The adolescent brain and age-related behavioral manifestations

In this article, we advance a unified hypothesis pertaining to combined dysfunction of dopamine andN-methyl-D-aspartate glutamate receptors that highlights N-methyl-D-aspartate receptor hypofunction as a key mechanism that can help explain major clinical and pathophysiological aspects of schizophrenia. The following fundamental features of schizophrenia are accommodated by this hypothesis: (1) the occurrence of structural brain changes during early development that have the potential for producing subsequent clinical manifestations of schizophrenia, (2) a quiescent period in infancy and adolescence before clinical manifestations are expressed, (3) onset in early adulthood of psychotic symptoms, (4) involvement of dopamine (D2) receptors in some cases but not others that would explain why some but not all patients are responsive to typical neuroleptic therapy, and (5) ongoing neurodegenerative changes and cognitive deterioration in some patients. We propose that since N-methyl-D-aspartate receptor hypofunction can cause psychosis in humans and corticolimbic neurodegenerative changes in the rat brain, and since these changes are prevented by certain antipsychotic drugs, including atypical neuroleptic agents (clozapine, olanzapine, fluperlapine), a better understanding of the N-methyl-D-aspartate receptor hypofunction mechanism and ways of preventing its neurodegenerative consequences in the rat brain may lead to improved pharmacotherapy in schizophrenia.

Glutamate receptor dysfunction and schizophrenia.

Child developmental risk-factors for adult schizophrenia in the british 1946 birth cohort

In the context of a Finnish birth cohort, we tested the hypothesis that viral infection during the latter two thirds of fetal development would increase the risk of adult schizophrenic outcome. Psychiatric hospital diagnoses were recorded for all individuals in greater Helsinki who were fetuses during the 1957 type A2 influenza epidemic. Those exposed to the viral epidemic during their second trimester of fetal development were at elevated risk of being admitted to a psychiatric hospital with a diagnosis of schizophrenia. This was true for both males and females and independently in several psychiatric hospitals. The second-trimester effect was seen in the elevated proportion of schizophrenics among those admitted to a psychiatric hospital and also in higher rates of schizophrenia per 1000 live births in the city of Helsinki. The study has several limitations: (1) We have no direct evidence that the subjects actually suffered a viral infection. (2) The psychiatric data were obtained only for subjects up to the age of 26 years, 56 days. (3) The findings are based on hospital diagnoses. (4) The determination of stage of gestation at time of exposure to the epidemic is based on date of birth. The viral infection might have occurred outside the official epidemic window; the infant may have had a preterm or postterm delivery. These sources of error, however, should not serve to enhance the findings. The observed viral effect is interpreted as being one of many potential perturbations of gestation. We suggest that it is less the type than the timing of the disturbance during fetal neural development that is critical in determining risk for schizophrenia.

Adult Schizophrenia Following Prenatal Exposure to an Influenza Epidemic

An emerging literature from epidemiologic, clinical, and preclinical investigations has provided evidence that gestational exposure to infection contributes to the etiology of schizophrenia. In recent years, these studies have moved from ecologic designs, which ascertain infection based on epidemics in populations, to investigations that have capitalized on reliable biomarkers in individual pregnancies. These studies have documented specific candidate infections that appear to be associated with an elevated risk of schizophrenia. Animal models of maternal immune activation inspired by this work have revealed intriguing findings indicating behavioral, neurochemical, and neurophysiologic abnormalities consistent with observations in schizophrenia. In parallel studies in humans and animals, investigators are working to uncover the cellular and molecular mechanisms by which in utero exposure to infection contributes to schizophrenia risk. In this review, the authors discuss and critically evaluate the...

https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2009.09030361

Prenatal Infection and Schizophrenia: A Review of Epidemiologic and Translational Studies

Background: We have previously reported an increase in schizophrenia diagnoses in a population exposed during the second trimester to the 1957 influenza epidemic. These basic findings together with a fair number of replications have been interpreted as supporting a neurodevelopmental contribution to the origins of schizophrenia. Recent neuroimaging findings suggest that affective illness may also have a neurodevelopmental origin. We examined the hypothesis that exposure to an influenza epidemic during the second trimester would increase the risk for adult major affective disorder. Methods: The subjects had been exposed as fetuses to the type A2/Singapore influenza epidemic in greater Helsinki, Finland. Control subjects were born in the 6 years before the epidemic. Results: We found a significant (P .05) were similar. The second-trimester effect remained when we estimated population-based rates (2.1 vs 0.6 per 1000) (P .05) elevation was observed for the bipolar forms of major affective disorder. Conclusions: These data are consistent with the hypothesis concerning the possible neurodevelopmental contribution to the origins of some forms of major affective disorder, especially unipolar depressive disorder. These encouraging findings, if replicated, may suggest that some mental disorders may stem, in part, from a disturbance in the development of the fetal brain during the second trimester.

Adult Major Affective Disorder After Prenatal Exposure to an Influenza Epidemic

Birth occurring in winter months, which are high viral infection months, have been repeatedly shown to produce a slight excess of later-diagnosed schizophrenics. As a result, some researchers have speculated on the possible aetiological effect of viral infections on some forms of schizophrenia. The implications of the viral hypothesis were indirectly tested in the context of an ongoing prospective study of Danish children at high-risk (HR) for schizophrenia. A third-order analysis of variance interaction was hypothesized. Genetically vulnerable individuals, born in winter, in an urban environment (which increases the likelihood of the presence and transmission of viruses) would be more likely, as foetuses or neonates, to have suffered some CNS damage due to the infection; thus they would show higher rates of schizophrenia in the HR-urban-winter birth condition reached 23.3 per cent, considerably above population base rates (1 per cent) or rates for the HR subjects (8.9 per cent). Alternative explanations for the results were explored.

The interaction of seasonality, place of birth, genetic risk and subsequent schizophrenia in a high risk sample.

Hospitalization patterns in schizophrenia: A 13-year follow-up

The excess of winter–spring births among individuals suffering from schizophrenia provides strong evidence for the existence of some prenatally occurring factors in the pathogenesis of schizophrenia. Recent epidemiological findings suggest that maternal viral infections during the second trimester of pregnancy may play a crucial role in the aetiology of adult schizophrenia. A ‘two-hit window’ hypothesis of the mechanism of action of prenatal factors in the pathogenesis of schizophrenia suggests at least two time-specific prenatal aetiological events. The observed association between prenatal viral infection and increased incidence of adult schizophrenia need not be a direct cytotoxic result of the viral infection, but may be caused indirectly, for example from foetal minor cerebral haemorrhages produced by the anticoagulant effects of aspirin.

Ricardo A. Machon

Papers

Adult Schizophrenia Following Prenatal Exposure to an Influenza Epidemic

Adult Major Affective Disorder After Prenatal Exposure to an Influenza Epidemic

The interaction of seasonality, place of birth, genetic risk and subsequent schizophrenia in a high risk sample.

Hospitalization patterns in schizophrenia: A 13-year follow-up

Prenatal factors in the pathogenesis of schizophrenia.