COS is defined as onset of psychosis before age 13 and is a rare and severe form of schizophrenia. Onset is usually after age 7, positive and negative symptoms are prominent, and prognosis is poor10
. In contrast, autism is defined by abnormal behavior in the spheres of communication, social relatedness, and stereotyped behaviors within the first three years of life. The broader category, Pervasive Developmental Disorder (subsuming Autism, Rett Syndrome, Asperger's Syndrome and Childhood Disintegrative Disorder) has a residual category, PDD-NOS (not otherwise specified), which is based on the social relatedness symptoms for autism but allows for different age of onset, and fewer other spheres. Thus, DSM IV-TR PDD-NOS requires failure to develop appropriate reciprocal social behaviors as a necessary defining feature11
. Inevitably, there will be further subdivisions and hopefully brain imaging and genetic studies will provide clues about how to do this. One particular category –Multiple Complex Developmental Disorder (MCDD), discussed below, is a possible bridge with schizophrenia 12-14
When advances in psychiatry permitted the field to conceptualize psychotic disorders and developmental disorders as distinct, the phenomena of PDD and COS as comorbid disorders could be explored. In the DSM-II, autism was referred to as schizophrenia, childhood type, and was characterized by “atypical and withdrawn behavior,” “failure to develop identity separate from the mother's,” and “general unevenness, gross immaturity and inadequacy in development.” However, important post DSM-II work conducted by Kolvin and others focused on the contrast between very early onset schizophrenia (with typical onset after age 7) 15
and earlier onset autism. This research was influential in making the distinction between childhood onset schizophrenia and autism in the DSM III. The phenomenology of childhood onset schizophrenia was described by Kolvin et al. in a groundbreaking study of 33 British children, of whom 12 had onset before age 13.16
In addition, the researchers stressed the severity and frequency of prepsychotic developmental disorders in COS.
The observations of Kolvin and colleagues have been replicated in virtually every study of early onset schizophrenia with findings of developmental abnormalities primarily for communication, motor abnormalities and/or social relatedness 10, 17
. For example, an early report from the UCLA COS study found that 39% of a sample of 33 patients had symptoms of autism years before onset of schizophrenia18
. Since the initial 1988 report, the UCLA group has examined an additional 52 COS probands using the K-SADS-E structured diagnostic interview . Of these, 28 (55%) had histories meeting DSM III-R criteria for autism or PDD (Dr. Robert Asarnow personal communication May 2008). The largest study to date of COS now includes 101 children and adolescents with onset of DSM IV defined schizophrenia before age 13. Of these, one (1%) met criteria for comorbid autism, 2 (2%) for Asperger's Syndrome and 25 (25%) for PDD-NOS, making for a total of 28% with comorbid autism or autism spectrum disorder (ASD) (unpublished data, Nitin Gogtay M.D.). These diagnoses were made by both screening questionnaire and agreement by two board certified child psychiatrists in recognition of the pitfalls of diagnosis by screening instrument alone 19
. PDD-NOS was a persisting and stable diagnosis in these cases, with onset in the first five years of life, while the onset of psychotic symptoms occurred typically 3-5 years later.
Premorbid developmental disturbance in schizophrenia is hardly a new concept and schizophrenia itself is widely regarded as a neurodevelopmental disorder 20
. Large cohort studies of the antecedents of schizophrenia have documented subtle developmental delays long predating the onset of psychosis 21 22-24
. A prospective pediatric population study found a relatively specific pattern of childhood developmental disturbance consisting of impairments in neuromotor, receptive language, and cognitive development that were seen only among children later diagnosed as having schizophreniform disorder25
. Developmental impairments also predicted self-reported psychotic symptoms at age 11. These impairments were termed “pan developmental dysmaturation,” more consistent with the findings of the (adult onset) schizophrenia cohort studies consisting primarily of developmental lags. These too are common in the NIMH COS cohort, and 39 patients (39%) exhibited one or more of these non-PDD developmental disturbances.
These data are shown in .
Thus two sets of somewhat different early developmental disturbances are seen. One set includes members of the COS sample who met criteria for a DSM-IV-TR PDD-NOS (n=28) and another set (n=39) who had language, motor or social impairments stemming from impulsivity or anxiety. Of note, the PDD + COS subjects' demographic patterns follow those reported in the literature for PDD generally, as they are primarily male (p = 0.04) and non-African American (p = 0.02) All had failure to develop reciprocal social behaviors as their defining common characteristic, which was temporally and clinically distinct from their later development of psychotic symptoms.
In the ongoing NIMH study to date, 263 family members have been evaluated with structured interviews and parents were administered the Autism Screening Questionnaire (ASQ) for siblings. The average ASQ score was higher among unaffected siblings of children with comorbid PDD/COS than among unaffected siblings of COS patients without PDD, as consistent with previous reports 26
. This finding implies that PDD symptoms are heritable and may serve as trait markers even in unaffected individuals.
Several models have been proposed to account for psychiatric comorbidity27
. As Krueger and Markon have reviewed, comorbidity may reflect causality between the conditions, alternate forms of the same disorder, unique subgroups that share both attributes, or different manifestations of a single or correlated underlying liability. The only one of these models with some research-based links to schizophrenia comes from a subgroup of PDD–NOS defined as Multiple Complex Developmental Disorder (MCDD). MCDD is observed in children ages 12-18 years and is characterized by impaired sensitivity to social stimuli, as well as thought disorder, bizarre and disorganized thinking, inappropriate affect and mood lability 12, 14
. Although less disturbed than children with autism with respect to social interaction, communication and stereotyped and rigid behaviors, children with MCDD were more disturbed with respect to flagrant thought disorder, anxieties and aggression14, 28
. The diagnosis of very early onset schizophrenia was considered by the initiators of the MCDD construct, but the relative frequency of the MCDD group suggested it was a broader group from which schizophrenia might emerge. Moreover, follow up studies of MCDD indicate that by adolescence and young adulthood, 22% and 64% respectively, convert to (some form of) psychosis29
or resembled subjects in psychosis high-risk groups 13
. The MCDD constellation remains relatively ignored by clinicians in the United States as almost all work on this has been carried out in the Netherlands.