Using psychosis dimension scores assessed in a sample 1,392 relatives of schizophrenia patients from 671 families we identified two family subtypes: “at risk for psychiatric disorder” and “healthy”. These family subtypes were mainly distinguished based on depression, mania, and positive symptoms. We subsequently investigated whether patient characteristics were different between family types. A difference was revealed in the level of positive symptoms; patients from “at risk for psychiatric disorder” families obtained higher positive symptom scores compared to patients from “healthy” families.
Previous studies have distinguished between sporadic and multiplex families based on either a simple distinction between families with one or more schizophrenia patients, or using a more sophisticated algorithm which takes the number of family members, the degree of genetic relatedness, age at the time of the study and gender into account
]. Differences in clinical presentation of patients from sporadic and multiplex families have been reported, but results were inconsistent; it remained unclear whether clinical differences represented etiological heterogeneity. In the present study, we used a relatively new statistical approach to perform a family based analysis of the subclinical levels of psychosis in family members of schizophrenia patients. We identified two different family types: 42% of the families was assigned to the “healthy” family class while 58% of the families was assigned to the “at risk for psychiatric disorder” family class. Relatives assigned to the “at risk for psychiatric disorder” were more often diagnosed with depression and obtained higher scores on the five psychosis dimensions (i.e., positive, negative, depression, mania, and disorganization) compared to relatives from “healthy families”. The higher psychosis dimension scores were not solely due to the higher prevalence of depression, as the differences between relatives were slightly less pronounced but still significantly different in relatives unaffected for depression (data not shown).
The main novelty of the approach presented in this article is the use of refined phenotypes to define family subtype. The distinction between family types is based on symptom dimension scores of all participating family members instead of a dichotomous distinction between affected and unaffected. Although our approach is much more labor-intensive in terms of data collection (i.e., the collection of symptoms instead of psychosis yes/no) the extra information appears to contribute to a valid assessment of family type.
Patients from the “at risk for psychiatric disorder” family type obtained higher scores on lifetime rated positive symptoms (i.e., the CASH positive dimension) compared to patients from the healthy family type. The difference was specific for positive symptoms; no differences were found for the remaining symptom dimensions, IQ, the number of needs, Cannabis abuse/dependence or age of onset of psychosis. This is in contrast to the scores in relatives while parents and siblings of the different family subtypes obtain different symptom scores on all five psychosis dimensions, with the largest differences found for positive, depression, and mania dimensions.
We will discuss two competing explanations for our findings which indicate that positive symptoms in patients are most strongly associated with positive, depression, and mania scores in their relatives and not with negative and disorganization symptoms. The first argument will be built on the premise that schizophrenia results from an increased risk for cognitive deterioration and an increased risk for psychotic features. We have previously shown the existence of a subset of schizophrenia patients with relatively low disorganization and negative symptoms and normal cognitive functioning
]. This suggests that disorganization and negative symptoms may be indicators, or clinical correlates, of the cognitive decline in schizophrenia patients. The fact that the scores on disorganization and negative symptoms in the “at risk for psychiatric disorder” relatives are relatively unaffected may suggest that these relatives do share the risk for developing psychotic features with their affected family member while they do not share the risk for cognitive deterioration. This would imply that negative symptoms, disorganization and cognitive decline are etiologically distinct from the other symptom clusters.
A second explanation is based on the argument that the relatively high level of positive symptoms in patients with schizophrenia in “at risk” families may not result from the increased familial loading for psychosis but may instead be related to the increased psychosis dimension scores in their relatives via a causal pathway whereby higher positive scores in siblings or offspring result in increased distress and lead to higher scores as a reflection of familial distress due to a more severe presentation of the illness. Such distress is more likely to be reflected in mania, positive, and depression scores than in disorganization and negative symptoms.
Cannabis abuse and/or dependence was not present at significantly different rates in patients from “at risk for psychiatric disorder” and “healthy” families. In addition, age of onset of psychosis was not significantly different between groups. Does this imply that our novel classification for family types does not have an etiological basis? Not necessarily, since the most important etiological risk factor: genetic variation, was not yet taken into account. Future studies should reveal whether genetic risk for schizophrenia, for example such as calculated in the study by Purcell and colleagues
], may be significantly different between subjects from “at risk for psychiatric disorder” and “healthy” families. We hypothesize that relatives from “at risk” families have a higher mean genetic risk score compared to relatives from “healthy” families, even though the relatives in both family types do not cross the threshold of “being affected”. If our symptom based differentiation between “at risk” and “healthy” families will be confirmed by genetic studies, this will have important implications for future gene finding studies. The statistical power to detect genetic risk factors involved in schizophrenia could be increased by selecting those families with a high genetic loading.
The results of this study should be interpreted in view of the following limitations. First, the design of this study does not allow conclusions on the direction of causality. It remains to be investigated whether the higher positive scores in patients from “at risk for psychiatric disorder” families are indicative of an increased familial loading for psychosis or whether these higher scores lead to higher psychosis dimension scores in the relatives. Second, only a limited number of etiological variables were assessed. So far, genetic variation appears the most important risk factor for schizophrenia, but we do not have the data needed to compare genetic risk between subtypes. Finally, while the advantage of our new approach is the use of more refined measures to define family subtypes, these refined measures are only available in the relatives who participated in the study. Not all relatives were willing to participate and we can not rule out the possibility that willingness to participate is associated with the level of symptomatology.