Prospective study of pandysmaturation and adult mental disorder in high-risk and normal-risk offspring.

More than 50 years ago, Fish postulated that a special form of early abnormal neurodevelopment, "pandysmaturation", defined a priori as constituting retarded cranial development in the first year of life, combined with delay in early motor milestone attainment, was related to genetic risk for schizophrenia, and was associated with schizophrenia-spectrum disorders in young adulthood. Fish confirmed this in a very small sample. We retested Fish's postulation in a larger prospective study. Pandysmaturation was blindly investigated through medical records and prospective researcher and maternal observations, studying 75 "high-risk" offspring of women with a history of schizophrenia or affective psychosis and 91 "normal-risk" offspring. Subjects were studied prospectively from mother's pregnancy to 22 years of age, at which time the offspring were independently assessed for schizophrenia-spectrum and affective disorders. Pandysmaturation (n = 13, with 10 "definite" and 3 "probable" degrees) was significantly related to genetic risk for schizophrenia (Odds Ratio 4.9, p = 0.02) but not to genetic risk for affective disorders (OR 1.2, p = 0.81). Pandysmaturation was significantly associated with schizophrenia-spectrum (OR 6.2, p = 0.02), but not affective (OR 0.9, p = 0.90), disorders in young adulthood. Pandysmaturation was more strongly associated than was retarded cranial development, motor milestone delay, or social/cognitive milestone delay by itself. Pandysmaturation has efficacy as an early life risk-indicator of schizophrenia-spectrum disorder in young adulthood at least in subjects at genetic risk, strengthening the evidence for a generally genetic-based neurodevelopmental model of schizophrenia-spectrum (as contrasted with affective) disorders. Pandysmaturation is a risk-indicator for future schizophrenia-spectrum disorder, for potential use in scientific studies and clinical practice.

Neurobehavioral deficits in young adult offspring with heightened risk for psychosis who developed schizophrenia-spectrum disorder.

Neurobehavioral deficits in neuromotor function, verbal memory, executive function and attention found in patients with schizophrenia and their relatives have been suggested to be liability indicators or predictors of schizophrenia. It remains uncertain which of these neurobehavioral deficits are components of the illness itself or characteristics associated with genetic risk for it. The purpose of this study was to investigate the relation between these neurobehavioral deficits and schizophrenia-spectrum disorder in young adults at genetic risk for psychosis. A 93%-effective follow-up (total n=166, mean 22.4 yr of age) of a sample longitudinally investigated since fetal age provided complete data for mental disturbance, neuropsychological performance and neurological abnormality for 74 offspring at increased risk for psychosis (38 offspring of mothers with schizophrenia and 36 offspring of mothers with affective psychosis) and 88 normal-risk offspring. Abnormal glabella reflex and deficits in verbal memory, attention and complex executive functions seem specifically to be related to schizophrenia-spectrum disorder (primarily Cluster A personality disorders) among offspring at genetic risk for psychosis, while neurobehavioral deficits in general characterized offspring at heightened (vs. normal) genetic risk for psychosis, with no relation to schizophrenia-spectrum disorders. The two patterns of neurobehavioral deficits observed here may possibly reflect different causes and different aspects of a deviant neurodevelopmental process, and potentially contribute to a more nuanced version of this all-pervasive (but often non-specific) "model" of schizophrenia's development.

Neuropsychological impairment and its neurological correlates in adult offspring with heightened risk for schizophrenia and affective psychosis.

OBJECTIVE: Schizophrenia is generally considered to be a neurodevelopmental disorder reflected in findings of neuropsychological impairments and neurological abnormality in patients and their relatives. The authors investigated whether neuropsychological impairments are related to neurological abnormality and whether such deficits also characterize risk for affective psychosis. METHOD: In a longitudinal study with a 93% rate of effective follow-up, the authors investigated neuropsychological impairment and its relation to neurological abnormality at a mean age of 22.3 years in 74 offspring of mothers with a history of psychotic disorders (38 offspring with heightened risk for schizophrenia and 36 with risk for affective psychosis) and 88 normal-risk offspring born to mothers with no history of psychosis. RESULTS: Offspring with genetically heightened risk for schizophrenia showed significantly impaired verbal memory, selective attention, and grammatical reasoning, compared with normal-risk offspring. Having impaired verbal memory, attention, and grammatical reasoning functions identified a significantly larger subgroup (16%) among offspring with heightened risk for schizophrenia than among offspring with heightened risk for affective psychosis (0%) and among normal-risk offspring (3%). Multiple neuropsychological functions were significantly related to neurological abnormality in offspring with heightened risk for schizophrenia and in normal-risk offspring but not among offspring with heightened risk for affective psychosis. The extension of schizophrenia and affective psychosis risk groups to include additional offspring of mothers with psychosis-spectrum disorders yielded results similar to those for the core risk groups. CONCLUSIONS: The neurocognitive dysfunction attending heightened risk for schizophrenia is likely based on genetically mediated neurodevelopmental factors, with schizophrenia and affective psychosis belonging to different biological spheres.

Prospective study of neurological abnormalities in offspring of women with psychosis: birth to adulthood.

OBJECTIVE: The authors prospectively investigated neurological abnormalities in 75 young adult offspring of mothers with psychotic disorders and 91 offspring of comparison mothers with no psychosis history. They also studied the stability of these abnormalities from birth to adulthood. METHOD: Neurological abnormalities were previously studied in infancy and at 6 years of age. In this study, they were blindly assessed with a comprehensive neurological assessment scale at a mean age of 22.4 years in a 93.3% effective follow-up of the sample. RESULTS: In relation to the comparison subjects (N=88) and offspring of mothers with affective psychosis (N=22), the adult offspring of mothers with schizophrenia (N=28) had significantly more neurological abnormalities. More soft signs, primitive reflexes, involuntary movements, and cranial nerve abnormalities characterized a subgroup (32%) among these offspring. The offspring of mothers with affective psychosis were not different from comparison subjects. The extension of schizophrenia and affective psychosis risk groups to include additional maternal "spectrum cases" (N=10 and N=14, respectively) generally yielded similar results. Neurological abnormalities at 22 years were significantly associated with neurological abnormalities at age 6, but not in infancy, among the total high-risk group, offspring of mothers with schizophrenia, and comparison offspring. CONCLUSIONS: High levels of neurological abnormalities are found in a substantial proportion of offspring of mothers with schizophrenia but not offspring of mothers with affective psychosis. This suggests that familial risk for schizophrenia is associated with neurodevelopmental disturbance that is manifest throughout life and belongs to a different biological continuum from that of affective psychosis.

Prospective study of adult mental disturbance in offspring of women with psychosis.

BACKGROUND: The high-risk method is an important strategy for studying the antecedents and causes of schizophrenia and other psychoses. The Swedish High-Risk Project is a prospective longitudinal study of offspring of women with a history of schizophrenic, schizoaffective, affective, or unspecified functional psychoses and control women with no history of psychosis. The offspring and their environments were studied beginning before birth, and again during childhood. This article reports the mental outcome results from the first adult follow-up at age 22 years. METHODS: Of 178 offspring, 166 (93%) were followed up and blindly assessed using standardized methods, including a self-report scale for mental symptoms and the Structured Clinical Interview for DSM-III-R. RESULTS: Compared with controls (n = 91), the offspring of mothers with schizophrenia (n = 28) showed a significantly increased frequency of DSM-III-R Axis I and Axis II disorders, poor global functioning, high Symptom Checklist-90 scores, and a history of mental health care and psychopharmacologic medication use. Offspring of mothers with affective disorders (n = 22) showed high Symptom Checklist-90 scores, more frequent poor functioning, and receipt of mental health care, with a significant increase in Axis I depressive disorders and no increase in Axis II disorders. The extension of schizophrenia and affective risk groups to include additional maternal "spectrum cases" (10 and 15 individuals, respectively) generally yielded similar results. CONCLUSIONS: Maternal schizophrenia is associated with widespread increases in offspring mental disturbance in adolescence and young adulthood, differing from offspring disturbance associated with maternal affective disorder.