Family matters: The influence of family history on phenomenology and IQ in patients with schizophrenia and their relatives

Although the exact aetiology of schizophrenia remains unknown, multiple genetic and environmental factors influence the development and expression of schizophrenia. The strongest risk factor to develop schizophrenia is the familial risk, thus having a family member with schizophrenia. The familiarity of schizophrenia is shown in the clustering of the diagnosis of schizophrenia as well as the clustering of (sub)clinical psychotic symptoms in certain families. In this thesis we aimed to explore the familiarity of schizophrenia by investigating the impact of family history on phenomenology in patients with schizophrenia and their unaffected siblings. First of all, we address some methodological issues concerning the collection of family history information and the calculation of familial loading. We investigated the role of a subject’s position in a pedigree on the validity of family history data collection. Moreover, we evaluated whether characteristics of the informant such as gender and personal history of psychiatric disorder influenced the assessment of family history. Second, an improved algorithm to calculate familial loading for schizophrenia is described in such a way that the algorithm i) allows for a non-linear increase in risk of illness; ii) takes sex differences into account; and iii) can be applied to data of first- and second degree relatives. Since the risk of clinically diagnosed schizophrenia is associated with a family history of a much wider range of psychiatric disorders, one could hypothesize that the definition of familial loading in schizophrenia, now based on the presence or absence of psychosis in family members, should be broadened to all psychiatric disorders. The association between family history of psychiatric disorder and IQ is investigated in patients with schizophrenia, their siblings and controls. The familiarity of schizophrenia is also characterized by the familial clustering of subclinical psychotic and other psychiatric symptoms. First, familial clustering of the positive, negative, and depressive symptom dimensions is explored in three groups: (i) patients with psychotic disorder and their healthy siblings, (ii) healthy sib-pairs of affected families, and (iii) healthy control sib-pairs. Second, the association between attention deficit, hyperactivity/impulsivity and psychotic symptoms is investigated in patients with schizophrenia, their siblings who are unaffected for psychosis and healthy controls. Taken together, the results of this thesis raise some important issues for unraveling the familiarity of schizophrenia. First, family studies encounter various methodological problems, which should also be addressed when examining schizophrenia. Second, the familiarity of schizophrenia includes more than psychotic disorders alone. For future studies in schizophrenia it is necessary to broaden the definition of family history to all psychiatric disorders, as narrowing the definition of family history to psychosis underestimates the psychopathology in families of schizophrenia patients. Moreover, as the familiarity of schizophrenia also includes subclinical symptoms across psychiatric disorders, one should consider assessing these in patients' relatives. Understanding the clinical (endo)phenotypes might further enhance the prediction of the transition to psychosis in (high risk) populations.