Separation Anxiety Disorder

Etiology

The etiology of most psychiatric conditions involves various degrees and types of biological, psychological, and social contributors. Although psychological factors particularly impact the development of anxiety disorders, there are multiple biological components to pathological anxiety. The study of inheritance patterns has revealed a general familial aggregation among major anxiety disorders.[10] Twin studies have demonstrated stronger inheritance patterns for monozygotic twins than dizygotic twins, suggesting a genetic component to the development of pathological anxiety.[11] Although the study of anxiety and gene-environment interactions is limited, it is known that epigenetic mechanisms, particularly DNA methylation, contribute to mediating transcription factors for stress-related genes, which may underlie the development of pathological anxiety.[12]

Behavioral scientists have contributed significantly to uncovering the psychological mechanisms contributing to anxiety, specifically separation anxiety. Conditioned responses of learned fear are more significant among anxiety-disordered individuals compared to controls, with an explanation of 2 likely mechanisms: first, there is greater excitatory conditioning to danger cues, and second, there is impaired inhibitory conditioning to safety signals.[13] Attachment theory describes a child's requirement to develop a relationship with a caregiver for normal social and emotional development. In attachment theory, there are 4 main attachment styles: secure attachment, anxious-avoidant attachment, disorganized attachment, and anxious-ambivalent attachment. Anxious-ambivalent attachment is the most common attachment style for those with SAD. A common symptom of anxious-ambivalent attachment is anxiety when the caregiver is absent and limited relief when the caregiver reappears.[14]

Evolutionarily, normal separation anxiety likely provided survival benefits given the human species' altriciality.[15] Separation anxiety is a universal phase of human development that typically emerges at or before 1 year of age, peaks between 9 to 18 months, and phases out by approximately 2.5 years. The re-emergence of transient separation anxiety is common in children when they enter school for the first time, which may be considered a normal response. However, conditioning this response can lead to the development of SAD, particularly when conditioned over multiple weeks.[13] Parenting behaviors implicate cross-generational influences on the development of childhood anxiety. These parenting behavioral systems include vicarious learning, social referencing, and modeling of parental anxiety. Further, overly protective and overly critical parenting styles, parental response to child anxiety, and family accommodation of a child's anxiety all contribute to the conditioning and development of childhood anxiety.[16] Children of parents who suffer from depression and anxiety disorders are at a higher risk of developing a depressive or anxiety disorder.[17]

Epidemiology

Anxiety disorders are among the most common pediatric mental health disorders, with an estimated prevalence of 5 to 25% worldwide.[18] SAD is the most frequently diagnosed childhood anxiety disorder, said to account for 50% of the referrals for anxiety-related mental health treatment.[18] The prevalence of SAD is estimated at 4% in population-based studies, with an increase to 7.6% in pediatric clinical samples.[9] Clinical data suggests that 4.1% of children exhibit a clinical level of separation anxiety, with approximately one-third persisting into adulthood if left untreated.[18] The average onset age is approximately 6 years, making it 1 of the earliest anxiety disorders to present in children.[9] In a United States-based study, SAD was found to have the highest lifetime prevalence at 6.7% of all anxiety disorders when specific and social phobias are excluded.[19] The lifetime prevalence of adult SAD is 6.6%, with 77.5% of the patients reporting onset in adulthood.[8]

Pathophysiology

Neuroanatomically, the amygdala is classically associated with provoking a fear response when stimulated. The amygdala and other fear-related neurocircuitry may share a similar neuroanatomy to anxiety neurocircuitry.[20] The amygdala and its connections to the frontal cortex (perirhinal cortex, ventrolateral prefrontal cortex, anterior insula) have received the most attention.[21] As the amygdala is part of the limbic system, other limbic system structures likely contribute to the development of anxiety, with a specific interest in the hippocampus as it plays an integral role in fear learning and extinction.[22] Functional magnetic resonance imaging studies have found that hypofunction of the prefrontal cortex and anterior cingulate cortex is associated with emotional dysregulation and cognitive dysfunction in those with anxiety.[23]

The activation of fear neurocircuitry, with presumed anxiety neurocircuitry overlap, involves the release of various neurochemicals that lead to sympathetic stimulation. Classically characterized as a "fight-or-flight" reaction, this sympathetic response evolved to be adaptive and for a prompt behavioral response to avoid actual or perceived danger.[1] However, this response can be conditioned to over-activate, leading to pathological anxiety even when exposure to threat is low or should be low.[13] There are many neurochemicals involved in producing a fight-or-flight response, including norepinephrine, epinephrine, cortisol, neurosteroids, and vasopressin.[24] Dopamine likely has a modulatory role in producing anxiety-like behavior.[25] Low activity of postsynaptic serotonin 5-HT1A receptors contributes to pathological anxiety, which has led to the development of pharmacotherapy attempting to modulate these receptors to reduce anxiety.[26]

History and Physical

A child's caregiver generally prompts the exploration of potential SAD because the child is "inseparable," causing interference with a major life activity of either the caregiver or the child. Investigating the impact of the child's behavior on the major life activity (ie, school or home life) can be used to obtain information on where symptoms most often occur and their severity. Academic performance is the life activity most frequently impacted by childhood SAD. If SAD is not the primary concern of the caregiver, it is still essential to investigate the child's academic performance.[27] Inquiring about all settings where separation anxiety occurs, age at symptom onset, and if symptoms worsen in any specific situation is essential. Caregivers should also be asked whether or not the child has verbalized catastrophization, including extreme fear that they may be kidnapped or seriously hurt in the caregiver's absence or if the caregiver have a serious illness, injury, or death in the child's absence.[27][28]

Obtaining a developmental and social history can clarify the diagnostic picture by providing context for the patient's risk factors for SAD. Inquiry into the child's living situation and relationship with his caregiver(s) can provide perspective if the patient experienced caregiver instability in early life and ultimately provide clues for the attachment style the child has developed with his current caregiver(s).[27] Obtaining a trauma history for the patient and caregiver to screen for sexual and physical abuse is essential, particularly if the child may have experienced an adverse event in the absence of a caregiver and fears this recurring. Although SAD is commonly a first-lifetime psychiatric illness, screening for past psychiatric history remains essential, mainly as children's anxiety disorders are often comorbid.[27] 

Obtaining a family psychiatric history may reveal a parent or caregiver with an anxiety disorder, which poses genetic loading and may be a source of behavioral modeling for the child to learn anxious behaviors. Developmental history can reveal whether or not the patient is currently at a developmentally appropriate stage for their age. If the patient is developmentally delayed, an in-utero and birth history should be obtained when possible. The patient's medical history can help differentiate between real physical pain and somatization from severe anxiety. Finally, when appropriate, interviewing the child alone may reveal first-hand the symptoms the child experiences.[27][28]

When interviewing an adult with potential SAD, understanding who the adult patient has difficulty separating from is a good starting point. If the patient has difficulty separating from a romantic partner, obtaining a history of the patient's dating history can be revealing.[29][30] Although important, caution should be used when obtaining a trauma history. Patients may find it difficult to speak about past physical and sexual abuse, particularly if it was from a past or current romantic partner. When appropriate and with patient consent, obtaining collateral information from the individual the patient has difficulty separating from can give more perspective on symptom severity.[8] The mental status examination is completed in psychiatric evaluations and has a variable presentation in SAD, but the following areas should be carefully considered:

• Behavior: How does the patient's behavior change when united and separated from their caregiver? Does the patient have anxious behaviors, such as constant movement, shaking, and small tremors? Are there clinging behaviors, such as requiring physical contact with the caregiver? 
• Speech: Is the patient's tone frightened when speaking about being separated from the caregiver? Does the patient ask for permission from the caregiver to speak?
• Affect: Is the patient always anxious or relieved when physically close to the caregiver?
• Thought content: Is catastrophization present (ie, thoughts of dying or the caretaker passing if separation is forced)? 
• Impulse control: Impulse control is expected to be poor for individuals with SAD.
• Insight: Insight for children is likely to be poor, but adults with SAD may be able to understand that their behaviors are maladaptive, and this should be assessed individually.

The transient re-appearance of separation anxiety when children first attend school is crucial in predicting the normal remission of separation anxiety versus the development of SAD.[13] Physical separation for children from parents to participate in academic settings is the most common prompt for identifying SAD. School functioning is generally significantly impaired by SAD, as many children may demonstrate disruptive behaviors until reunited with their caregiver or refuse to attend school altogether. An estimated 75% of children suffering from SAD have school-refusal behaviors.[18] These behaviors are variable but can include refusal to enter the school building once arrived, physically clinging to a parent, screaming when attempting to be separated, and vocalizing somatic symptoms such as a headache, "stomach ache," or other types of illness.[18] Due to the severity of separation anxiety, children may fall behind in coursework or have significant absence that impairs their ability to progress appropriately in school. Additionally, they may become isolated from school peers, and conflict may develop in the family if parents become frustrated by their child's condition.[18][31]

Separation anxiety can additionally occur in the home setting. Common manifestations at home include a child being afraid to be in a room alone, refusing to sleep alone, and shadowing or clinging to the caregiver's side. When the child is separated from the caregiver, similar severe anxiety can occur, including crying and screaming. These symptoms can become a significant burden for the caregiver, who may feel suffocated by their child's extreme demands for attention and decreased privacy.[18][31]

Another common SAD symptom is the pervasive worry that harm come to the caregiver if separated, leading to severe distress and nightmares. Similarly, the child may worry about becoming lost, kidnapped, or having an accident if separated from their caregiver.[18][31] When children are distraught and have a forced separation, they may show aggression toward the person separating them from their caregiver. When physically separated, adults with SAD likely resort to calling, texting, or using other technological means to communicate with their attached figure. Often, the person suffering from SAD is perceived as having excessive demands and can be a source of frustration for family members or the caregiver, leading to further resentment and familial conflict, perpetuating the course of the condition.[8]

Evaluation

Individuals with suspected SAD should be referred for a psychiatric evaluation, and if available, evaluation by a child and adolescent psychiatrist is optimal. The initial goals are to develop rapport with the patient, obtain detailed historical information from the patient and affected caregiver(s), and conduct a mental status examination. To make a formal diagnosis, evaluation for applicable DSM-5-TR diagnostic criteria should be performed. 

Separation Anxiety Disorder DSM-5-TR Criteria

1. Developmentally inappropriate and excessive anxiety when separated from whom the individual is attached, evidenced by at least 3 of the following:
   • Recurrent excessive distress with actual or anticipated separation from home or attachment figure(s)
   • Persistent and pervasive worry about losing the attachment figure(s) or possible harm befalling them, such as illness, injury, disasters, or death
   • Persistent and pervasive worry that an untoward event be experienced by the patient and lead to prolonged or permanent separation
   • Reluctance or refusal to go out, such as to school or work, because of fear of separation
   • Refusal to be alone at home or in other settings
   • Refusal to sleep without being near the attachment figure(s)
   • Repeated nightmares about separation
   • Repeated physical symptoms when separation occurs or is anticipated [8]
2. The symptoms must last at least 4 weeks in children and adolescents but typically occur for 6 months or more in adults.
3. The disturbance causes clinically significant impairment in a major life function (ie, academic or occupational functions).
4. The symptoms are not better explained by another psychiatric condition.

Screening Tools

Multiple screening tools for anxiety disorders in children exist and have wide availability and validation. When there is difficulty in obtaining the full diagnostic criteria from the interview alone, implementing a validated screening tool can be helpful in the diagnosis of SAD and in identifying possible comorbid conditions. 

Screen for Child Anxiety-Related Emotional Disorders (SCARED): SCARED is 1 of the most commonly used assessment tools for diagnosing anxiety disorders in children. SCARED is a child and parent self-report measure evaluated in numerous settings worldwide.[32] Various versions/revisions of the questionnaire have been developed. The most commonly used version consists of 41 questions. The total score is based on 5 subscale scores for the most common pediatric anxiety disorders: generalized anxiety disorder, social phobia, SAD, somatic symptoms/panic disorder, and school phobia. Each response is scored between 0 and 2, with a total score of 25 or higher having high sensitivity and specificity for discriminating between anxiety and non-anxiety disorders.[32] A 55% or higher reduction in the total score with treatment best predicts treatment response and a 60% or higher reduction in SCARED-parent scores predicts remission.[32] 

The SCARED assessment tool can be used free of charge with an acceptable time burden on clinicians and families, making it an excellent tool for diagnosing and managing anxiety disorders in children. SCARED cutoffs can also be used to guide treatment. For example, an insufficient reduction in the SCARED score after an adequate trial of behavioral therapy may indicate the need for pharmacotherapy.[32] Studies have shown some discordance in the information provided by the child and parent on this questionnaire without apparent contributory factors.[33] More research is warranted to understand the cause of "low informant agreement" and what factors contribute to this discrepancy. Still, the SCARED assessment tool is considered a stable, reliable, valid, and sensitive measure of anxiety despite the informant discrepancy, which interestingly also stays stable over time.[33] The SCARED screening tool has shown strict measurement invariance and solid test-retest reliability.

Separation Anxiety Avoidance Inventory (SAAI): SAAI is specifically designed to aid in diagnosing SAD. The SAAI child (SAAI-C) and parent (SAAI-P) versions have demonstrated good internal consistency, test-retest reliability, and construct and discriminant validity.[34] This assessment tool was also sensitive to treatment change with a substantial parent-child agreement. SAAI is a self-report questionnaire designed to assess the avoidance of 7 separation situations (when age-inappropriate questions are excluded). The severity of the avoidant behavior is rated on a scale of 0 to 4.[34] The disadvantage of SAAI is that it focuses exclusively on avoidance behaviors and neglects subjective aspects of worry and distress, which are core features of SAD.[35] 

Children's Separation Anxiety Scale (CSAS): The CSAS consists of 20 items grouped into 4 factors:

1. Worry about separation
2. Distress about separation
3. Opposition to separation
4. Calm at separation

The unique feature of this tool is the presence of a positive factor, "calm at separation." Validation studies report good internal consistency with good temporal stability and test-retest reliability.[35] The validation study reports that it is a reliable indicator of anxiety and differentiates anxiety symptoms from those of depression in children.[35] The authors also state that finding a weak relation with trait anger and no correlation with state anger supports the discriminant validity of the CSAS.[35] This study only analyzed child-reported surveys; the psychometric properties of the CSAS with clinical samples and validation of the parent version are still lacking.

Youth Anxiety Measure (YAM): YAM is a new parent-child questionnaire developed to assess anxiety disorder symptoms in children and adolescents according to the DSM-5. The scale consists of 2 parts: part I consists of 28 items and measures the major anxiety disorders, including SAD, and part II contains 22 items relating to specific phobias and agoraphobia.[36] The validation study for this questionnaire reports acceptable "face validity" with items successfully linked to the intended anxiety disorders and phobias. The authors report good internal consistency and reliability of the new measure with the parent-child agreement and concurrent, convergent, divergent, and discriminant validity.[36] An analysis of the psychometric qualities of the scale with the collection of normative data in non-clinical and clinical populations is still needed.

Anxiety Disorder Interview Schedule (ADIS): ADIS is a well-validated diagnostic interview suitable for measuring all anxiety disorders, mood disorders, and attention-deficit/hyperactivity disorders in children.[37] The ADIS is a semi-structured diagnostic interview that primarily assesses child anxiety disorders and the diagnoses are derived from interviews with both the child and the parent.[38] The interviews cover the entire range of anxiety-related disorders outlined by the DSM-5. Each diagnosis is assigned a clinician severity rating (CSR), a symptoms severity rating, and a functional impairment rating. A CSR of 4 or higher is required to provide a particular diagnosis. If the child and parent interviews yield different diagnoses and CSRs, the interviewer makes a composite diagnosis using recommended guidelines in the clinician manual. The ADIS's parent and child versions possess high inter-rater and test-retest reliability. One study reported almost perfect agreement on both the child and parent interview for diagnosing an anxiety disorder using ADIS. They also report almost perfect agreement regarding the severity of the primary diagnosis.[37] The ADIS is considered the gold-standard diagnostic evaluation for anxiety disorders. 

Pediatric Anxiety Rating Scale (PARS): PARS is a clinician-rated scale of anxiety severity using the frequency of distress symptoms, avoidance behaviors, and interference in daily functioning.[39] In a multisite study evaluating 128 children aged 6 to 17, PARS was shown to have high inter-rater reliability, adequate test-retest reliability, and fair internal consistency.[39] PARS scores are sensitive to treatment and parallel change in other measures of anxiety symptoms. This assessment tool has been validated in various populations and is frequently used worldwide in clinical and research settings.[40]

Treatment / Management

Appropriate treatment and management of SAD often depend on the symptom severity. In the case of mild symptoms, patient and parent education, support, and encouragement may be sufficient to help the patient resume normal activities.[41] Maintaining regular eating, sleeping, and exercise schedules and removing inconsistent routines should be encouraged. Anxiety symptoms should be reassessed with validated screening tools to monitor for changes.[41] When treatment is required, the recommended first-line therapy is cognitive behavioral therapy. Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed and are known to be successful at managing anxiety disorders; however, there are no medications with an FDA-labeled indication for SAD.[41] 

Cognitive Behavioral Therapy (CBT)

CBT is considered the first-line treatment for SAD and is an optimal choice for its efficacy and low risk of adverse effects. CBT should include techniques involving psychoeducation, changing maladaptive thought patterns, and gradual exposure to anxiety-provoking situations. Effective CBT typically requires 10 to 15 outpatient sessions (60-90 minutes each) to practice newly acquired skills at home. The treatment regime may be shortened or prolonged depending on the severity of symptoms and comorbid factors.[41] Notably, up to 44% of the pediatric population treated with CBT for anxiety disorders do not improve.[42]

Exposure therapy effectiveness is postulated to help increase the treatment response rate. Subjective reporting and heart rate measurements are unreliable indices of distress or emotional arousal during exposure. A reliable and alternate method of accurately measuring distress during exposure therapy is electrodermal activity (EDA). EDA is specific to sympathetic arousal and measures the activity of the eccrine sweat glands. Higher EDA indicates greater emotional and physiological arousal.[42] Physiological arousal during exposure therapy is the strongest predictor of treatment response. Physiological arousal negatively predicts the response rate, with 1 study reporting that high physiological arousal predicted poorer treatment response to brief CBT.[42] 

Combination Therapy with CBT and an SSRI

Although various reports describe improvement in SAD with pharmacotherapy, there are no medications with FDA-labeled indications to treat SAD, and high-quality (double-blind, placebo-controlled) studies are lacking. Some studies report CBT and SSRIs as equally efficacious for children with anxiety disorders; others report CBT to be superior to pharmacotherapy on some indices. More recent data suggest that combination treatment with CBT and SSRIs is more efficacious than either treatment alone, with as many as 81% of children with anxiety disorders who received sertraline and CBT being classified as responders compared to a 60% response rate for CBT alone and 55% response rate for sertraline alone.[41] Interestingly, patients receiving placebo pharmacotherapy had a 23% response rate.[41]

A randomized control trial published in 2008 reported the superiority of combination CBT and SSRI therapy, attributed to the synergistic effects of the 2 therapies.[43] The study included children with moderate-to-severe anxiety and did not report any significant adverse effects using SSRIs. They concluded that CBT and sertraline, either in combination or as monotherapy, were effective for treating childhood anxiety disorders, including SAD; however, combination therapy was superior to either alone.[43](A1)

Authors of a recent systematic review evaluating the comparative effectiveness and safety of CBT and various pharmacotherapies for childhood anxiety disorders reported that SSRIs and serotonin and norepinephrine reuptake inhibitors (SNRIs) improved anxiety symptoms when compared to placebo. The efficacy of benzodiazepines and tricyclic antidepressants (TCAs) was supported by insufficient or low-quality evidence for treating these disorders.[44] Benzodiazepines and TCAs are, therefore, not recommended for the management of childhood anxiety disorders.[45](A1)

Differential Diagnosis

The correct identification of the anxiety-inducing stressor is necessary to make an accurate diagnosis. In the case of SAD, the primary stressor is the patient being away from their attachment figure. The associated anxiety may manifest similarly to other anxiety disorders, which include generalized anxiety disorder, social anxiety disorder, specific phobia, and panic disorder. In addition, patients may present with multiple anxiety disorders. To assist with accurate diagnosis in children, using SCARED is recommended for assessment as it can differentiate various anxiety disorders from others.[46] Adults with SAD may have symptoms and traits related to borderline personality disorder, including fears of abandonment, anxiousness, and separation insecurity.[47]

Prognosis

A longitudinal study surveying anxiety symptoms in 242 participants with a mean age of 10 years found that 56% had an elevated SCARED score at 1-year follow-up and 32% had elevated scores at 3-year follow-up. Eight percent of the participants in this study had a fluctuating course.[48] Most studies report that anxiety disorders tend to have a chronic and unremitting course if left untreated.[41] With treatment, childhood anxiety disorders are believed to have a good prognosis[43], but long-term longitudinal data supporting this claim is limited.[49] A 4-year study evaluating adolescents and young adults with childhood anxiety disorders reported that only 21.7% of the patients were in stable remission, 48% relapsed, and 30% were "chronically ill" at the 4-year mark. The assigned treatment in the study (SSRI, CBT, SSRI plus CBT, or placebo) did not correlate with the likelihood of remission.[50] 

A 2013 meta-analysis states that a childhood diagnosis of SAD significantly increases the risk of panic disorder and other anxiety disorders in adulthood. The researchers found no association between SAD in childhood with major depression or substance use disorders in adulthood.[51] The latter finding is in direct contrast to other studies that suggest an association between childhood anxiety disorders and depression and substance use disorder in adulthood.[41][52] However, these studies did not investigate separation anxiety exclusively.

Complications

Childhood anxiety disorders are associated with school absenteeism and educational underachievement as young adults. Anxiety disorders also confer considerable functional impairment and economic costs due to lost caregiver productivity and treatment.[41][52] A recent study reported higher impairment in visuospatial working memory, semantic memory, oral language, and word writing in children with anxiety disorders. Approximately 83% of the children studied in this group had a diagnosis of SAD (after a formal diagnostic interview with a clinician), but most of the children had more than 1 anxiety-related disorder. Children with higher anxiety severity performed poorly in all tested fields, which included visuospatial working memory, inferential processing, word reading, writing comprehension, copied writing, and semantic verbal fluency. This study suggests memory and language deficits are present in some children with anxiety disorders, and the severity and number of anxiety diagnoses correlate with lower performance in memory and language domains.[40]

Recent studies have also suggested a link between SAD and adult personality disorders. One study found that adult patients with SAD and heightened early separation anxiety had higher rates of Cluster C personality disorder when compared to those without elevated early separation anxiety.[53] Additionally, fear of abandonment is an overlapping symptom with borderline personality disorder.[47] An anxiety disorder is also reported as a risk factor for suicidality, even after controlling for co-occurring mental health disorders and life stress.[54] Estimates of population-attributable risk suggested a 7 to 10% risk of suicidality in adolescent patients with anxiety disorders.[54]