Background Obstetric complications, particularly fetal hypoxia, are associated with increased risk for schizophrenia later in life. Such factors are also related to increased severity of certain ...neuropathological features of schizophrenia, including hippocampal and cortical gray matter reduction, among individuals with a genetic susceptibility to the disorder. However, the molecular mechanisms underlying these associations are unknown. Here, we sought to determine whether neurotrophic factors, which are stimulated as part of a neuroprotective response to fetal distress, are differentially expressed in cord blood samples at the time of birth following fetal hypoxia, maternal hypertension/small for gestational age status, and/or prematurity among individuals who developed schizophrenia as adults, as compared with control subjects. Methods One hundred eleven cases with psychotic disorders (70 with schizophrenia) and 333 control subjects matched for gender, race, and date of birth were drawn from the Philadelphia cohort of the National Collaborative Perinatal Project in a nested case-control study. Brain-derived neurotrophic factor (BDNF) was assayed from cord and maternal blood samples taken at delivery and stored at −20°C for 45 to 50 years. Results Among control subjects, birth hypoxia was associated with a significant (10%) increase in BDNF in cord samples, while among cases, hypoxia was associated with a significant (20%) decrease in BDNF. This differential response to fetal hypoxia was specific to schizophrenia and was not explained by other obstetric complications or by the BDNF valine (val) to methionine (met) polymorphism at codon 66 (val66met). Conclusions These findings provide serologically based prospective evidence of disrupted neurotrophic signaling in response to birth hypoxia in the molecular pathogenesis of schizophrenia.
The objective of the present study was to examine if the monthly variation in births of individuals diagnosed with schizophrenia currently differs from that of unaffected individuals in Sweden. In an ...extensive linkage of Swedish national and regional population registers we here investigate the birth pattern of the population born 1940–97 (5,995,499 individuals) which included 30,684 individuals diagnosed with schizophrenia in the National Patient Register by December 31, 2016. Among 2,409,862 individuals born since 1973 we investigated potential confounding by co-variates associated with pregnancy and birth. We also compared the monthly birth pattern of 22,570 affected individuals to that of their 41,528 unaffected full siblings. We observe a significant birth excess of individuals with schizophrenia in December, HR 1.07 95%CI (1.01–1.13). Patients born in December received a registered diagnosis of schizophrenia at a slightly younger age than those born during other months. A number of co-variates were associated not only with schizophrenia but also varied across birth months. Inclusion of these in the models however had virtually no influence on the risk for schizophrenia associated with December birth. In comparisons between full siblings, the association between December birth and later diagnosis of schizophrenia remained, albeit slightly attenuated, HR 1.06 (0.99–1.12). Risk for schizophrenia associated with birth in December in Sweden during the study period does not appear to be fully explained by our investigated co-variates or factors shared between family members and may thus represent monthly/seasonal variation in environmental factors involved in the etiology of schizophrenia.
Abstract Background Pregnancy and birth complications, particularly those associated with maternal inflammation and fetal hypoxia, are associated with increased risk for schizophrenia later in life. ...However, the molecular mechanisms underlying these associations are not fully delineated. This study sought to examine the effect of exposure to maternal inflammation on risk of developing psychosis in adulthood. Maternal serum levels of pro-inflammatory Th1 cytokines (IL-2, interferon gamma IFN-γ, IL-12) and Th17 cytokines (IL-1b, IL-6, IL-8, tumor necrosis factor alpha TNF-α, granulocyte macrophage colony stimulating factor gm-csf) and anti-inflammatory Th2 cytokines (IL-4, IL-5, and IL-13) and Treg cytokines (IL-10) were evaluated for association with later psychosis in the offspring. Methods Subjects were 43 adults with psychoses and 43 matched controls followed from gestation as part of the Philadelphia cohort of the National Collaborative Perinatal Project. Adult symptoms of psychosis were assessed via medical records review and confirmed with a validation study. Archived maternal serum samples collected at the time of birth were analyzed for cytokine levels using a multiplex bead assay. Results Individuals exposed to elevated maternal levels of anti-inflammatory Th2 cytokines (≥ 75th percentile) were significantly less likely to develop psychosis in adulthood. Conclusions These results may suggest that increased maternal levels of anti-inflammatory cytokines during the perinatal period could protect against the development of psychosis.
Background Viral exposure during gestation is thought to be a risk factor for schizophrenia. Previous studies have indicated that prenatal exposure to herpes simplex virus type 2 (HSV-2) may be a ...risk for the subsequent development of schizophrenia in some populations. In this investigation, we tested a large and diverse population to assess the risk of psychoses among offspring of mothers with serological evidence of HSV-2 infection. Methods We conducted a nested case-control study of 200 adults with psychoses and 554 matched control subjects (matched for city and date of birth, race/ethnicity, gender, and parent history of treatment for mental disorder) from three cohorts of the Collaborative Perinatal Project (Boston, Providence, and Philadelphia). We analyzed stored serum samples that had been obtained from these mothers at the end of pregnancy for antibodies directed at HSV-2, using type-specific solid-phase enzyme immunoassay techniques. Results Offspring of mothers with serologic evidence of HSV-2 infection were at significantly increased risk for the development of psychoses (odds ratio OR = 1.6; 95% confidence interval CI = 1.1–2.3). This risk was particularly elevated among women with high rates of sexual activity during pregnancy (OR = 2.6; 95% CI = 1.4–4.6). Conclusions Maternal exposure to herpes simplex virus type 2 is associated with an increased risk for psychoses among adult offspring. These results are consistent with a general model of risk resulting from enhanced maternal immune activation during pregnancy.
Abstract In 1873 Skeffington Lutwidge, a Lunacy Commission inspector of asylums in England, was killed by an asylum patient. Lutwidge was the uncle and close friend of Charles Lutwidge Dodgson, also ...known as Lewis Carroll. One year later, Carroll began writing The Hunting of the Snark , a poem whose meaning has mystified Carroll enthusiasts. In fact, the poem is a description of the Lunacy Commission inspection team and reflects Carroll's personal understanding of, and reaction to, the killing of his uncle by an individual with a severe mental illness. Carroll's close relationship with his uncle also explains the prominence of psychotic thinking in Carroll's work, including the Mad Hatter's tea party.
The NIMH Research Portfolio: An Update Torrey, E Fuller; Simmons, Wendy W; Dailey, Lisa
Primary care companion for CNS disorders,
2023-Aug-01, Letnik:
25, Številka:
4
Journal Article
Recenzirano
To examine the funding priorities of the National Institute of Mental Health (NIMH) since 2016 to assess whether NIMH was continuing to prioritize basic research at the expense of clinical research.
...Six psychiatric disorders (schizophrenia, bipolar disorder, depression, anxiety disorders, eating disorders, autism) were assessed using 2 publicly available data sources (ClinicalTrials.gov and the National Institutes of Health Research, Condition, and Disease Categorization RCDC) to determine the degree of NIMH support for drug trials and research on these disorders in general since 2016.
From 2017 through 2022, ClinicalTrials.gov lists just 1 drug trial each for schizophrenia and bipolar disorder. The RCDC database for 2016 through 2021 shows that NIMH support for research projects on schizophrenia and bipolar disorder decreased by 22% and 20%, respectively. During that time, Congress increased the budget of NIMH by 40%.
NIMH has continued to prioritize basic research over clinical trials, resulting in a steep decline in funding for possible treatments for the most serious and costly psychiatric diseases.
.
Previous studies have shown that maternal antibodies to
Toxoplasma measured during pregnancy are associated with an increased risk of schizophrenia and other psychoses in adult offspring. Recently, ...it has been recognized that different genotypes of
Toxoplasma have distinct neuropathogenic potential. The objective of this study was to investigate whether parasite genotype is a contributing factor to disease risk. We have developed an enzyme-linked immunosorbent assay (ELISA) that uses polymorphic polypeptides specific to the three clonal parasite lineages and derived from three dense granule antigens, GRA5, GRA6 and GRA7. We used this assay to measure type-specific antibodies in the sera from 219 pregnant women whose children developed schizophrenia and affective psychotic illnesses in adult life, and 618 matched unaffected control mothers from three cohorts of the Collaborative Perinatal Project. We found that the offspring of mothers with a serological pattern consistent with
Toxoplasma type І infection were at significantly increased risk for the development of psychoses as compared with the matched unaffected control mothers (odds ratio
=
1.94; 95% confidence interval
=
1.08–3.46;
p
=
0.03). The risk was particularly elevated for affective psychoses (OR
=
5.24; 95% CI
=
1.67–16.5;
p
=
0.005). In contrast, we did not find an association between maternal antibodies to other genotypes and risk of psychoses in the offspring. These findings suggest an influence of the parasite genotype on increased risk of psychosis and provide further support for a substantive role of
Toxoplasma in the etiology of psychosis.
Abstract Cognitive impairment is a core feature of schizophrenia. Previous studies have indicated that exposure to neurotropic infectious agents such as Herpes Simplex Virus type 1 may contribute to ...cognitive deficits and neuroanatomical abnormalities in individuals with schizophrenia. We examined the association between exposure to neurotropic infectious agents and cognitive function in 1308 participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial. This sample included all of the individuals in the CATIE trial for whom baseline blood samples were available. Cognition was evaluated at baseline by a test battery which yielded composite scores in the domains of processing speed, verbal memory, vigilance, reasoning, and working memory as well as a summary neurocognitive score. Solid phase immunoassay techniques were used to measure IgG class antibodies to Herpes Simplex Virus type 1 (HSV-1), Herpes Simplex Virus type 2 (HSV-2), Cytomegalovirus (CMV), and to Toxoplasma gondii ( T gondii ) in the sera of the study individuals. We found a significant association between the neurocognitive summary score and antibodies to HSV-1 but not to HSV-2, CMV, or T. gondii . There was also a significant association between HSV-1 exposure and the Verbal Memory, Vigilance, and Processing Speed composite scores. HSV-1 may modulate the neurocognitive function of individuals with schizophrenia through its ability to establish latency in the central nervous system and undergo periodic reactivation. A better understanding of the role of HSV-1 may lead to better methods of treatment for the cognitive impairments associated with schizophrenia.
Objectives: Epidemiological and experimental evidence suggests that the endocannabinoid system plays a pathophysiological role in schizophrenia. This is reflected by elevated cerebrospinal levels of ...the endocannabinoid anandamide in schizophrenia and its initial prodromal states.
Methods: We analyzed plasma concentrations of anandamide, 2-arachidonoyl-sn-glycerol, palmitoylethanolamide and oleoylethanolamide from 25 twin pairs discordant for schizophrenia, six discordant for bipolar disorder and eight healthy twin pairs to determine hereditary traits.
Results: Twin pairs discordant for schizophrenia or bipolar disorder had significantly higher levels of anandamide and palmitoylethanolamide compared to healthy twins (both P < 0.002). Non-affected twins discordant for schizophrenia, who developed a psychotic disorder within 5 years follow-up showed lower anandamide (P = 0.042) and 2-arachidonoyl-sn-glycerol levels (P = 0.049) than twins who remained healthy.
Conclusions: We suggest that the protective upregulation of endocannabinoid signalling reflects either a hereditary trait or mirrors a modulating response to genetically influenced cerebral function involving, e.g., other neurotransmitters or energy metabolism.
Abstract Being born in and/or raised in an urban area is a proven risk factor for developing schizophrenia. Migrating from countries such as Jamaica or Morocco to countries such as England or the ...Netherlands is also a proven risk factor for developing schizophrenia. The transmission of Toxoplasma gondii oocysts to children is reviewed and proposed as a partial explanation for both of these risk factors.
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