Developmental high-risk criteria for severe mental illness: a neurodevelopmental framework for premorbid detection

Le résumé fourni par la source

Severe mental illnesses (SMIs) such as schizophrenia, bipolar disorder and major depressive disorder are increasingly conceptualized as neurodevelopmental in origin; i.e. clinical symptoms emerge during prodromal stage leaning on a neurobiological substrate of vulnerability unfolding along neurodevelopment, usually expressed in the phenotype in terms of unspecific premorbid features at the neurocognitive and behavioral levels (1). According to this perspective, rather than abruptly emerging during late adolescence or early adulthood, SMIs often evolve gradually through earlier, often subtle, developmental alterations reflecting complex dynamic interactions between individual and familial strengths and risk factors (2).Contemporary models of psychiatric staging (3) suggest that the visible prodromal onset of attenuated psychotic or affective symptoms represents only the distal phase of a longer trajectory, sometimes altered since birth or even gestational age (2). Moreover, only a fraction of help-seeking individuals intercepted by early detection services inspired by clinical high-risk models [for psychosis (CHR-P) or bipolar disorder (BAR)] undergo a homotypic transition to SMIs (i.e., from CHR-P to frank psychosis as well as from BAR to bipolar disorder) (4,5) as well only a minority of adult patients with SMIs were previously intercepted by CHR criteria (6).To reach a wider audience of individuals that could potentially benefit of early prevention interventions, the focus of detection should shift from a narrow focus on attenuated or intermittent symptomatic prodromes to a broader, developmentally grounded profile of early (apparently unspecific) vulnerabilities (2,7). There is accumulating evidence that the premorbid stage of several SMIs, usually coinciding with childhood and early adolescence, is concretely characterized by phenotypic manifestations that are unspecific as regards the prognostic outcome but signal the underlying atypical neurodevelopment. For example, childhood motor clumsiness, dys-coordination and neurological soft signs have been associated with an increased likelihood of later psychotic outcomes at the group level in offspring of schizophrenic or bipolar parents (8), without implying deterministic or specific trajectories, and a childhood diagnosis of attention deficit/hyperactivity disorder is a precursor of later SMIs (9). Finally, the prognostic long-term salience of early neurodevelopmental manifestations for later SMIs is supported by register-based studies, showing a substantial proportion of future psychotic and bipolar disorder cases emerging in individuals who had attended child and adolescent mental health services (CAMHS) (10).The prognostic salience of early neurodevelopmental phenotypic expressions was already caught for example by the ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) construct (11), profiled for children (and their parents) presenting in clinical settings with impairing child symptoms before age 3 (-5) years in the fields of (a) general development, (b) communication and language, (c) social inter-relatedness, (d) motor coordination, (e) attention, (f) activity, (g) behaviour, (h) mood, and/or (i) sleep. However, being ESSENCE a construct profiled for infancy, long-term prognostic outcomes up to adolescence or early adulthood are lacking.Overall, early neurodevelopmental manifestations (due to the aggregation and interaction of genetic and early environmental risk factors) and later (if not concomitant) psychiatric manifestations could longitudinally represent two sides of the same coin along clinical staging (3), with the p factor (i.e. liability for psychopathology) putatively intercepting such vulnerability (12).With the aim to operationally implement such shift from prodromal symptomatic manifestations to premorbid signals of risk, we attempt to profile a set of criteria for the construct of Developmental High-Risk for Severe Mental Illness (DHR-SMI), based on empirically-supported, easily collectable features, not limited to neurodevelopmental expressivity but including also other risk factors that may cause or maintain such expressivity along time.The profile is based on 5 domains, resumed in Table 1 and operationalized in Table 2: three domains are based on risk factors that may affect neurodevelopment (presumed genetic risk, prenatal and perinatal hazards, adverse childhood experiences), one domain based on severity of neurodevelopmental expressivity (CAMHS access and neurodevelopmental diagnoses) and one domain based on sociodemographic vulnerability, capable of boosting stressing effects of the first three domains. Each domain can be scored 0/1/2 (absent/subthreshold/definite) to capture doseresponse without forcing artificial cut-offs. Sum produces a 0-10 DHR-SMI score, that can be treated as a continuous predictor in survival models. Such score can be profiled once as a baseline and longitudinally updated, considering that some domains are fixed (presumed genetic risk and prenatal/perinatal hazards) while other may undergo modifications along time.Family psychiatric history remains one of the most reliable and accessible indicators of heritable vulnerability. Having a first-degree relative with SMI is associated with a significantly elevated risk for future SMI in offspring: i.e. in the most recent meta-analysis, The Risk Ratio and lifetime risk of developing any mental disorder were 3.0 and 55% in offspring of parents with anxiety disorders; 2.6 and 17% in offspring of those with psychosis; 2.1 and 55% in offspring of those with bipolar disorder; 1.9 and 51% in offspring of those with depressive disorders; and 1.5 and 38% in offspring of those with substance use disorders (13).While polygenic risk scores currently show limited clinical utility due to modest predictive accuracy and the omission of complex transgenerational and epigenetic factors, family history encompasses both genetic and shared environmental contributions, rendering it a pragmatic marker in early risk stratification (14).Obstetric complications such as low birth weight, caesarean delivery, hypoxia, and prenatal infections represent early biological stressors that may disrupt normative brain development (15,16). These insults can early constrain neurodevelopment, predisposing individuals to later childhood cognitive and emotional dysfunctions, which are core unspecific premorbid features of several SMIs (2,7).Their routine documentation in perinatal medical records enhances their feasibility as screening variables in early risk assessment.Early prolonged psychosocial stress, related to a dysfunctional familial environment and epidemiologically signalled by subjective reports of adverse childhood experiences in terms of abuse, maltreatment and neglect, is consistently associated with elevated risk for psychotic and mood disorders (17). These adversities exert neurobiological effects through stress-sensitization pathways and alterations in affect regulation, social cognition, and Self-concept. Recognizing these experiences as foundational developmental disruptions rather than merely contextual variables is key to constructing comprehensive early risk profiles. Importantly, neurodevelopmental vulnerabilities may themselves increase exposure to adverse environments (e.g., through peer rejection, academic difficulties, or family stress), suggesting a bidirectional interaction between individual characteristics and environmental adversity across development. Along development, also adverse experiences outside the familial environment as bullying or social rejection boost subjective psychosocial stress and constraint intersubjectivity, contributing to increase the risk of mental illness (18). Conversely, early and targeted interventions (e.g., parenting support, school-based programs) may modify these trajectories, supporting functional reorganization and more adaptive developmenta

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