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Discussion
When a mother or father with SMI, such as bipolar disorder, asks a clinician how likely it is that their child will also become ill, the likely answer informed by previous literature is that the risk is about 1 in 10. The present meta-analysis suggests that, by early adulthood, the offspring has a 1-in-3 risk of developing a psychotic or major mood disorder and 1-in-2 risk of developing any mental disorder. Given the limited number of studies on adult offspring of parents with mood disorders and child offspring of parents with schizophrenia, these results should still be considered preliminary. The fact that not all disorders were assessed in most studies and that rates of diagnoses increased with repeated assessments suggest that these may be underestimates. Clinicians should seriously consider how to inform patients of the elevated risks of mental disorders in their children, as the perceived risk can be a factor in decisions of whether or not to have children. Evidence suggests that providing risk descriptors along with probabilities as part of an in-depth discussion with patients reduces the risk of miscommunication and misperception of risk. Following the present results, a clinician may consider the risk of the same disorder, risk of other SMI and risk of less severe mental disorders, taking into account the age of the offspring and the nonnegligible base rates of mental disorders in the general population. Such fine-grained discussion will give the parents and prospective parents honest and complete information.
The specificity of familial transmission of risk is relevant to thinking on etiology of illness, classification of diseases and to the planning of early interventions. The present meta-analysis finds that familial risk extends across diagnostic boundaries. This confirms results from population registry and genetic studies that report overlap of familial and genetic risk to various mental disorders. The results of the meta-analysis also suggest that familial transmission can be heterotypic (different from parent diagnosis), yet diagnosis specific: the risk of anxiety disorders was elevated in offspring of parents with bipolar disorder or depression, but not in offspring of parents with schizophrenia. The heterotypic familial transmission supports recent findings from molecular genetic analyses suggesting shared genetic factors underlying schizophrenia, bipolar disorder and major depression. However, to what extent the observed parent-offspring association is due to genetic factors vs environmental factors remains open.
The finding of limited specificity suggests that cross-disorder approaches may be useful not only in etiological studies but also in planning of early preventive interventions aiming to reduce the risk of SMI. To appreciate the degree of specificity, it is necessary to consider both absolute and relative rates. Because major depressive disorder is more common than schizophrenia, a smaller RR for depression among adult offspring of parents with SMI (RR = 1.52) caused greater increase in the absolute risk of SMI than a higher RR for schizophrenia among adult offspring of parents with SMI (RR = 6.19). When comparing RR and absolute risks, it is clear that homotypic risks are numerically greater (especially in relative terms), but heterotypic risks are still significantly elevated and substantially contribute to the elevated absolute risk for any SMI in offspring of parents with SMI. The fact that familial risk extends across disorders suggests that it may be more efficient to target common mechanisms and antecedents preceding the development of various mood and psychotic disorders. Finally, the heterotopy and limited specificity of familial transmission is relevant to the development of psychiatric classification where increasing number of categories contrasts with the lack of evidence supporting most diagnostic boundaries. Future research into biological and environmental causes of SMI may be more fruitful if it is not constrained by current consensus diagnostic categories. Future studies may also examine the value of dimensional constructs cutting across the diagnostic categories in explaining heterotypic transmission.
The meta-analysis overcame to some extent the limited statistical power of individual FHR studies to detect smaller cross-diagnostic risks. Yet, the results must be interpreted in the context of limitations inherent in the methodology and heterogeneity of the contributing studies. First, the coverage of offspring of different age was uneven with sparse data for adult disorders among offspring of parents with depression and of childhood disorders among offspring of parents with schizophrenia. This means that some disorder-specific questions (eg, whether the risk of schizophrenia is significantly elevated among offspring of parents with depression) remain open. Some apparently surprising disorder-specific findings may be due to small numbers included. For example, the rate of schizophrenia and related disorders among offspring of parents with schizophrenia aged under 20 was surprisingly high at 10%. However, this estimate was based on a small number of offspring and may not be reliable. This highlights the need for examining more adolescent offspring of parents with schizophrenia. In addition, some cases of major depressive disorders among offspring may be reclassified as bipolar disorder if manic or hypomanic episode develop on further follow-up. Future FHR research would complement current data with investigation of childhood disorders in offspring of parents with schizophrenia and follow-up into adulthood of offspring of parents with mood disorders. Second, the diagnosis of the co-parent was not reported in most studies and as a result we were unable to assess effects of multiple affected parents. These effects may be nonnegligible in context of assortative mating and dose-response relationships between the number of affected parents and risk of mental disorders in offspring. Third, most studies made their diagnoses based on single cross-sectional assessment. Cross-sectional assessment has been shown to underestimate the lifetime rates compared with sequential assessments. We found that the rates of SMI were higher in longitudinal studies where offspring were assessed repeatedly. In addition, most offspring had not been followed up through the age of peak risk of SMI onset. Thus, the current results are likely to underestimate the actual lifetime risks.
This meta-analysis of family high-risk studies of SMI found that familial transmission of risk is only partly diagnosis specific. As a result, the total risk of SMI and any mental illness in offspring of parents with psychotic or major mood disorders are higher than previously thought. This should be reflected in genetic counseling and information provided by clinicians. Cross-diagnostic research may be needed to advance the knowledge of etiology and plan effective preventive interventions.
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