Review
The association between autism and schizophrenia spectrum disorders: A review of eight alternate models of co-occurrence

https://doi.org/10.1016/j.neubiorev.2015.04.012Get rights and content

Highlights

  • Autism and schizophrenia have been reported to co-occur at elevated rates.

  • We overview phenomenological, genetic, environmental, and imaging evidence for this.

  • We examine eight possible alternate models of explanation.

  • We then set out a research agenda to test these models.

Abstract

Although now believed to be two distinct disorders, autism spectrum disorders (ASD) and schizophrenia spectrum disorders (SSD) share multiple phenotypic similarities and risk factors, and have been reported to co-occur at elevated rates. In this narrative review, we give a brief overview of the phenomenological, genetic, environmental, and imaging evidence for the overlap between ASD and SSD, highlighting similarities and areas of distinction. We examine eight possible alternate models of explanation for the association and comorbidity between the disorders, and set out a research agenda to test these models. Understanding how and why these disorders co-occur has important implications for diagnosis, treatment, and prognosis, as well as for developing fundamental aetiological models of the disorders.

Introduction

SSD and ASD are currently conceptualised as separate illnesses. Schizophrenia spectrum disorders (SSD), as defined by the DSM-5, include schizophrenia, other psychotic disorders, and schizotypal personality disorder. They involve delusions, hallucinations, disorganized thinking, disorganized behaviour, and negative symptoms. Autism-spectrum disorders (ASD), included by the DSM-5 under neurodevelopmental disorders, are diagnosed when deficits of social communication and interaction are accompanied by markedly repetitive patterns of behaviour, interests, or activities. ASD traits are present in the early developmental period and may be with or without an accompanying intellectual or language impairment. This however, has not always been the case. Definitions of ASD and SSD have undergone many revisions (with much of the research cited in this review using DSM-IV or earlier definitions). Bleuler (1950) believed that autism was a central feature of schizophrenia, while others viewed it as the childhood onset of the disorder (Bender, 1947). In fact, the term autism was used interchangeably with schizophrenia until the 1970s, when Rutter (1972) and Kolvin (1971) proposed that they were distinct disorders. The nosologic separation between ASD and SSD may initially appear justified. SSD has a typical adolescent onset with prominent positive psychotic symptoms, while ASD is characterised by deficits in social interaction, communication and behaviour that begin within the first few years of life (American Psychiatric Association, 1994). Despite apparent differences, SSD and ASD share multiple phenotypic similarities and risk factors (Hamlyn et al., 2013, Spek and Wouters, 2010), have both been conceptualised as neurodevelopmental rather than neurodegenerative disorders (Goldstein et al., 2002), and have been reported to co-occur at elevated rates (Mouridsen et al., 2008a, Mouridsen et al., 2008b, Rapoport et al., 2009, Solomon et al., 2011, Stahlberg et al., 2004). Systematic research on their co-occurrence has been limited, although emerging genetic and neuroanatomical evidence has led to increasing recognition of the overlap between the conditions (Carroll and Owen, 2009, Cheung et al., 2010).

In this paper we briefly review the phenomenological, genetic, environmental, and imaging evidence for the overlap between ASD and SSD, in order to highlight similarities and areas of distinction between the disorders. We then examine alternative models of explanation for the association between the disorders, and set out a research agenda to test these models. Understanding how and why these disorders co-occur has important implications for diagnosis, treatment, and prognosis, as well as for developing a fundamental understanding of the aetiologies of these disorders.

Section snippets

Co-occurrence at the diagnostic level

Although there have been reports that SSD and ASD do not co-occur at elevated rates (Volkmar & Cohen, 1991), the majority of research suggests that the disorders co-occur at a higher rate than would be expected in the general population. A brief literature search (database: Web of Science, search terms: Autism and psychosis and diagnosis, conducted March 2015) reveals 14 papers published in the past 10 years, which investigate diagnostic rates of ASD in individuals with SSD, or vice versa. Of

Genetic evidence

Genetic evidence also highlights points of similarity and distinction between the disorders. The phenotypic similarities between SSD and ASD are mirrored by many overlapping genetic mechanisms. ASD and SSD rates of heritability are both estimated to be high at around 50–80%, (Cardno and Gottesman, 2000, Freitag, 2006, Sandin et al., 2014). What is particularly interesting is the fact that as well as showing high levels of heritability within each disorder, there is evidence of relatively high

Brain structure and functioning

Neuroimaging evidence presents a similar picture to phenomenological, genetic, and environmental risk factor research, with many similarities apparent between the disorders, but also some differences. In terms of similarities, both individuals with ASD and those with SSD have been found via meta-analysis to show reduced grey matter volume in limbic-striato-thalamic circuitry, predominantly on the right, including the insula, posterior cingulate and parahippocampal gyrus (Cheung et al., 2010).

Models of association

Levels of co-occurrence and association within psychiatric disorders have long been considered contentious (Krueger & Markon, 2006). A differentiation can be made between the co-occurrence of two unrelated disorders, anorexia and hearing impairment for example, and disorders which correlate or co-occur above the level of chance, such as depression and anxiety disorders, or morbid obesity and heart failure. Many explanations of co-occurrence or association between disorders/diseases have been

Evaluation of the co-occurrence and comorbidity of disorders

Of the eight models presented there is only limited evidence for the chance, stages, independence, and multiformity models. The evidence for the association between ASD and SSD is relatively robust and multifaceted, suggests strongly that the disorders co-occur at elevated rates, and thus precludes the possibility that the disorders co-occur due to chance (the chance model). Given the evidence provided, the stages model also seems unlikely. The finding that there are genes which appear to

Suggestions for future research

Presently no one model can currently be seen as being the ‘best fit’ for explaining the co-occurrence of ASD and SSD, and further research is therefore needed to establish this. It is important that future research takes into account the strong evidence for the existence of different subgroups within both disorders. Additionally, subgroups should ideally be defined by multivariate data, rather than pre-specified. Hypotheses need to be investigated for each subgroup individually, as not all

Conclusions

It is becoming increasingly evident that it is necessary to prospectively investigate the co-occurrence of, and commonalities between SSD and ASD at the trait level using multi-factorial data from large samples. Undiagnosed co-occurring disorders may result in individuals not receiving appropriate services, benefits, or treatment, and given the similarities between disorders, misdiagnosis is possible (Davidson et al., 2014, Wing, 1981a). It is important that future research account for the

Acknowledgements

We would like to thank Professor Andrew Whitehouse from Telethon Kids Institute, The University of Western Australia, for his helpful comments on an earlier draft of this paper. The work was supported by the Birmingham & Solihull Mental Health Foundation Trust through a grant to SJW. AL is supported by an NHMRC fellowship (#1072593).

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