Anxiety Disorders

This chapter provides a brief overview of the adjunctive role for psychotropic medications in treating anxiety disorders (AD) in people with Intellectual and developmental disabilities (IDD) and autism spectrum disorders (ASD). In this context, pharmacotherapy is part of a comprehensive treatment plan, rather than a stand-alone intervention. 

ADs are the most common psychiatric disorders among people with IDD.¹ The higher prevalence rates of anxiety reflect an imbalance between resilience, negative life experiences (including trauma) and other susceptibility factors.^2,3 Diagnostic uncertainty stems from cognitive and communication impairments, misinterpretation of baseline exaggeration, and diagnostic overshadowing.⁴ In people with severe/profound IDD, distinguishing AD subtypes is difficult, often limiting the diagnosis to unspecified AD (overlapping trauma or adjustment disorder), AD due to another medical disorder, and generalized anxiety disorders.^5-7

Anxiety is a ubiquitous emotional response and arises from environmental, temperamental, and psychosocial factors. Typically, anxiety is transient, follows a developmental trajectory, and does not cause significant functional impairment.⁸ Pathological anxiety is a step beyond, arising from trauma, early loss, family chaos, and significant skill/problem solving deficits.⁹ Anxiety presents as internalizing and externalizing symptoms without meeting full criteria for anxiety disorders. In at-risk children (genetically/environmentally at risk), ADs may also represent prodromal or subsyndromal forms of anxiety disorders. Progression to a full anxiety disorder is influenced by genetic risk, life stressors, and compromised resilience.¹

Anxiety disorders (AD) cause functional impairment and meet DSM-5-TR¹⁰ and/or DM-ID-2³ diagnostic criteria (see Table 1). People who meet criteria for ADs are more likely to respond to psychotherapies and adjunctive pharmacotherapies. People with transformed or complex AD frequently have a history of multiple diagnoses and polypharmacy because of persistent treatment resistance, creating obstacles for engagement in community programs.¹¹

People with complex ADs experience a reduced quality of life, intense emotional distress and suffering, a mixture of externalizing and internalizing patterns of behavior, as well as mood and psychotic-like symptoms, and chronic disruptive behaviors.¹² Their developmental histories frequently reveal early onset of symptoms, family and ecological dysfunction, adverse childhood experiences/trauma-related symptoms, and vulnerability to substance abuse. Many such individuals require extensive treatment interventions.

Treatment selection may also depend on the subtypes of anxiety. Current transdiagnostic approaches applying the research domain criteria are moving away from specific diagnosis to a shared trait and biomarkers approach to treatment.^13-15 This approach transcends the scope of this chapter, but Table 1 provides a glimpse into the process. 

Table Notes:

AD due to another medical condition, unspecified, and anxiety/trauma anxieties may fall within each of the categories above.

Trauma-focused interventions are important regardless of a documented history of adverse experiences and/or trauma.

• Positive psychology, interactive behavior therapy, CBT with modifications with/without exposure response prevention, and other systemic family/ecological psychosocial interventions are preferred frontline treatments.
• Current literature suggests that despite differences in types of etiology and presentation, various psychotherapies have similar response rates to frontline psychotropic medications (SSRIs and SNRIs).^2-3,16,18
• Combining therapies is a practical solution, but this may be a case-by-case decision.
• Psychological therapies are useful for bracketing pharmacotherapies – used prior to assess need, and as a tool in reduction/elimination strategies as a means of relapse prevention.

Pharmacotherapy^16-18

Meta-analytic studies also suggest that algorithmic approaches may be useful (see treatment algorithm for anxiety disorders). There are a variety of drug classes and possible mechanisms of action in treatments. The treatment algorithm does not address the problems associated with co-morbidities and issues with polypharmacy in medical, neurological, or psychiatric settings. 

• SSRIs and then SNRIs as first-line pharmacotherapy treatment. 
• If SSRIs or SNRIs are ineffective or intolerable, and diagnostic and pharmacokinetic parameters are not contributory, then interclass exchanges within tier 1 and/or moving to the next tier, or augmentation is next.
• Early during treatment, the decision to move down the algorithm or add adjunctive /augmentative strategies is on a case-by-case basis.
• CBT-ERP therapist, if not already on board, should be consulted and a referral to systems/ecologically minded psychotherapists. Conjoint therapy can be effective, but remission may be a long-term outcome.
• A common approach to non-responders to several medications(e.g., SSRIs) usually warrants a change to a less commonly utilized SSRI (fluvoxamine), clomipramine, or SNRIs.
• The second and third treatment tiers are frequently older treatments or those without sufficient research support. There are occasions when older treatments (tricyclics, benzodiazepines) can serve as replacements for ineffective SSRI/SNRIs.
• The third-tier treatments are consistent with a high degree of variability within AD drugs. They can be effective in general Anxiety and social anxiety disorders (performance specifier). The need for second and third tier treatments reinforces the biopsychosocial complexity of ADs in people with IDD.

Consensus Treatment Algorithm-Anxiety Disorders
TIER 1

• First Line Treatment: 1st and 2nd generation SSRIs (e.g., fluoxetine, sertraline) or SNRIs (e.g., duloxetine, venlafaxine)
• Short term benzodiazepines
• Beta-blockers (social anxiety-performance related)
• Buspirone

Treatment non-responders: review diagnoses and current team-based treatment plan

TIER 2

• Mirtazapine
• Pregabalin – pregabalin is used in limited fashion due to side effect profile
• Benzodiazepine and other GABA-Calcium channel mediating treatments
  3rd generation SSRI (e.g., vortioxetine)
• Tricyclic Antidepressants- clomipramine

Treatment resistance: define tier level and comfort zone. Do not hesitate to seek second opinions/consults. It is useful to refer for a second opinion.

TIER 3

• Reversible and standard MAO-A and B Inhibitors
• Valproic acid and other anticonvulsants
• 2nd and 3rd generation antipsychotic augmentation
• Beta-blockers
• TMS, low dose NMDA antagonists, and somatic therapies

Phase 1. Interface between temperament, attachment, separation anxiety, and preventive interventions    

AK was a four-year-old male, referred by his parents who were concerned about acute school avoidance upon starting Pre-K. AK presented as shy with slow to warm up temperament, rarely speaking outside the family setting. His medical history included: premature birth at 32 weeks, significant intrauterine growth retardation, mild cerebral palsy (left side weakness), and articulation disorder. Early intelligence testing suggested borderline/mild ID. Family history was positive for panic disorder in Ms. K. and mild OCD in Dr. K. Examination revealed mild delays in most motor milestones, mild spastic left hemiplegia, mutism, and mild separation anxiety. AK responded quickly to a brief school-based exposure-response prevention, graduated desensitization program, and speech therapy. There were no clear signs for short-term, adjunctive pharmacotherapy. 

AK’s presentation illustrates the importance of an adaptive and stable family system in matching temperament, attachment needs, and enhanced resilience in early childhood. It is important to understand the complex roles genetic risk, behavioral inhibition, articulation disorders, and neurodevelopmental issues can play in anxiety disorders. A positive family history of panic disorder and behavioral inhibition may contribute to separation anxiety, Selective Mutism and later onset anxiety and mood disorders.

Phase 2. Interface between loss and grief, increasing anxiety, and a panic attack in a child vulnerable to panic disorder   

The eighth grade presented new challenges for AK. First, his maternal grandfather died suddenly. Then in rapid succession, AK had his first panic attack, an intensification of worries about dying, and “not keeping up” at school. AK described worries about his mother’s sadness, his father’s constant worrying, and missing his sisters, who entered college. The mental status exam revealed significant grief response and growing anticipatory anxiety about another panic attack. The patient’s therapist noted similar findings. His working diagnosis was anxiety disorder (suspected panic disorder). CBT-ERP was less effective than hoped. At this point, his therapist and family agreed, and AK assented to a trial of sertraline. Within weeks, AK was euthymic and less anxious, but his sporadic nocturnal panic attacks persisted. After two years on sertraline and modified CBT, we slowly tapered then discontinued his SSRI but continued his CBT. 

Phase 3: Interface between transitions, worry, resurgence of panic attacks, and newly emergent seizure disorder  

AK did well off sertraline until the beginning of his final year in high school. In May, his father called to report an intensifying of his panic attacks and sleep episodes. AK described a “funny feeling” in his belly that “felt like a mouse running up chest” that anteceded his “scary spells.” His parents and soccer coach noted that AK “had an odd look” then froze for a few seconds before he started fumbling with his clothes. The episodes ended with a period of confusion. 

Clinically these ictal events suggested “complex partial seizures” intertwined with worsening anxiety. His paternal uncle, with complex partial seizures, responded extremely well to valproic acid (VPA). They consented to VPA, so we titrated doses to a serum trough level of 85 mcg/d. He was free of seizure activity, but his panic disorder relapsed with mild depressive features. On VPA his seizures improved, but his panic attacks and depressed mood persisted. We restarted outpatient CBT and titrated his sertraline to 200 mg/d. His mood improved over the next 2 months. 

Treatment: How to Get the Fly Out of the Bottle

The vignette highlights two issues:

1. The diagnosis and treatment of anxiety disorders require a longitudinal, systemic/ecological perspective for mapping his changing clinical status. 
2. The potential for diagnostic overshadowing of disorders can represent a two-way street. AD, neurodevelopmental, medical, and/or neurological disorders are not an either/or situation. Focusing exclusively on one or the other can backfire.

These caveats support the concept that diagnoses are working and evolving hypotheses, not written in stone.

This review provided an overview of AD in people with IDD and the role of pharmacotherapy in their treatment. SSRIs and SNRIs, along with several psychotherapeutic interventions are generally front-line, trans-diagnostic treatments that are effective across the spectrum of anxiety disorders (including comorbid or externalizing variants). 

In general, “starting low and going slow” is the most sensible approach but even at “therapeutic ranges,” prescribers can struggle with low remission, high relapse rates, and substantial numbers of non-responders to both psychotherapy and pharmacotherapies. One should remain cognizant that psychotropic medications are adjunctive treatments, and that their true value lies in the context of ecologically based interventions. 

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