Introduction
Autistic and psychotic disorders have historically been considered as related diagnostic entities. In the late 1970s, autism spectrum disorders (ASD) and schizophrenia (SZ) were split into two different diagnostic categories (DSM-III). The boundaries between the two disorders, however, continue to be debated. ASD and SZ share common neurobiological processes [
1,
2] and genetic risk factors [
3‐
5]. In addition, the presence of autistic traits in early childhood increases the risk of psychotic experiences in adolecence [
6] and of SZ and SZ spectrum disorders in adulthood [
7]. Conversely, a significant proportion of adults with SZ also fulfils criteria of childhood ASD [
8]. Better characterisation of psychosis-related symptom profiles in children with ASD is likely to advance our understanding of these overlaps.
A potentially fruitful approach is to improve the clinical charaterisation of children with ASD that present with psychotic experiences. There is some evidence that affective symptoms in children with ASD may mediate the emergence of psychotic symptoms. In particular, formal thought disorder in ASD has been found to be induced by anxiety and stress [
9]. This concept is also supported by reports of higher rates of psychotic symptoms in ASD children with significant symptoms of anxiety and throught disorder. It has been suggested that these children may represent a particular subgroup of ASD refered to as multiple complex developmental disorder (MCDD) [
10‐
12]. The criteria for MCDD are shown in Table
1 and highlight the importance of peculiar and idiosyncratic fears, panic episodes and explosive emotional behaviours [
10]. Although anxiety symptoms were noted in the original description of classic autism [
13] they do not feature as core symptoms of autism in more recent operational descriptions of the disorder. However, large-scale epidemiological studies (e.g. [
14] ) and a recent meta-analysis [
15] estimated that approximately 40 % of ASD children have a comorbid anxiety disorder. A comprehensive review by White and colleagues [
16] also reported that ASD children experiencing anxiety are more likely to show explosive behaviours in response to their fears and phobias. Weisbrot and colleagues [
17] examined the relationship between specific types of anxiety and psychotic experiences in 483 children with ASD. The 6- to 12-year olds with ASD whose parents and teachers considered as highly anxious were also more likely to receive more severe ratings of psychotic symptoms (hallucinations, odd thoughts, bizzare behaviours) compared to those with with low levels of anxiety. The association with psychoticism was more evident for children who reported peculiar fears and phobias. Therefore, the MCDD criteria regarding affect regulation may be useful in capturing the symptom profiles of ASD children most likely to experience psychosis.
Table 1
Multiple complex developmental disorder research criteria
(1) Impaired regulation of affective state and anxieties |
a. Unusual or peculiar fears and phobias or frequent idiosyncratic or bizarre anxiety reactions |
b. Recurrent panic episodes or flooding with anxiety |
c. Episodes of behavioural disorganisation punctuated by markedly immature, primitive or violent behaviours |
(2) Impaired social behaviour |
a. Social disinterest, detachment, avoidance or withdrawal despite evident competence |
b. Markedly disturbed and/or ambivalent attachments |
(3) The presence of thought disorder |
a. Irrationality, magical thinking, sudden intrusions on normal thought process, bizarre ideas, neologism or repetition of nonsense words |
b. Perplexity and easy confusability |
c. Overvalued ideas including fantasies of omnipotence, paranoid preoccupations, over-engagement with fantasy figures, referential ideation |
Diagnostic rules |
A diagnosis of MCDD can be made if an individual meets total of five (or more) criteria from (1), (2), and (3) with at least one item from (1), one item from (2) and one item from (3)a
|
The MCDD criteria also highlight thought disorder as a dimension of psychoticism. More recent studies have suggested that thought disorder is a feature of ASD that relates more closely to the degree of language abnormalities rather than to SZ or spectrum disorders [
9,
18]. However, the study by Weisbrot and colleagues [
17] demonstrated a link between odd thoughts, strange beliefs and illogical thinking (considered as symptoms of thought disorder according to MCDD criteria), in highly anxious ASD children who also experienced hallucinations. However, thought disorder, characterised by odd thinking, is a symptom domain that is similar between patients at high risk for SZ and ASD children meeting diagnostic criteria for MCDD [
19]. In addition, thought disorder is a symptom domain that is highly predictive of conversion to psychosis in those at high risk regardless of developmental history [
20]. It therefore appears important to consider the presence of thought disorder when attempting to define clinical profiles of ASD children likely to present with psychotic features.
The evidence summarised above suggests that the concept of MCDD is highly relevant to psychosis. At the same time, the argument for MCDD as a separate diagnostic entity has not received widespread support [
4] and is not included in the latest, fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) or the planned revision of the International Classification of Diseases (ICD). Our interest in the MCDD does not relate to whether or not it constitutes an independent diagnostic syndrome. We consider, however, that the constellation of symptoms identified by the MCDD criteria may be in fact helpful in delineating a subgroup of ASD individuals with higher burden of psychotic symptoms. We consider the identification of more homegeneous subgroups as the first and necessary step in improving our understanding of the relationship between psychosis and developmental disorders.
Based on the above, we employed Latent Class Analysis (LCA) [
21,
22] to classify children with ASD on the basis of the MCDD criteria as they provide an evidence-based framework for exploring further whether psychotic symptoms cluster within specific ASD classes. We elected to study a unique cohort of patients admitted between 2003 and 2012 to a specialist children’s inpatient unit based at South London and Maudsley NHS Foundation Trust which receives national referals for children with severe and complex developmental and neuropsychiatric disorders. The advantage of this cohort is that it complements community-based studies (a) by focusing on children with severe and complex phenomenology where differential diagnosis between ASD with psychotic symptoms and early onset schizophrenia is a recurring and challenging clinical problem, (b) because of the availability of detailed professional observations of children’s behaviour which allows for the disambiguation of complex symptoms that is not always feasible based on parental or teacher reports. Our goals were (a) to specify the number and types of ASD classes according to MCDD criteria (b) to validate the derived classes on the basis of the presence of hallucinations, a psychotic symptom outside the MCDD criteria, and (c) to determine whether the identified classes differ in terms of their overall function and response during inpatient treatment.
Discussion
We found that LCA of the MCDD criteria resulted in two classes of ASD patients, one with (ASD-P) and one without (ASD-NonP) psychotic features. Children that met full criteria for MCDD represented a significant subset of the ASD-P class. Our results therefore confirm the usefulness of the MCDD concept in exploring the relationship between ASD and psychosis but suggest that MCDD as a diagnosis is probably too restrictive.
The identification of two classes of ASD children using LCA is a significant and novel finding because these classes were derived directly from data, rather than defined a priori based on theoretical assumptions. To our knowledge, this is the first empirically derived classification of ASD children in terms of clinical profiles related to psychosis. Consistent with previous literature we identified bizarre anxiety reactions/peculiar phobias and thought disorder as two key symptom domains associated with psychosis in ASD [
12,
17]. This is particularly reassuring since the sample in this study cannot be considered representative in epidemiological terms. Our results, however, suggest that the association of idiosyncratic fears and thought disorder with psychosis is present regardless of sampling biases. Our study design does not allow us to comment on the neurobiological underpinnings of these observations. Our family history data are limited by sample size but hint to an over-representation of children with a first-degree relative with SZ in the ASD-P class.
It is noteworthy that affective psychopathology and thought disorder are emerging as key predictors of transition to overt psychosis in a wide range of high-risk groups [
12,
20]. Therefore, from the perspective of clinicians treating individuals with ASD, the presence of abnormalities in both these domains in a child with ASD is likely to result in psychotic experiences. The MCDD concept as a diagnostic entity may be restrictive, but the MCDD criteria highlight the importance of thought disorder and unusual or peculiar fears and phobias or frequent idiosyncratic or bizarre anxiety reactions in children with ASD and are particularly useful in defining an ASD subgroup more closely linked to psychosis.
On admission, children with ASD had very low CGAS scores (Table
2) indicative of inability to function in most situations. The ASD-P and ASD-NonP classes did not differ in this respect probably because of a floor effect. Both classes were able to benefit considerably by inpatient specialist intervention and at the point of discharge they presented with similar CGAS scores in the range of moderate impairement in most areas (Table
2). During the admission, both classes were equally likely to receive antipsychotics (Table
2). The ASD-P group remained in the unit for an average of 36 days longer than the ASD-NonP group (Table
2). This finding opens a new direction of enquiry to define the reasons for the delayed discharge of the ASD-P class. Future studies on this issue may identify either social or treatment-related reasons for this delay and suggest ways to optimise the clinical care of this group.
Several methodological issues need to be considered. First, LCA analysis is a powerful analytical tool for the identification of more homegeneous classes of patients but it does not provide proof that these classes exist. This will require studies examining the reproducibility of our findings. Second, the sample size in this study is relatively small, which is inherent to the population under study, and the study’s naturalistic design. The cross-sectional design also does not allow us to comment on the long-term clinical outcome of these children. Further investigations in significantly larger and independent samples are required to determine the prognostic value of our classification and their relationship to treatment response.Third, the variables entered in the LCA models were based on the MCDD concept. Other disease dimensions (e.g. genetic, brain structural and functional measures) may also be relevant and may be used to refine our classification in future studies.
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