Introduction

In recent history, autism has been identified in several gifted artists and scientists, although it’is more generally associated with severe and impairing conditions. Today, we talk about “autism spectrum disorder” (ASD), a definition that recognizes the heterogeneity and complexity of a lifelong condition, whose symptoms fall into a continuum and account for large variations from patient to patient. A number of medical and psychiatric comorbidities ranging from gastro-intestinal and autoimmune disorders, to ADHD, depression, OCD and anxiety disorders, contribute to challanges in assessment and treatment of this condition, which requires a multidisciplinar approach. 

Although anxiety is not considered a core feature of ASD, anxiety disorders are the most common comorbid conditions in these patients. Because of the great impact on the course of the disorder, recognizing anxiety and treating it properly is particularly important for the wellbeing of these patients. 

Core Aspects Of ASD And Their Clinical Presentation

As the Diagnostic and Statistical Manual of Mental Disorders- 5th edition states, the core symptom domains of ASD are constituted by deficits in social communication across multiple contexts (deficits in social-emotional reciprocity, non-verbal communication and developing relationships), as well as restricted, repetitive patterns of behavior and interests. 
These symptoms must be present in the early developmental period, however they may not become apparent until later in life.

• Deficits in social communication 
  • Atypical or absent eye contact is one of the first symptom observed in early childhood. Facial expressions may be difficult to read; vocal characteristics also appear to be atyical, such as monotonous, flat, exaggerated or inappropriate voice; atypical gestures may also be present, with a lack of pointing to orient other’s attention.  On the other hand, these children have troubles in reading facial expressions, gestures, and emotions in others; these difficulties along with language delays promote consequent difficulties in social interactions. 
• Repetitive patterns of behavior, restricted interests and resistance to change 
  • Children with ASD typically present with lack of interest in others, showing preference for objects that may be used in a nonplay stereotyped manner or for self stimulation, sometimes linked to unusual response to sights, sounds, smells or textures. Rigidity may encompass ritualistic habits (eg eating the same food everyday) and restricting interests, defined as unusually intense interest with an object or a topic that usually lead to activities with no functionality (eg because of a preoccupation with cars, memorizing all makes and models). Resistance to change is usually expressed with any deviance to routine (for example, during travel routes, if a detour is taken, children can act out with tantrum and self-injury).

When Do These Patients Seek Help?

The main reasons why patients with ASD seek help can be divided into two categories, reflecting two different subgroups of the disorder: 

• behavioral issues, such as aggression, irritability, self-injurious behaviors,  linked to the core aspect of repetitive behaviors and compulsivity; these issues especially concern the subgroup with intellectual disabilities and language difficulties.
• internalizing symptoms, such as depression and anxiety, that patients with ASD, especially those with “high functioning autism” may develop as a result of their insight but continued lack of social communication skills. 

Is Anxiety An Important Problem In Autism?
Although anxiety is not considered a core feature of ASD, 40% of young people with ASD have clinically elevated levels of anxiety or at least one anxiety disorder, including obsessive compulsive disorder. 
It is particularly important to recognize and treat anxiety in ASD since it has a great impact on the course and the core aspects of the disorder, exacerbating social withdrawal as well as repetitive behaviors. 
Moreover, while untreated comorbid anxiety has been associated with the development of depression, aggression, and self-injury in ASD, an early recognition and treatment may convey better prognosis for these patients. 

How Anxiety Arises In ASD And How To Recognize It
It’s not easy to recognize the presence of anxiety in patients with ASD, because of overlapping symptomatology and altered presentations of symptoms. 
Patients who are minimally verbal may be unable to report their internal states (eg worry) and instead demonstrate anxiety through disruptive behaviors, while others may be verbally fluent but present with difficulties in understanding ones’ own emotions and expressing these emotions. 

Typically, anxiety may present with different features at different times in the course of ASD and in association with different demands from environment:

• Specific phobia: a specific phobia, namely an intense, irrational fear of something that poses little or no actual danger, may arise early in the course of ASD because of over responsiveness to sensory stimulation, such as a loud environment; specific phobias in these patients usually involve highly unusual stimuli  (eg advertisement jingles, balloons popping, vacuum cleaners, toilet flushing, alarms at school..), but may also present fears (eg of the dark, insects, needles) that are typical of developing youth.
• Obsessive compulsive disorder:  characterized by unwanted and intrusive thoughts and consequent compulsive behaviors, OCD is often comorbid with ASD; identifying comorbid OCD in these patients is important because while the engagement in repetitive behaviors which is typical of ASD is unrelated to distress, compulsions are performed as a coping mechanism to relieve anxiety.
• Social anxiety: as the patient ages and the environment becomes more demanding, social communication impairment may underline the development of social anxiety, especially if the patient is high functioning and aware of his/her social incompetence. Social anxiety, defined as intense anxiety or fear of being negatively evaluated in a social or performance situation, in turn leads to avoidance of social situations, therefore limiting the patient’s opportunities to practice social skills, and may predispose the individual to negative reactions from peers and even bullying. 
• Separation anxiety: social impairment may evoke overprotective reactions from parents that in turn may strengthen avoidance behavior in the child; separation anxiety may then arise when the patient has to separate from attachment figures, for example at the moment of leaving the family for college.
•  Other atypical symptoms of anxiety: youth with ASD often experience symptoms of anxiety that not necessarily fit within a diagnosis, for example intense levels of distress related to changes in their routine or environment.

How To Treat Anxiety In ASD. A Personalized Approach 

The evidence concerning the impact of anxiety on the course of ASD highlight the importance of treating anxiety problems in a timely fashion to improve overall functioning of individuals with ASD. 
While not a core aspect of ASD, but rather a distinct disorder arising in the course of ASD, anxiety can be treated separately from the other domains of the disorder, but treatments have to be adapted to this population. 
Specific approach for the treatment of anxiety in this population include:

• Pharmacological treatment for anxiety in ASD
  • Although selective serotonin reuptake inhibitors (SSRIs) are considered the first line of pharmacological treatment for anxiety disorders and OCD in the general population, research examaning their use in ASD is limited and controversial, with modest efficacy and high rates of negative effects. Our studies on Fluoxetine in adults and children with ASD showed improvement in ripetitive behaviors, however a large controlled trial showed that Citalopram doesn’t differ from placebo in reducing repetitive behaviors and that some patients have negative behavioral effects, such as hyperactivity, impulsivity and insomnia. ASD patients may be sensitive to low doses of drugs and present considerable variations in treatment responses and adverse events to medications. Our group has seen that a genetic variant can be associated with adverse events to SSRIs in these patient. There is limited evidence to support the use of Buspiron for anxiety in autism.  
• Psychotherapy and social skills interventions for anxiety in ASD
  • Cognitive behavioral therapy (CBT) has demonstrated robust efficacy for treating anxiety disorders and OCD in youth with ASD, especially in those with high functioning and adequate verbal skills. The core treatments components of CBT for anxiety involve: 
    • psychoeducation about anxiety (eg learn to differentiate between helpful and unhelpful anxiety, identify physiological components of anxiety)
    • cognitive strategies (eg learn to identify anxious cognitions and improve executive functions and flexibility) 
    • behavioral strategies (eg graded exposure to feared stimuli) 
    • interventions with parents: psychoeducation and parent-meditated interventions for core symptoms (eg building helpful parenting responses to anxious behaviors and assisting the child to implement techniques outside the session) and maladaptive behaviors (eg changing maladapting behaviors in parenting style, such as overprotection that limit the child’s independent daily skills). 
  • Just as ASD patients need personalized use of medications, psychological interventions should be adapted to the characteristics of these patients to be fully effective.
  • Clinicians should integrate standard CBT with approaches that focus on the core characteristics of autism that can mediate the development of anxiety or also limit the effectiveness of standard approach:
    • emotional literacy and mindfulness-based approach may be helpful to improve those emotional recognition skills that are required to consequently tolerate the experience of aversive emotions and respond flexibly to stressors; 
    • social skills interventions, such as in vivo practice of reciprocity skills, in order to improve engagement with others and emotional responses;
    • make large use of concrete examples, visual prompts and also virtual reality environment to help the patient to cope with difficulties in abstract thinking.
• New investigational approaches:  our research group is currently conducting clinical trials investigating oxytocin, vasopressin receptor 1A antagonists and cannabinoids (CBDV) as treatments to specifically target the mechanisms thought to be involved in the core aspects fo ASD, namely social communication and repetitive behaviors, which are also linked to anxiety. Further research is needed.

Take Home Messages

• There are many treatments for ASD patients, such as pharmacotherapy, psychotherapy, educational therapy, occupational therapy, physical therapy and family interventions.
• These patients need a personalized and multimodal assessment and treatment. 
• Consideration of co-occurring conditions is particularly important in designing interventions that improve overall functioning. 
• Anxiety should never be neglected in ASD and may be treated as a separate diagnosis, but therapy should be adapted for these patients.
• Early intervention programs for infants with or at-risk for ASD with the goal of facilitating skills to improve coping and resilience, may prevent the escalation of anxiety symptoms.