Psychiatric comorbidities in asperger syndrome and high functioning autism: diagnostic challenges

Asperger Syndrome (AS) and High Functioning Autism (HFA) are two conditions within the broad category of the Autism Spectrum Disorders (ASDs) that are often overlapping and characterized by social-communication impairment and over-focused, repetitive interests and behaviours, without any significant learning disabilities or language delay in the case of AS. Individuals suffering from AS/HFA typically show pedantic speech often with monotonous or exaggerated vocal intonation [1], poor nonverbal communication [2] and motor clumsiness. Despite AS and classic autism both belonging to the same category of ASDs, individuals with AS tend to show a distinct pattern of social impairment that seems to be milder than in classic autism [3], and it has been hypothesized that the differences between AS and classic autism may be both quantitative and qualitative [4].

The management of behavioral problems in children and adolescents with autism spectrum disorders is a challenge for clinicians and families and the psychiatric symptoms in comorbidities could even exacerbate the behavioral dyscontrol [5‐7]. Individuals with AS and HFA may show an impairment in describing their own feelings and emotions [4], so it is not easy to detect and recognize another psychiatric comorbidity that could be masked by the autistic symptoms themselves. One of the main problems with individuals suffering from AS/HFA is that behavioral symptoms due to one of the comorbid conditions that often run together with this type of ASD (see section “AS/HFA and comorbid psychiatric conditions” and Table 1) could arise in different social environments, including family and school, and during social activities. For these and other reasons in the daily clinical practice it is difficult to make a decision about the most appropriate diagnosis and therapeutic strategies.

In this review we examine the interplay between common psychiatric comorbidities and AS/HFA. In particular, we will discuss which psychiatric disorders have been more frequently reported in association with AS/HFA. We will also point out the difficulties that clinicians and researchers have to face when trying to make the correct diagnosis of a comorbid condition in AS/HFA basing on the currently available psychometric tools (i.e. scales, checklists and questionnaire).

Furthermore, we will discuss the important role played by the environment and finally we will outline some useful strategies to address these issues and challenges for therapeutic implications.

A systematic literature search was performed using PubMed to identify clinical studies that assess psychiatric comorbidities in individuals with AS or HFA. Trial quality was assessed according to a standardized and validated set of criteria.

In details, we searched Medline databases from January, 2000, to December, 2011, with the search terms “autism”, “autistic disorder”, “pervasive developmental disorder”, “autism spectrum disorder”, and “Asperger syndrome” in combination with “comorbidity”, “depression”, “anxiety”, “bipolar disorder”, “adolescent”, “childhood”, “obsessive compulsive disorder”, “attention deficit hyperactivity disorder”, and “conduct disorder”. We also searched references from recent reviews and other reports identified by this search strategy, and selected those we judged relevant. Review articles and book chapters are cited to provide more details and references.

Recognizing psychiatric comorbidities in individuals with AS/HFA can be challenging for clinicians. Considering that individuals with AS/HFA may show an impairment in processing and describing their own feelings and emotions, the clinical information is often obtained by interviewing family members rather than the AS participants themselves or detected from a direct observation in their social environment.

Moreover, the symptoms of psychopathological conditions may be masked by those typical of AS/HFA and the threshold between autism spectrum core symptoms and comorbid symptoms can be blurred. For instance, a sudden decrease of repetitive and obsessive behaviors in individuals with AS may represent a manifestation of depressive symptoms, but could also be mistakenly ascribed to an improvement in one of the diagnostic dimensions of AS itself [66]. In the clinical practice, various psychometric instruments, such as clinical interviews, self-report questionnaires and checklists, are widely used to assist in the diagnosis and they constitute a valuable support for clinicians. However, these diagnostic tools have been designed and standardized to spot different clusters of psychopathological symptoms referring to the general population and they may not be appropriate to AS/HFA.

For this reason, not only the validity of these instruments need to be tested in ASDs, but also their administration may be problematic in individuals with AS/HFA because of their difficulties to sustain a reciprocal conversation, to talk about their self, to report events and their lack of understanding and empathy for the feelings of other people. All these issues render the correct interpretation of the answers even more complicated, thus misleading the real nature of symptoms in comorbidity.

There are currently no scales specifically designed to evaluate psychiatric comorbidity in persons with ASDs, and the studies that investigated comorbid disorders in AS/HFA either referred to the DSM-IV diagnostic criteria, or tried to adapt the scales used for the general population, and this obviously has several limitations. In one of these studies, Hedley & Young investigated the link between social comparison processes and depression in children and adolescents with AS [9], by using the Children's Depression Inventory (CDI) to detect depressive symptoms. The CDI is a self- report scale, which investigates the presence of negative moods, interpersonal difficulties, negative self-esteem, and ineffectiveness and implies intact abilities to understand and report about internal state of mind, feeling and emotions. These abilities can be, to various degrees, impaired in AS, thus decreasing the sensitivity of the clinical assessment. For instance, items 11, 12 and 25 refer to the sense of self in the social interactions, and may be altered per se in AS/HFA individuals without being a sign of depression. The same might account for items 20, 21 and 22, which presuppose children's comprehension of different perceptual perspectives and preserved mental ability to infer mental states from people’s behavior, another capability that might be impaired per se in AS. Another study investigated the presence of DSM-IV-defined bipolar disorder in adolescents and young adults with HFA [13]. According to this study it seems that adolescents and young adults with HFA show a higher prevalence of bipolar disorders as compared to controls. Most of the studies addressing the presence of psychiatric conditions in ASDs are made by listing, with a categorical approach, the presence of certain target symptoms, without extensively describing the type and peculiarity of those symptoms in the specificity of HFA neuropsychological profile. This constitutes a critical issue and raises the question of whether the diagnostic criteria for psychiatric conditions listed in the DSM IV-TR or ICD-10 can be applied to ASDs or need to be revised and better contextualized. For example, signs of manic and hypomanic mood are the core symptoms of bipolar disorder according to DSM-IV. In the context of ASDs, however, it is difficult to define manic or hypomanic mood. Although, according to Leibenluft and colleagues (2003) criteria for the broad phenotype of juvenile mania, symptoms such as irritable or anger mood, excessive reactivity and hyperarousal (agitation, racing thoughts/flight of ideas, pressured speech) could be strongly suggestive of a comorbid severe mood dysregulation disorder [67, 68], on the other hand, the impairment to modulate the arousal state, especially in social situations, may lead to motor overexcitement, laugh bursts or exacerbation of body stereotypies and mannerisms that may simply well depend on impairments in social understanding.

Anxiety symptoms have also been documented in individuals with AS/HFA. An interesting study performed on adolescents with AS/HFA showed an age-related increase in social anxiety within the HFA/AS group; by contrast, a decrease of behavioral avoidance by age was seen in control participants [69]. In this study, the Social Phobia and Anxiety Inventory for Children (SPAI-C), the Social Anxiety Scale for Children - Revised (SASC-R), and the Child Behavior Checklist (CBCL) were administered to participants. The Child Behavior Checklist (CBCL) is indeed an important scale to perform psychopathological assessment of psychiatric comorbidities. However, the validity of this scale in AS/HFA is controversial with some studies considering some items of the CBCL (i.e., repeats acts, strange behavior, strange ideas, and withdrawn) extremely useful in identifying children with ASDs [69], whereas others documenting reliability in only a subgroup of individuals with ASDs [70]. Once again, these studies arise the clear need for psychometric tools designed specifically to assess anxiety disorders in the ASD population, keeping in mind that participants with AS/HFA may have a compromised sociability, that could provide a certain level of social anxiety, without necessarily meaning the presence of an overlapping anxiety disorder. On the other hand, a compromised sociability would not necessarily lead to anxiety, especially in individuals with AS/HFA that do not socialize in the same way and may not become anxious. In this context, anxiety may be a separate dimension.

One of the most controversial comorbidities, in children with AS/HFA, is the co-occurrence of Attention Deficit Hyperactivity Disorder (ADHD), and this is mainly due to specific diagnostic difficulties in the clinical practices. However according to the DSM-IV co-diagnosis of AS and ADHD cannot be done, thus further complicating the diagnostic process. Indeed, study results from the literature on this issue are controversial, because of the lack of validated scales to investigate ADHD symptoms in AS/HFA. For instance, one of these studies showed an higher prevalence of ADHD symptoms - investigated retrospectively by a self-report scale - in AS participants, [28]; however, the risk of recall bias or biased self-awareness about ADHD symptoms in AS/HFA group may represent a threat to the internal validity of this kind of investigations.

Another important issue regarding the comorbidity in AS/HFA is represented by the broader spectrum of Obsessive Compulsive and related disorders [71]. Symptom overlapping among OCD and AS/HFA makes it difficult to clearly differentiate the clinical phenomenology of obsessive- compulsive and repetitive behaviors in AS/HFA. The development of appropriate scales adapted for ASDs are warranted to shed light on the various aspects of this comorbidity. An instrument that could help to perform diagnosis of OCD comorbidity in ASDs is the Children's Yale-Brown Obsessive Compulsive Scales (CYBOCS), modified for pervasive developmental disorders [72], validated by raters from five Research Units on Pediatric Psychopharmacology (RUPP) Autism Network that were specifically trained to reliability. However, this scale has been developed in particular for low functioning participants and not for AS/HFA individuals.

In our point of view, the CYBOCS modified for ASDs represents a good example of a reliable specific measure to be used to assist the diagnosis of OCD comorbidity in ASDs. It also indicates that already existing tools may be successfully modified to be applied to AS/HFA individuals in a reliable way.

Another common challenge for clinicians is to determine if psychiatric symptoms observed in AS/HFA are part of the same dimension – i.e. the Autism Spectrum itself – or rather represent different categorical factors – i.e. a psychiatric disorder in comorbidity. This happens because, as mentioned above, the core symptoms of ASDs often mask the symptoms of the comorbid condition. A helpful strategy to disentangle this issue could be to look prospectively at the overall clinical outcome through longitudinal studies.

Longitudinal studies allow to closely follow the developmental trajectories of AS\HFA and to detect subtle changes in behavior at different stages of development in terms of progressive appearance of clinical symptoms and impact of life experiences.

Unfortunately, most of the clinical studies on AS/HFA conducted so far typically have been cross-sectional, comparing one particular clinical measure at a single time point across samples. The interpretation of these cross-sectional findings is mostly focused on the abnormalities in the patient group as compared to healthy controls and on the contributions that these abnormal clinical abnormalities may have on disease evolution. If the need for longitudinal, prospective research is common to the study of all developmental psychopathology, it is especially crucial for AS/HFA in order to understand the lifetime history of the disorder and the role of comorbid disorders. Indeed, children suffering from AS have a different pattern of development compared to normal children and their life experiences influence their cognitive and emotional status beginning within their first years of life. For instance, numerous cross-sectional studies that investigated the presence of mood and anxiety disorders in AS, found that the rate of depression among children with Asperger syndrome is higher than within a community control group [7]. Anxiety and depression are highly related, and high levels of anxiety have been shown to predispose to depression [73, 74]. However cross-sectional studies do not provide any kind of information about different degrees of remitting versus non-remitting symptoms, as well as about the different etiological subtypes of depression.

Therefore, there is a clear need for longitudinal population studies to identify whether individuals with high anxiety levels and AS/HFA have increased susceptibility for depression during lifetime.

The correct identification and attribution of depressive symptoms in individuals with AS/HFA as well as their change over time is crucial to avoid inaccurate diagnostic interpretation. For instance, it is well documented [75] that the onset of depression in individuals with AS is usually, if not always, associated with a decrease in repetitive and obsessive behaviors, a reduction that may be considered as an improvement of an OCD, rather than a co-occurring depressive condition. In this context, longitudinal studies could be helpful to monitor and understand the lifetime course of psychiatric symptoms in these patients, thus allowing a better discrimination between different comorbid situations. Longitudinal studies could also be useful to better clarify the association with ADHD, that, if properly investigated, can be frequently found in comorbidity with AS. Various neuropsychological studies reported that individuals with AS show different patterns of manifestation of ADHD symptoms [76]. However, the developmental trajectory of attention problems and motor hyperactivity symptoms development in relation to age, is still not completely clear, even if some studies suggest that certain symptoms are more likely associated with specific periods of life (i.e. preschool years or adolescence) [5]. Longitudinal studies that would follow these individuals across time could help to better clarify the dynamics of this comorbidity in AS/HFA.

Hence, in our opinion, although cross-sectional studies are extremely useful for generating hypotheses, these hypotheses in turn need to be further confirmed by longitudinal investigations. The development of lifespan approaches could help to clarify the core of pathophysiological processes of the main disorder in ASDs, thus allowing an easier discrimination between those symptoms that are part of the AS/HFA clinical phenotype from those that are the expression of a comorbid disorder.

The environmental context differentially affects individuals with AS/HFA and it is an additional crucial player that may influence the onset, expression and severity of the psychiatric disorder in comorbidity. Indeed, the heterogeneous expression of psychiatric difficulties in children with AS/HFA may be directly related to environmental factors and this suggests the opportunity of planning differential intervention. For instance, family and daily routines have to be considered as environmental factors that could potentially lead to a different burden of the psychiatric comorbidities.

The challenge of understanding the special needs of a AS/HFA child and the difficulties to build a close relationship with him/her contributes to increase the overall level of stress in the parents, as reported by several studies [77, 78]. Parents of children with AS/HFA have been shown to have an impaired sense of well being, and to display a lower quality of life even in comparison with parents of children with other psychiatric and neurological disorders, such as cerebral palsy or mental retardation [79]. Moreover, mothers were found to perceive a higher level of stress than fathers and this maternal impairment was shown to be related to peculiar behavioral characteristics of the child, such as higher hyperactivity and conduct problems [80]. Other studies also reported elevated rates of anxiety-related personality traits among the relatives of AS/HFA participants [81]. Elevated anxiety and stress levels in the parents of AS/HFA children can be considered as an important environmental factor that intersects and acts as trigger in the context of innate genetically determined personality traits - eventually shared with other family members - constituting a genetic family loading for psychiatric conditions. For this reason, investigating the psychiatric family history may inform about the comorbidity risk in the proband as well.

The importance of environmental context in psychiatric symptoms expression has been recently investigated in a sample of youths with ASDs including AS and their siblings, with an evaluation reported independently by parents and teachers. Reports by teachers show a much lower prevalence of psychiatric comorbidity, in particular for affective, anxiety, attention, conduct, oppositional, and somatic problems, in these individuals, as compared to the reports of their parents. These results support the notion that the manifestations of psychopathology in people with AS/HFA may vary depending on the context and that their identification depends on the type of observer, suggesting that informant discrepancies may constitute an additional variable element for the proper identification of comorbidities [70]. In this regard, we have to keep in mind that in the clinical practice there is often a lack of consensus between parent’s and teacher’s reports about the behavioral aspects in children with AS/HFA, thus suggesting caution when making conclusions or interpretations regarding the presence of comorbid psychiatric problems based on a single informant source or just an environmental context, and emphasizing the importance of gathering information from multiple sources and settings, including direct observation by clinicians [70].

The difficulties that a child suffering from ASD experiences in terms of social relationships are likely to be even greater outside of the home environment. The lack of social support, adequate communication and coordination among social service providers often leaves the family alone with the burden of providing any additional support and a more intensive level of care. Indeed, schools are not always ready to cope with the specific needs of AS/HFA and this may drive them to develop feelings of sadness, self-blame and low self-esteem, [82] that may lead to depression, as well as conditions such as hyperactive behaviors or conduct problems. Finally, several studies have reported that negative events such as death, parental discord or frequent changes of own residence may have substantial influence on the child’s mood and functioning, and have been associated with clinical depression [83]. It is likely that AS/HFA participants react to negative life events more severely than individuals from the general population, or, at least, in a different way. This could also be explained by the observation that AS/HFA group seems to be more vulnerable than control individuals to develop mood disorders and depressive symptoms [82], and this vulnerability appears to be correlated to a genetic predisposition.

In conclusion, since the environment seems to considerably influence the expression of psychiatric comorbidities in AS/HFA individuals, more attention should be focused on the interactions between these individuals and their different everyday life environments, in order to provide a better social support and therefore develop coping strategies that could in the end even contribute to a decrease in the incidence of psychiatric disorders in AS/HFA.

As reviewed, several studies investigating the psychiatric comorbidity in individuals with AS/HFA have been conducted. Still, there is uncertainty as to the best way of identifying and conceptualizing psychiatric disorders in AS/HFA.

Although people with AS/HFA can suffer from important comorbidities, according to what Ghazziudin observed, psychiatric disorders go unrecognized in many individuals with AS/HFA [83].

The occurrence of psychiatric disorders in AS/HFA may be the result of a combination of genetic and environmental factor. We believe that an effort should be done to better understand the needs of AS/HFA children in school and family environments, to avoid feelings of low self-esteem and distress, socially inappropriate behaviors, anxiety and other externalizing or internalizing problems. Considering that there is evidence supporting the fact that Asperger syndrome clusters in families and that there is a high prevalence of psychiatric disorders such as depression and schizophrenia in relatives of individuals with AS/HFA [83], the role played by the environment becomes even more relevant on the development and onset of psychiatric conditions in children and adolescents with AS/HFA. Indeed, school and family settings can modulate the behavior of children and adolescent with AS/HFA, thus positively preventing the onset of a psychiatric condition in comorbidity, even in the presence of high genetic predisposition or alternatively precipitating a fragile balance and trigger the development of a psychiatric comorbid condition.

An additional concern regards the suitability of the psychometric tools used in clinical practice to assess comorbid conditions in AS/HFA. Of course, the psychiatric diagnosis of comorbidity relies on the competence of clinicians, but adequate tools such as scales or questionnaires adapted for ASD could be helpful to somehow standardize the recognition of psychiatric symptoms in this clinical sample. So far, most of the studies have used questionnaires, checklists and scales designed for individuals with a normal awareness of their own and other’s mental status. These instruments were not specifically adapted to take into account the neuropsychological characteristics of AS/HFA in terms of deficits in mind reading, impairments in processing and reporting their own feelings, emotions and communication problems. Hence, new psychometric instruments, developed or adapted specifically to AS/HFA, are needed. In the absence of specific tools for ASDs, an alternative strategy could be gathering information from multiple sources and settings, including both direct observation and multiple assessments within- informant and across-informants [70]. We agree with other reports suggesting caution when making conclusions or interpretations regarding the presence of comorbid psychiatric problems based on a single informant source or environmental context, because this may lead to incorrect diagnostic conclusions in particular in ASDs [84, 85]. Moreover the current systems of classification do not make it easy to give additional psychiatric diagnoses to persons with AS/HFA. For instance, according to DSM-IV-TR classification, ADHD cannot be diagnosed during the course of a pervasive developmental disorder. Longitudinal studies could allow to understand if individuals with AS may have an increased risk or a constitutive predisposition to develop psychiatric disorders or whether the incidence of the onset is similar to normal population.

Despite the many challenges that we have outlined in this review, the study of psychiatric comorbid disorders continues to provide an increasingly important contribution to the understanding of the clinical phenomenology of ASDs. In this context, the definition of psychiatric disorders that are often found in association with ASD and of the psychiatric symptoms peculiar to the natural course of ASD itself is of crucial help as it could provide insights regarding the developing pattern of these individuals.