In this new NEFS high-risk study of psychoses, we demonstrated an increased risk of psychoses among the offspring of parents with psychoses. Consistent with rates reported in the high-risk literature (), there was a prevalence of 9.9% for psychoses and 8.5% for SPS disorders among offspring of parents with SPS disorders, representing an approximately 6-fold increased risk for SPS disorders among offspring of parents with SPS disorders. Among offspring of parents with APs, 13.6% developed psychoses and 10.6% developed AP, representing a 14-fold increased risk of APs among offspring of parents with APs.
The magnitude of risk estimates in this study is similar to that in a number of reports of other high-risk studies (), in particular studies that clinically interviewed subjects by using current diagnostic criteria and used similar inclusion criteria for the definition of psychoses for both offspring and parents. Furthermore, there were differences in control for potential confounders and age at follow-up assessment across studies. The risk estimates (in the following studies, represented by odds ratios [ORs]) for the Copenhagen High-Risk Study31
(OR, 8.6), the Finnish Adoptive Family Study42
(OR, 4.9), and the Copenhagen Perinatal Project49
(OR, 4.5) are similar to our relative risk for psychosis of 5.4. In each of these studies, the offspring were assessed at 34 to 48 years of age and diagnoses were made on the basis of personal interviews and medical record information, similar to our study. In contrast, for example, the Helsinki High-Risk Project19
and Swedish registry study by Lichtenstein and colleagues59
resulted in higher risks (OR, 12.9 and 10.3, respectively). These 2 studies included schizoaffective disorder, bipolar type, in the definition of SPS. Finally, they used clinical diagnoses, which we know maybe accurate with regard to “presence of psychosis” but not necessarily with regard to type of psychosis. The highest risk estimate was the study in Myles-Worsley et al.60
However, there is substantial use of betel nut (a muscarinic agonist) chewing in the healthy population as well as in patients with schizophrenia, particularly high in women,74,75
which may contribute to the substantially high rate of psychosis in the high-risk offspring, a hypothesis that warrants investigation.
However, a rate of SPS of 8.5% among offspring of parents with SPS is still on the lower side of the high-risk study literature. The lower rate of psychoses may be partially accounted for by nonparticipation among study offspring in general. Our design required location, interview, and diagnosis of offspring of both healthy and affected parents and, as in all such studies, we did not have complete participation (although our response rate of approximately 79% is excellent for a 40-year follow-up study). It may be the case that we were less successful in enrolling offspring with psychotic disorders either because they were more transient and difficult to locate and/or because of a lack of willingness to participate in this research project. Both of these methodologic points would result in a reduced estimate of the rate of psychosis among the offspring generation in general. However, there is little reason to expect that this reduction would be greater among high-risk offspring vs healthy control offspring. In other words, irrespective of the parental diagnosis, one might anticipate lower participation rates among offspring with psychoses. This “nondifferential attrition” is well recognized in the epidemiologic literature and is likely to generate lower absolute estimates of the rate of offspring psychoses in both the high-risk and healthy control groups, but would not alter the relative risk comparing the rates of these 2 groups.
Family history diagnostic information, obtained by using the Family Interview for Genetic Studies from first-degree relatives, was used to assess psychosis or other major psychopathology in non-CPP siblings. Of the non-CPP siblings, 5 were diagnosed as having psychoses. However, for the current analytic sample we included only offspring who participated in the CPP because of the rich amount of early-life data available for these subjects that were not available for their non-CPP siblings. This would not bias our RR estimates because CPP offspring represented all offspring born to these parents between 1959 and 1966. We would argue that these offspring are representative of the experience of offspring born to these parents at other periods; thus, excluding non-CPP offspring would not introduce a bias into our RR estimates. That is, the rate of psychoses in offspring born between 1959 and 1966 should not be different from rates of psychoses in offspring born to these parents at other times.
In this study, we demonstrated specificity of risk by psychosis subtype (SPS vs AP), a relationship that has not been previously reported, to our knowledge. In previous literature, the affective high-risk groups included offspring of subjects with both psychotic and nonpsychotic affective disorders, and in some studies43
it was not clear whether psychosis in the parent was included at all. The Finnish Adoptive Family Study,42
New York High-Risk Project,45
and Helsinki High-Risk Project19
examined APs in the offspring but did not explore the rates of APs in the offspring of parents with such disorders. The affective high-risk groups in the latter 2 studies were based on offspring of parents with unipolar disorder and bipolar disorder with and without psychosis. The Finnish Adoptive Family Study42
combined APs among parental schizophrenia spectrum disorders. Thus, our study findings are unique because we investigated specificity of transmission of illness in offspring of parents with SPS disorders compared with APs.
These findings must be replicated because, owing to sample size, we have limited power to test whether the 2-fold RRs we found for these “cross-disorder rates” (ie, AP in offspring among parents with SPS and vice versa) are in fact significant compared with the 6-fold increased risk of SPS in offspring of parents with SPS and the 14-fold increased risk of AP in offspring of parents with AP. However, the magnitude of the risks within each diagnostic grouping (ie, RRs of 5.5 and 14.0) are much higher than the cross-disorder risk estimates for both groups (ie, RRs of 2.1 and 2.2). This suggests, at least, that there is some cross-disorder risk but not as high as within psychosis type.
The reason for the specificity of the transmission of SPS disorders and APs found in our study is currently unknown. In fact, recent molecular studies suggested nonspecificity of transmission by psychosis type or some common genetic susceptibility genes for both classes of psychoses.76
However, the results of this study indicating relative specificity of transmission for type of psychosis must be seen in a larger context of an increasing focus on identifying similarities and differences between schizophrenia and APs. This effort includes identifying commonalities and dissimilarities in endophenotypes, such as auditory P30077
and other measures. An emerging model suggests that there is an overlapping genetic background to psychosis,81
but that schizophrenia, more than bipolar psychosis, is likely to be associated with additional neurodevelopmental insults.82
Our high-risk study suggests that clinical phenotypes (operationalized as lifetime diagnoses of these disorders in adult offspring and their parents) are relatively specifically linked within families to type of psychosis. This does not rule out the possibility that there will be overlapping neural phenotypes in our study, a question that is under active investigation by our group.
Recent molecular studies identifying unique and shared genes and environmental factors will help to elucidate mechanisms. The NEFS sample also provides a unique opportunity to contribute to this because we have stored prenatal and adult blood from these subjects to assess prenatal risk factors and genotyping in our family-based strategy. Furthermore, the sample has enriched childhood environmental variables to assess gene-environment interactions in our ongoing work with these cohorts.
Our family high-risk (FHR) study, along with other studies focused on offspring of parents with psychoses, provides an understanding of the transmission of psychosis from parents to their offspring. In addition, clinical high-risk (CHR) studies83-86
are based on enriched samples of adolescents or young people with prodromes for psychosis, individuals who already exhibit subthreshold symptoms and who are likely to develop psychosis within a relatively short time. This popular design provides an efficient approach to prospectively investigate the transmission of high-risk persons from the prodromal state to disease onset and potentially allows for targeted interventions during a treatment-seeking phase with a favorable risk to benefit ratio. Thus, CHR studies have a number of strengths not found in FHR studies, which have a lower rate of conversion to psychosis over longer periods.
However, we would argue that CHR studies complement but should not supplant the FHR design because each approach has strengths and weaknesses. For example, the FHR design enables investigators to study early precursors to illness, beginning with fetal life, thus enabling the identification of premorbid characteristics that may ultimately lay the foundation for early interventions and prevention strategies. In addition, assessment at earlier ages in FHR studies typically allows for evaluation without the potential confounding effects of medication use, which is far more common in treatment-seeking CHR individuals. The FHR studies tend to allow for more homogeneous cases, at least with respect to family diagnosis, whereas CHR studies include a mix of families in which there may be only 1 or multiple members with psychoses. Thus, the FHR studies, such as the one presented herein, have considerable value for understanding the developmental course of these illnesses given that there are few FHR-based studies in the literature, including the NEFS, with the potential for studies of lifelong development.