

Epidemiology

Anxiety disorders are the most common psychiatric disorders presenting in children and adolescents, with prevalence rates as high as 20%,^17,18 and they are often the earliest mental health problems to emerge in children.¹⁹ Although preschoolers with anxiety disorders are often not recognized and may not be as clearly differentiated as in older children, overall prevalence rates have been reported to be similar to those in older children, with reported rates of 19.4%.²⁰ Anxiety disorders are often undertreated, with only 18% of adolescents with an anxiety disorder receiving treatment.²¹ Obsessive-compulsive disorder (OCD) affects approximately 1% of children, and this increases to up to 4% in late adolescence.²² The prevalence rates for posttraumatic stress disorder (PTSD) vary but have been estimated to be between 3% and 6% in an unreferred population.²³ In children with a history of sexual abuse, nearly 50% may develop PTSD,²⁴ and approximately 5% of children develop PTSD after exposure to natural disasters.²⁵

There are a number of different types of anxiety disorders. Obsessive-compulsive disorder, which had been included within anxiety disorders in prior iterations of the Diagnostic and Statistical Manual, is now in a new section in the DSM-5² (“Obsessive-Compulsive and Related Disorders”), and PTSD is now described in DSM-5 under the section of “Trauma and Stressor-related Disorders.”2 Despite their inclusion outside of “Anxiety Disorders” in the DSM-5, they are included within this chapter, as many treatments are similar for both.

Anxiety disorders may be differentiated from each other by situations that trigger the anxiety or fear. Separation and specific phobias emerge first, with performance anxiety and social phobia/social anxiety emerging later in childhood; these are followed by panic disorder and OCD in adolescence. Generalized anxiety disorder is the most common type of anxiety disorder, and panic disorder and agoraphobia are the least common.¹⁸ The gender profiles of the different anxiety disorders vary over childhood. Overall, anxiety disorders and PTSD are more prevalent in girls compared to boys, with prevalence ratios reaching 2:1 to 3:1 by adolescence.^2,23

Anxiety disorders tend to be enduring, and more than three-quarters of young adults with psychiatric disorders report first having a diagnosis between the ages of 11 and 18 years.³ A specific anxiety disorder may persist or change to another anxiety disorder later, or there may be a syndrome shift to multiple anxiety disorders, depression, and/or substance use disorders. Preventing this “cascade of psychopathology” is one key reason for early recognition and treatment.²⁶

Comorbidity within anxiety disorders and between other psychiatric disorders is common. In a recent population-based study of preschoolers, approximately 23% of children met criteria for 2 anxiety disorders, and 8% met criteria for 3. Preschoolers with generalized anxiety disorder were most likely to have a co-occurring anxiety or nonanxiety disorder.²⁰ The literature often refers to the “pediatrics anxiety disorder triad,” which consists of generalized anxiety disorder, social phobia/social anxiety disorder, and separation anxiety disorder, as these tend to co-occur, have similar trajectories, and respond similarly to pharmacological and behavioral treatment. In a study that examined the comorbidity of 1,035 adolescents between 12 and 17 years old, the comorbidity rate within anxiety disorders was 14.1%, and it was 51% for other psychiatric disorders, such as depression, somatoform disorders, and substance use disorders, with depression being the most common.²⁷

There are many risk factors for developing an anxiety disorder. There is significant heritability, and some studies have indicated that children of parents with an anxiety disorder are 7 times more likely to develop an anxiety disorder than children whose parents have no mental health disorder.²⁸ Recent studies suggest that genes account for as much as 30% of the variance in childhood anxiety. Temperamental factors, such as shyness or behavioral inhibition, which also have a genetic component, also play a role. Additional factors associated with developing an anxiety disorder include insecure attachment, parental characteristics that include overprotection, lack of warmth, significant criticism, parental negative beliefs about a child’s coping ability leading to low expectations and high accommodation, and environmental factors, such as living in poverty or high psychosocial stress.²⁸ Risk factors for the development of PTSD include childhood characteristics, including IQ and temperament, early environmental conditions, such as loss of a parent before 1 year of age, self-perception of the severity and impact of the traumatic exposure, and genetic predisposition.29,30

Etiology and Pathophysiology

The etiology of anxiety disorders is almost always multifactorial. Although there are clear genetic underpinnings, developmental and psychosocial vulnerabilities, as well as acute and chronic stressors, contribute to their genesis and presentation.

Many studies have investigated the heritability of anxiety disorders in familial and twin studies, and there is evidence that the brain-derived neurotrophic factor (BDNF) protein may play a role. The BDNF protein regulates neuronal survival, and lower levels of this protein have been associated with anxiety disorders.³¹ On neuroimaging studies, anxiety disorders are related to atypical activity of the prefrontal cortex–amygdala circuitry. Functional imaging studies have shown decreased activity in the right orbitofrontal cortex and anterior cingulate cortex and increased activity in the amygdala, which is linked to fear responses. In studies where subjects were shown pictures of faces with angry, disgusted, or fearful expressions, people with generalized anxiety disorder showed increased activation of the amygdala and decreased activation of the ventrolateral prefrontal cortex (VLPFC).³² Activity of the VLPFC has been shown to be inversely related to the severity of anxiety symptoms, and both cognitive behavioral therapy (CBT) and fluoxetine have been shown to increase activity in the VLPFC. Biological abnormalities in the levels of neurotransmitters in the central nervous system, such as serotonin, gamma-aminobutyric acid (GABA), dopamine, and glutamate, have been associated with anxiety disorders.³³ The exact mechanism in which brain neurotransmitter levels modulate anxiety symptoms has been unclear, and there have been many theories postulated. Although medications that prevent the reuptake of serotonin, thereby increasing serotonin levels, have been correlated with a reduction in anxiety symptoms, the exact mechanism of this is unclear.³³ Levels of GABA, the major inhibitory neurotransmitter, have been postulated to be lower in people with anxiety disorders.³⁴ Dopamine may increase amygdala activation, heightening anxiety symptoms; however, increases in dopamine have also been shown to reduce anxiety and result in positive feelings of self-efficacy and confidence.^35,36 Neurochemical studies have correlated glutamate and glutamatergic tone, the major excitatory neurotransmitter in the brain, in the anterior cingulate with symptom severity in generalized anxiety disorder.^16,36

Obsessive-compulsive disorder has been found to be familial in origin, with higher lifetime prevalence in people with first-degree relatives.³⁷ Neurobiological studies have revealed dysfunction in the orbitofrontal cortex, temporolimbic cortices, caudate nuclei, and thalamus, and recent evidence has suggested a larger network of cerebral dysfunction than previously appreciated.³⁸ Similar to non-OCD anxiety disorders, how neurotransmitters modulate OCD symptoms in the brain is not entirely clear.

However, increased levels of glutamate, a predominant excitatory neurotransmitter, have been found in the cerebrospinal fluid (CSF) of patients with OCD.39

Exposure to traumatic events in early childhood may have a lifelong effect on the functioning of the cortisol system and stress regulation that may increase the risk of PTSD later in life (see Chapter 3, Environmental Influences on Child Development and Behavior).

Changes from DSM-IV-TR to DSM-5

There have been several changes to the section on “Anxiety Disorders” in the DSM-5² from the DSM-IV-TR. In the DSM-5, OCD, PTSD, and acute stress disorder are no longer categorized under “Anxiety Disorders.” Separation anxiety disorder is now included in “Anxiety Disorders” and can now have an onset after age 18 years. There have also been changes to the diagnostic criteria for agoraphobia, specific phobia, and social anxiety disorder, along with changes in symptom duration requirements. In the DSM-5, anxiety symptoms need to be present for at least 6 months for everyone, not only for people under 18 years of age. In addition, in the DSM-5, what was previously known as social phobia is now called social anxiety disorder. Lastly, a new developmental subtype of PTSD, Posttraumatic Stress Disorder in Children 6 Years and Younger, is described and makes use of developmentally appropriate criteria for young children.

DSM-5 Categories and Definitions

– Separation Anxiety Disorder (F93.0)

Separation anxiety disorder is defined by excessive fear or anxiety when experiencing or anticipating separation from a caregiver (or someone the individual is attached to) that lasts at least 4 weeks in children and adolescents and 6 months or more in adults and causes significant impairment. The child may become socially withdrawn, exhibit sadness, or have difficulty concentrating on work or play. Children with separation anxiety disorder tend to restrict social experiences away from home or attachment figures, and there is often excessive worry of potential harm, such as illness, injury, disasters, or death, to the attachment figure. The child may also experience excessive worry about getting lost or being kidnapped, if separated from his or her attachment figure. Additional problems triggered by separation or fear of separation may include sleep disturbances (eg, refusal to sleep alone), repeated nightmares, and somatic symptoms (which may include headaches, stomachaches, nausea, and/or vomiting).

– Selective Mutism (F94.0)

Selective mutism is the persistent failure to speak in certain social situations, while speaking in other ones. The symptoms last longer than 1 month, and their onset is generally before 5 years of age. The child may speak at home or with immediate family members but may not verbally respond to others when spoken to. The failure to speak is not due to any underlying expressive language deficit, and the child does not have any speech disturbances. Selective mutism results in impairment of social communication, occupational, and academic achievement.

– Specific Phobia (F40.2XX)

– Generalized Anxiety Disorder (F41.1)

A child or adolescent with a generalized anxiety disorder worries excessively about routine life circumstances, multiple events, and/or activities for at least 6 months. These children or adolescents usually find it difficult to control their worries and have concerns related to their competence or quality of their performance, and whether or not others are evaluating them. They exhibit at least 3 symptoms that include feeling on edge, fatigue, difficulty concentrating, irritability, muscle tension, and sleep disturbance. Functional impairment is often secondary to the associated symptoms and the considerable time spent worrying.2

– Obsessive-Compulsive Disorder (F42)

A child or adolescent with obsessive-compulsive disorder has uncontrollable obsessions, which are defined as recurrent thoughts that are intrusive and unwanted, and compulsions, which are defined as repetitive behaviors or mental acts that he or she feels to the urge to repeat over and over. Obsessions and compulsions may be related to themes of contamination, symmetry, and fear of harm to oneself and others.

– Posttraumatic Stress Disorder (F43.10)

This occurs after exposure to one or more traumatic events—actual or threatened death, serious injury, or sexual violence—either by directly experiencing or witnessing the traumatic event, having the traumatic event occur to a close family member or friend, or having repeated exposure to the consequences of the traumatic event more than through electronic media alone. Children aged 6 years or younger may not experience the traumatic event themselves but may witness it. Symptoms include: (1) intrusion symptoms, such as re-experiencing recurrent and distressing memories and dreams, dissociative reactions, intense psychological distress, and/or marked physiological reactions; (2) persistent avoidance of associated stimuli; (3) negative alterations in cognition and mood associated with the traumatic event or feelings of detachment; and (4) marked alterations in arousal and reactivity associated with the traumatic event.

Anxiety Screening Tools

Structured and semistructured diagnostic interviews, self-report rating scales, and clinician-rated instruments are the most common methods for identifying and measuring anxiety in the pediatric population.⁴⁰ Screening questions should use developmentally appropriate language, have adequate psychometric properties, and be based on criteria as highlighted in the DSM. Ideally, information should be obtained from multiple informants, including parents and teachers.^17,41 For children 8 years or older, self-reported measures for anxiety may include the Multidimensional Anxiety Scale for Children (MASC) or the Screen for Child Anxiety Related Emotional Disorders (SCARED). Younger children should be screened with parent report measures or interviewed with the use of visual aids, such as a feeling or mood thermometer. Measures such as the Children’s Yale Brown Obsessive Compulsive scale,⁴² which is not particularly amenable to use in pediatric primary care, or the Obsessive-Compulsive Inventory– Child Version⁴³ can be used to assess for obsessive or compulsive symptoms.

It is often necessary for the clinician to ask questions specifically about trauma and symptoms of PTSD because children and adolescents are unlikely to volunteer information.44 Repeated evaluation over time may be necessary, as symptoms may present months or years after a traumatic incident.⁴⁴ School-based screening should be considered after community-level traumatic events.⁴⁵ There are several well-validated tools available that can be used by primary pediatric health care professionals for screening both trauma exposure and symptoms of PTSD, including the Child PTSD Symptom Scale, Traumatic Events Screening Inventory, and UCLA Child/Adolescent PTSD Reaction Index.

If the screening measures are positive for anxiety symptoms, the primary pediatric health care professional should determine which anxiety disorder might be present, the severity, and the degree of functional impairment. Instruments available to screen for anxiety disorders, OCD, and PTSD are detailed in Tables 22.1–22.3.

Differential Diagnosis

The differential diagnoses of anxiety disorders include hyperthyroidism, pheochromocytoma, migraines, medication side effects, excessive caffeine intake, attention-deficit/hyperactivity disorder (ADHD), other mental health problems, and/or learning disabilities.^4,17

Although the defining characteristic of PTSD is that it is triggered by a traumatic event, other mental health disorders may be preceded by trauma as well. An acute stress reaction refers to the development of fear behaviors lasting from 3 days to 1 month after a traumatic event and may be a precursor to PTSD. Depression and anxiety are often comorbid with PTSD. Specific phobias and dissociative disorders have also been known to occur in response to a traumatic event. Finally, any neurological damage that may have occurred due to the traumatic event should be assessed.

Treatment

Due to the shortage of mental/behavioral health professionals in almost all communities, primary pediatric health care professionals often need to become involved with the treatment and ongoing symptom reassessment of children with anxiety disorders. In follow-up studies of children who received treatment for their anxiety disorders, there was a decreased risk of developing another mental health disorder after 3 to 4 years.⁴⁶ Pharmacological and nonpharmacological options are available to treat anxiety disorders. In children with mild to moderate anxiety or OCD symptoms, CBT is the first recommended line of treatment,¹⁷ although evidence supporting CBT for children under 7 years old is lacking.^47,48 In children and adolescents with moderate to severe anxiety disorders or OCD, a partial response to psychotherapy alone, or complex comorbid conditions, a multimodal treatment approach is often needed. This approach includes pharmacotherapy, CBT, and family therapy.^17,22,49 Clinical trials in the Child/Adolescent Anxiety Multimodal Study (CAMS), which was a 6-year randomized controlled trial involving 488 children and adolescents between the ages of 7 and 17 years who had diagnoses of separation anxiety disorder, generalized anxiety disorder, and social phobia, compared the efficacy of pharmacotherapy (sertraline) alone, behavioral intervention (CBT) alone, or a combination of pharmacotherapy and behavioral intervention together. The results showed that combination treatment was more effective than monotherapy with pharmacotherapy or CBT alone.4,49 The Pediatric Obsessive Compulsive Disorder Treatment Study (POTS), a multicenter, randomized clinical trial of 112 children and adolescents with OCD who were 7 to 17 years old, was designed to compare the efficacy of sertraline treatment only, CBT only, and a combination of sertraline and CBT, or placebo. The results showed that monotherapy with either sertraline or CBT alone or combination therapy was more effective than placebo. As in the CAMS, combined treatment of sertraline and CBT was the most effective treatment.⁵⁰ There were comparable rates of improvements in patients who received either sertraline or CBT alone. For PTSD, trauma-focused cognitive behavioral therapy (TF-CBT) has the largest evidence base and is proven to be the most effective treatment for PTSD among all psychological therapies.⁵¹

Nonpharmacological treatment includes cognitive behavioral interventions, psychodynamic psychotherapy, and family therapy.15 Children with anxiety actively seek escape from and avoidance of their anxiety triggers in order to prevent distress. Cognitive behavioral therapy works by examining the relationship between cognitions, behaviors, and feelings.^21,52 Components of CBT include: (1) psychoeducation; (2) teaching children adaptive coping skills, such as relaxation techniques like deep breathing; (3) changing negative self-talk and distorted negative expectations; (4) exposing children through gradual desensitization to feared stimuli, so that they can tolerate and modify negative emotions; and (5) relapse prevention plans.¹⁷ The goal of CBT is to teach children to experience their symptoms and deal more effectively with them rather than to avoid or escape them.¹⁵ Cognitive behavior therapy performed individually or in a group setting is comparable and has been effective in treating anxiety disorders in children. Individual programs, such as Coping Cat, have been shown to be effective in treating children with anxiety disorders by reducing symptoms and functional impairment,⁵³ and these improvements have been shown to be sustained up to 1 year later.⁵⁴ Group cognitive behavior therapy, such as Social Effectiveness Training for Children, may offer opportunities for peer modeling and social interactions and has been beneficial for children with all anxiety disorders, especially social phobia.^21,48

Parents and families play an important role in the development and maintenance of child anxiety. The quality of the parent-child relationship and parenting behaviors have been associated with anxiety symptoms in children.²⁸ Nearly all parents of anxious children report accommodating their child’s avoidant and escape behaviors. Accommodation predicts symptom severity, degree of child impairment, family dysfunction and distress, and poor treatment outcomes.⁵⁵ Therefore, in treating childhood anxiety disorders, parental anxiety, parenting styles, and parent-child interactions need to be addressed. Both excessive accommodation or being overly demanding, which denies the child’s fear and delegitimizes the anxiety, need to be replaced with support, which acknowledges the child’s distress but also affirms confidence in the coping abilities of the child.

The first step of any treatment for PTSD is ensuring the child’s safety, as ongoing trauma can undermine any effective treatment.44 Treatment planning for PTSD should also incorporate appropriate interventions for comorbid mental health disorders, such as anxiety, depression, and substance abuse.⁴⁵ Psychotherapy remains the first-line treatment for children and adolescents with PTSD.⁴⁵ Trauma-focused cognitive-behavioral therapy has been shown to be effective in treating the core symptoms of PTSD, as well as trauma-related depression and anxiety.⁵¹ Trauma-focused cognitive-behavioral therapy utilizes exposure therapy and adds skill-building modules following the PRACTICE acronym: psychoeducation and parenting skills, relaxation skills, affect regulation skills, cognitive coping, trauma narrative, in vivo mastery, child-parent sessions, and enhancing future safety and development. There is evidence for the use of TF-CBT across a wide range of traumatic experiences, including sexual abuse, domestic violence, traumatic loss, and acts of terrorism.⁴⁴

For children who have experienced large-scale disasters or community violence, group CBT protocols, such as Cognitive-Behavioral Intervention for Trauma in Schools (CBITS), have been shown to be effective and provide a component of psychoeducation for teachers addressing the potential impact of trauma on classroom behavior and learning.⁴⁵

Involving parents in PTSD treatment is more effective than treating the child or adolescent alone. Parents and other family members need psychoeducation, as they may themselves have PTSD, feel guilty for not protecting the child, or may be inadvertently triggering a child’s symptoms with reminders of the trauma.⁴⁴ Child-parent psychotherapy is a dyadic therapy intended for children 3 to 5 years of age that combines elements of TF-CBT with attachment theory and is a relationship-based model for children who have experienced family trauma such as domestic violence.⁴⁵

– Pharmacotherapy

Due to the lack of research in the use of medications to treat childhood anxiety disorders, many medications used to treat children with anxiety disorders are considered off-label.⁴⁹ In 2014, duloxetine became the only medication approved by the US Food and Drug Administration (FDA) for the treatment of generalized anxiety disorder in children. However, multiple randomized trials of children and adolescents with anxiety disorders have shown reduction in anxiety symptoms with the use of selective serotonin reuptake inhibitors (SSRIs), including sertraline,⁵⁶ fluvoxamine,⁵⁷ paroxetine,⁵⁸ and fluoxetine⁵⁹ over placebo in children with generalized anxiety disorder, social phobia, and separation anxiety disorder^21,49 In addition, clinical trials of escitalopram,⁶⁰ citalopram,⁶¹ and duloxetine⁶² have been shown to be effective in decreasing anxiety symptoms in children versus placebo.²¹ In deciding which SSRI to use, it may be helpful for the primary pediatric health care professional to inquire about positive responses with SSRIs in first-degree relatives, as enzymes that metabolize the SSRIs may have a genetic disposition. The greatest safety evidence otherwise is for fluvoxamine, which had the highest rate of clinical response and tolerance in a comparison meta-analysis of 16 clinical trials. The results of this comparison study showed that the probability of efficacy in ascending order was placebo, venlafaxine (a selective serotonin-norepinephrine reuptake inhibitor [SNRI]), sertraline, paroxetine, fluoxetine, and fluvoxamine, with fluvoxamine being the most efficacious. In addition, fluoxetine, fluvoxamine, and paroxetine were better tolerated than sertraline and venlafaxine.63

The effects of SSRI medications may not be seen for 4 to 8 weeks, but early effects of SSRI medication have been reported in the first 1 to 2 weeks. If a child experiences absent or partial response with the maximum dosage for at least 6 to 8 weeks on the first SSRI, a second SSRI should be trialed.²¹ If a child fails a second SSRI at the maximum tolerated or recommended dose, a referral to a child psychiatrist or developmental-behavioral pediatrician should be considered. When remission is achieved, treatment should be continued for at least 6 to 12 months before consideration of discontinuing the medication. SSRI medications need to be tapered over a minimum of 1 to 2 months in order to avoid flulike symptoms, including agitation, dizziness, nausea, headache, and fatigue. These side effects are often reversed by resuming the preceding SSRI dose and decreasing the dose at a more gradual rate. SSRIs are typically well-tolerated, with the most common side effects being gastrointestinal (GI) symptoms, sleep difficulties, and sexual dysfunction. Gastrointestinal symptoms tend to be self-limited and are rarely severe enough to warrant discontinuation. More significant adverse reactions may include disinhibition, agitation, mania, or psychosis. Up to 2% of children taking SSRIs experience the emergence of suicidal thoughts and behaviors. There is an increased risk during the first 9 days of treatment or if the starting doses are higher than usual, confirming the need for close follow-up during the titration period.¹⁷ Clinicians should watch for the development of serotonin syndrome, a potentially severe adverse effect of SSRIs and SNRIs. Serotonin syndrome is a triad of mental status changes, autonomic hyperreactivity, and neuromuscular abnormalities and symptoms that can range from mild to life-threatening.⁶⁴ Most cases will present within 24 hours of the initiation or change in dosage. Guidelines for prescribing SSRIs are detailed in Table 22.4.

Selective serotonin-norepinephrine reuptake inhibitors, such as venlafaxine ER, have also been shown efficacious in the treatment of anxiety disorders; however, an increase in suicidal ideation has been noted.^4,65

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