Liability indicators aggregate many years before transition to illness in offspring descending from kindreds affected by schizophrenia or bipolar disorder
Introduction
Major psychoses, as other complex disorders, have determinants in childhood (Maziade and Paccalet, 2013, Shonkoff et al., 2009). Research on major psychoses is shifting from psychotic symptoms to dimensional components and neurodevelopmental trajectories (Insel, 2010, Insel, 2014). Congruently, the “Just the Facts” series published in this Journal proposed to convert our reasoning about schizophrenia by rethinking the disease modeling (Keshavan et al., 2011b). In a new era where knowledge is acquired in developmental vulnerabilities and in new interventions in clinical high-risk (CHR) youths (Seidman and Nordentoft, 2015), longitudinal risk studies beginning in childhood can transform our views of the early phases of the trajectories preceding major affective or non-affective disorders.
Many documented risk indicators may characterize the risk trajectories. For instance cognitive impairments are present before the prodromal phase of major psychoses although their relative predictivity is still being debated (Bora et al., 2014, McGorry, 2013). Other childhood-adolescence risk factors, such as psychotic-like experiences (Dominguez et al., 2011, van Os et al., 2009), non-psychotic DSM diagnosis (Axelson et al., 2015, Hans et al., 2004, Maziade et al., 2008), drug use (Gage et al., 2015, Kraan et al., 2015) and trauma (Berthelot et al., 2015, Varese et al., 2012) may also provide meaningful information. Few longitudinal studies have investigated the relative predictive value of cognitive impairments in the context of these four other childhood-adolescence risk indicators in offspring at genetic risk.
Previous long-term longitudinal studies of offspring of parents affected by schizophrenia (SZ) that reached the age of disease incidence (reviewed in Erlenmeyer-Kimling, 2000) found delays in developmental milestones and cognitive impairments in 50% of these offspring (Agnew-Blais and Seidman, 2013, Maziade et al., 2008). Longitudinal studies of offspring of bipolar (BP) patients overall showed that early psychopathologies (Duffy et al., 2014) or sub-threshold manic symptoms (Axelson et al., 2015) tended to predict the later incidence of mood disorders.
Our 25-year longitudinal research in children and adults from a quasi-total sample of multi-affected kindreds in the Eastern Quebec population has bridged family-genetics and developmental psychopathology. The program produced many complementary bodies of familial and developmental findings recently revisited in this Journal (Maziade and Paccalet, 2013). This re-examination led to four empirical observations that needed to be reconciled. Inspired by research in cancer mechanisms, we posited a protective-compensatory model in which a ‘defective protective gene’ running in families would impact the developmental trajectory of the child at risk inheriting it.
We found that many risk endophenotypes would be shared by offspring of parents with SZ or BP, which is congruent with the genetic and phenotypic commonalities otherwise observed in adult SZ and BP patients (Maziade et al., 2011, Van Snellenberg and de Candia, 2009), which does not exclude a degree of specificity. These findings appeared in continuity with new populational data suggesting that the earliest expression of psychosis or mood disorder would be a non-specific mix of symptoms across multiple diagnostic categories (Fusar-Poli et al., 2014; McGorry and van Os, 2013, van Os, 2013). In the young offspring descending from these families, we also found that trauma may negatively impact in childhood/adolescence the cognitive domains (Berthelot et al., 2015) that are impaired in adult patients.
We have never before presented a complete clinical and developmental portrait of the high-risk offspring descending from these kindreds. The present objective is thus to provide this portrait composed of many behavioral and environmental risk indicators such as cognitive dysfunctions, psychotic-like experiences, non-psychotic DSM diagnosis in childhood, drug use and childhood trauma, and to use these risk indicators to characterize trajectories. Also, since many offspring have now reached the age of incidence and some have progressed to a major affective or non-affective DSM-IV disorder (schizophrenia spectrum disorders, bipolar disorder or major depressive disorder) or other axis I disorders, our second objective was to describe their adult outcome in relation to their earlier trajectories.
Section snippets
Kindred sample
We targeted all the multigenerational families densely affected by schizophrenia (SZ) or bipolar disorder (BP) in the Eastern Quebec (Canada) catchment area as described in Supplemental Methods and in Maziade et al. (2005). Over 1800 adult family members in 48 kindreds have been enrolled and > 400 hundred patients were diagnosed DSM-IV schizophrenia or mood disorders (Fig. S1). This regional screening setting facilitated the follow-up of the offspring as defined below and the tracking of all
Characteristics of the whole offspring sample in childhood-adolescence
Clinical and demographic features of the whole sample and of transitioners and non-transitioners are in Table 1 and Table 3, respectively. Overall, the childhood-adolescence rate of cognitive impairment was 65%, non-psychotic DSM diagnoses 56%, psychotic-like experiences 17%, drug use 45%, and trauma 44% (Fig. S2).
The offspring were divided into 4 subgroups of outcome. The first subgroup of 15 youths had transitioned to a major DSM-IV affective or non-affective disorder (i.e. transitioners,
Strengths and limitations
As in most longitudinal cohorts, the number of subjects who transitioned to an axis I disorder was relatively small and type 2 errors are possible. Second, we relied on established risk indicators. Our observations are thus limited by the choice of measures. Third, the age of non-transitioners was 30 or older and some may still experience a transition. Fourth, the descent from highly familial patients may limit generalization although evidence suggests that familial samples may generate
Role of funding source
This work was funded by a Canada Research Chair (#950-200810) in psychiatric genetics of which Maziade is the Chair and by Canadian Institute of Health Research grants (#MOP-74430 and #MOP-114988). The funding organizations had no role in the writing of this article.
Contributors
Conceived and designed the experiments: MM, TP, and EG. Performed and analyzed the clinical and cognitive assessments: EG, NB, and DL. Performed the statistical analyses: VJ. Analyzed the data: MM, TP, EG, and PM. Contributed to participant recruitment and lifetime diagnosis evaluations: RHB, DC, and NG. All authors contributed to and have approved the final manuscript.
Conflict of interest
All authors declare that they have no conflicts of interest.
Acknowledgements
We would like to thank the family members, adults and children, who participated in the Eastern Quebec Kindred Study. We are also grateful to our professional research assistants, Marie-Claude Boisvert, Valérie Beaupré-Monfette, Linda René, Claudie Poirier, and Joanne Lavoie.
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2022, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Furthermore, the above preclinical risk indicators have been shown to progressively accumulate in young children and adolescents at risk (Paccalet et al., 2016). This progressive clustering of risk indicators has shown up as a better predictor of a later transition to illness than any single risk factor taken alone (Paccalet et al., 2016). Such an accumulation process and its greater long-term predictivity would not be exclusive to psychiatric disorders as risk clusters have also been observed in children at risk of other complex illnesses, such as in metabolic-cardiovascular disorders (Magge et al., 2017) which is also part of the regular practice of psychiatrists and family doctors.
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