Large-scale study of Toxoplasma and Cytomegalovirus shows an association between infection and serious psychiatric disorders.

BACKGROUND: Common infectious pathogens have been associated with psychiatric disorders, self-violence and risk-taking behavior. METHODS: This case-control study reviews register data on 81,912 individuals from the Danish Blood Donor Study to identify individuals who have a psychiatric diagnosis (N = 2591), have attempted or committed suicide (N = 655), or have had traffic accidents (N = 2724). For all cases, controls were frequency matched by age and sex, resulting in 11,546 participants. Plasma samples were analyzed for immunoglobulin G (IgG) antibodies against Toxoplasma gondii and cytomegalovirus (CMV). RESULTS: T. gondii was detected in 25·9% of the population and was associated with schizophrenia (odds ratio [OR], 1·47; 95% confidence interval [CI], 1·03-2·09). Accounting for temporality, with pathogen exposure preceding outcome, the association was even stronger (IRR, 2·78; 95% CI, 1·27-6·09). A very weak association between traffic accident and toxoplasmosis (OR, 1·11; 95% CI, 1·00-1·23, p = 0.054) was found. CMV was detected in 60·8% of the studied population and was associated with any psychiatric disorder (OR, 1·17; 95% CI, 1·06-1·29), but also with a smaller group of neurotic, stress-related, and somatoform disorders (OR, 1·27; 95% CI, 1·12-1·44), and with attempting or committing suicide (OR, 1·31; 95% CI, 1·10-1·56). Accounting for temporality, any psychiatric disorder (IRR, 1·37; 95% CI, 1·08-1·74) and mood disorders (IRR, 1·43; 95% CI, 1·01-2·04) were associated with exposure to CMV. No association between traffic accident and CMV (OR, 1·06; 95% CI, 0·97-1·17) was found. CONCLUSIONS: This large-scale serological study is the first study to examine temporality of pathogen exposure and to provide evidence of a causal relationship between T. gondii and schizophrenia, and between CMV and any psychiatric disorder.

Cytomegalovirus infection and risk of Alzheimer disease in older black and white individuals.

BACKGROUND: Human cytomegalovirus (CMV) is prevalent in older adults and has been implicated in many chronic diseases of aging. This study investigated the relation between CMV and the risk of Alzheimer disease (AD). METHODS: Data come from 3 cohort studies that included 849 participants (mean age [±SD], 78.6 ± 7.2 years; mean education duration [±SD], 15.4 ± 3.3 years; 25% black). RESULTS: A solid-phase enzyme-linked immunosorbent assay was used for detecting type-specific immunoglobulin G antibody responses to CMV and herpes simplex virus type 1 (HSV-1) measured in archived serum samples. Of 849 participants, 73.4% had serologic evidence of exposure to CMV (89.0% black and 68.2% white; P < .001). During an average of 5.0 years of follow-up, 93 persons developed AD. CMV seropositivity was associated with an increased risk of AD (relative risk, 2.15; 95% confidence interval, 1.42-3.27) and a faster rate of decline in global cognition (estimate [±standard error], -0.02 ± 0.01; P = .03) in models that controlled for age, sex, education duration, race, vascular risk factors, vascular diseases, and apolipoprotein ε4 level. Results were similar in black and white individuals for both incident AD and change in cognitive function and were independent of HSV-1 status. CONCLUSIONS: These results suggest that CMV infection is associated with an increased risk of AD and a faster rate of cognitive decline in older diverse populations.

Did the human genome project affect research on Schizophrenia?

The Human Genome Project was undertaken primarily to discover genetic causes and better treatments for human diseases. Schizophrenia was targeted since three of the project`s principal architects had a personal interest and also because, based on family, adoption, and twin studies, schizophrenia was widely believed to be a genetic disorder. Extensive studies using linkage analysis, candidate genes, genome wide association studies [GWAS], copy number variants, exome sequencing and other approaches have failed to identify causal genes. Instead, they identified almost 300 single nucleotide polymorphisms [SNPs] associated with altered risks of developing schizophrenia as well as some rare variants associated with increased risk in a small number of individuals. Risk genes play a role in the clinical expression of most diseases but do not cause the disease in the absence of other factors. Increasingly, observers question whether schizophrenia is strictly a genetic disorder. Beginning in 1996 NIMH began shifting its research resources from clinical studies to basic research based on the promise of the Human Genome Project. Consequently, three decades later NIMH's genetics investment has yielded almost nothing clinically useful for individuals currently affected. It is time to review NIMH`s schizophrenia research portfolio.

Mercury and Parkinson's Disease: Promising Leads, but Research Is Needed.

Environmental toxicants are thought to play a major role in the pathogenesis of Parkinson's disease. In reviewing the literature on heavy metals known to be toxicants, we noted several recent studies on mercury suggesting a possible role in the etiology of some cases of this disease. We therefore undertook a review of this association, focusing especially on peer-reviewed articles to avoid the bias inherent in much of the literature regarding mercury. For most people, our contemporary exposure to mercury comes from dental amalgam tooth restorations and from eating fish contaminated with mercury. In both cases, mercury is known to get into the brain in utero and at all ages. It remains in the brain for many years and is known to produce permanent neuropsychological deficits. Mercury toxicity can produce tremors and other Parkinsonian clinical symptoms. It can also produce neurochemical and neuropathological changes similar to those found in Parkinson's disease, including the loss of dopamine neurons, degeneration of tubulin and axons, dysfunction of mitochondria, and the aggregation of alpha-synuclein. Relatively few studies have assessed mercury in parkinsonian patients, but almost all reported a statistically significant association. Published studies suggest some promising leads in the relationship between mercury exposure and Parkinson's disease. However, studies of patients are relatively few, and the need for research is clear. A search of Parkinsonian research studies currently funded by the US National Institutes of Health, Parkinson's Foundation, and the Michael J Fox Foundation yielded no studies on mercury. We believe such studies should be supported.

The NIMH Research Portfolio: An Update.

Objective: 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.Methods: 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.Results: 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%.Conclusions: 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.Prim Care Companion CNS Disord 2023;25(4):23m03486. Author affiliations are listed at the end of this article.

The Continuing Decline of Clinical Research on Serious Mental Illnesses at NIMH.

It has been claimed that the National Institute of Mental Health (NIMH) budget, which traditionally has been evenly balanced between basic and clinical research, has shifted sharply and that 90% of NIMH resources are funding basic research. The authors used public data sources to assess this claim: the Research Condition and Disease Categorization Database, ClinicalTrials.gov, and the NIMH Strategic Plan for Research for 2020-2024. From 2016 to 2019, NIMH expenditures on bipolar disorder research decreased 25%, and those for schizophrenia research decreased 17.5%. From 2003 to 2019, NIMH support for treatment trials for schizophrenia, bipolar disorder, and major depressive disorder decreased 90%. NIMH's Strategic Plan for Research for 2020-2024 suggests that the shift toward basic research will continue. Because NIMH's primary purpose is to develop better treatments for current patients as well as future ones, the authors recommend that the ratio of basic to clinical research be readjusted to approximately 50:50.

Increased alpha-defensins as a blood marker for schizophrenia susceptibility.

Schizophrenia is a severe psychotic illness affecting 1% of the general population. There are no consistent pathological features, and the disorder is defined by a complex symptomatology, which overlaps with other psychiatric illnesses. Diagnosis is based on a clinical interview, relying on the patient meeting criteria according to diagnosis manuals, including Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. and International Statistical Classification of Diseases, 10th Revision. Because of the ambiguous symptoms, the diagnostic process can take many months and often years. Rapid and effective treatment has been shown to impact positively on disease progression and outcome, and it is therefore important to identify disease-associated biomarkers allowing early diagnosis. Reliable biomarkers can be used for the development of diagnostic tests and may also help us understand the underlying pathology of this disorder. In the present study, proteins from anti-CD3 stimulated and unstimulated peripheral blood T cell lysates from 15 minimally medicated and unmedicated patients and 15 age-, sex-, race-, and smoking-matched controls were profiled on cation exchange (CM10) chips using SELDI-TOF. Partial least squares discriminate analysis was used to separate patient and control groups according to the expression of 108 detected peaks, and two peaks of 3,374 and 3,450 Da, corresponding to alpha-defensins based on masses and cationic properties, were found to contribute significantly to the separation of patient and control groups. Reduction of T cell lysates with DTT resulted in a 6-Da shift in the mass of these peaks consistent with the presence of three cysteine bonds in the structure, confirming them as alpha-defensins. Quantification of alpha-defensins in T cell lysates from six patients and 18 healthy controls was carried out by ELISA, which also showed that alpha-defensin levels were significantly increased in patient lysates when compared with matched controls (p = 0.0197). Plasma from 21 monozygotic twins discordant for schizophrenia and eight healthy unaffected twin pairs was also analyzed for the expression of alpha-defensins by ELISA. Notably both affected and unaffected twins were found to have significantly elevated alpha-defensin levels compared with healthy control twin pairs (p = 0.0014 and p = 0.0115, respectively). Increased expression of alpha-defensins in unaffected as well as affected discordant monozygotic twins is of particular interest as monozygotic twins share genes and usually environmental upbringing. The unaffected twin therefore represents the biological and environmental risk of developing schizophrenia in the absence of overt symptomatology and therapeutic medication. These findings suggest that alpha-defensins could be an important early indicator of the risk of schizophrenia.

Using the NIH Research, Condition and Disease Categorization Database for research advocacy: Schizophrenia research at NIMH as an example.

In 2008 the National Institutes of Health established the Research, Condition and Disease Categorization Database (RCDC) that reports the amount spent by NIH institutes for each disease. Its goal is to allow the public "to know how the NIH spends their tax dollars," but it has been little used. The RCDC for 2018 was used to assess 428 schizophrenia-related research projects funded by the National Institute of Mental Health. Three senior psychiatrists independently rated each on its likelihood ("likely", "possible", "very unlikely") of improving the symptoms and/or quality of life for individuals with schizophrenia within 20 years. At least one reviewer rated 386 (90%), and all three reviewers rated 302 (71%), of the research projects as very unlikely to provide clinical improvement within 20 years. Reviewer agreement for the "very unlikely" category was good; for the "possible" category was intermediate; and for the "likely" category was poor. At least one reviewer rated 30 (7%) of the research projects as likely to provide clinical improvement within 20 years. The cost of the 30 projects was 5.5% of the total NIMH schizophrenia-related portfolio or 0.6% of the total NIMH budget. Study results confirm previous 2016 criticisms that the NIMH schizophrenia-related research portfolio disproportionately underfunds clinical research that might help people currently affected. Although the results are preliminary, since the RCDC database has not previously been used in this manner and because of the subjective nature of the assessment, the database would appear to be a useful tool for disease advocates who wish to ascertain how NIH spends its public funds.

Second Chance.

My second career as a schizophrenia researcher will focus on infectious agents as a cause. It will include the collection of serial sera, cerebrospinal fluid, functional magnetic resonance imaging, and diffusion tensor imaging on a cohort of affected individuals over 20 years. Since I believe that the initial transmission of these agents occurs in childhood, I will also follow a cohort of children from birth to age 20. Additional projects will focus on rheumatoid arthritis, geographic case clusters, immigrants, and epidemiology.

Schizophrenia as a pseudogenetic disease: A call for more gene-environmental studies.

In recent years schizophrenia has been assumed to be largely a genetic disease with heritability estimates, derived primarily from family and twin studies, of 80%-85%. However, the results of genetic research on schizophrenia have not yielded results consistent with that estimate of heritability. In particular, extensive genetic studies have not led to new methods for diagnosis and treatment. An examination of the twin studies on which heritability is based shows why such studies exaggerate the genetic component of schizophrenia. In addition, the effects of infectious agents such as Toxoplasma gondii and the composition of the microbiome can produce a clinical picture that would also appear to be largely genetic due to familial aggregation and a role for a partial genetic contribution to the immune system. It is concluded that the genetic component of schizophrenia may have been overestimated and an increased focus on gene-environmental interactions is likely to accelerate research progress on this disease.

Birth month and later diagnosis of schizophrenia. A population-based cohort study in Sweden.

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.

Familial abnormalities of endocannabinoid signaling in 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.

Putative psychosis genes in the prefrontal cortex: combined analysis of gene expression microarrays.

BACKGROUND: Recent studies have shown similarities between schizophrenia and bipolar disorder in phenotypes and in genotypes, and those studies have contributed to an ongoing re-evaluation of the traditional dichotomy between schizophrenia and bipolar disorder. Bipolar disorder with psychotic features may be closely related to schizophrenia and therefore, psychosis may be an alternative phenotype compared to the traditional diagnosis categories. METHODS: We performed a cross-study analysis of 7 gene expression microarrays that include both psychosis and non-psychosis subjects. These studies include over 400 microarray samples (163 individual subjects) on 3 different Affymetrix microarray platforms. RESULTS: We found that 110 transcripts are differentially regulated (p < 0.001) in psychosis after adjusting for confounding variables with a multiple regression model. Using a quantitative PCR, we validated a set of genes such as up-regulated metallothioneins (MT1E, MT1F, MT1H, MT1K, MT1X, MT2A and MT3) and down-regulated neuropeptides (SST, TAC1 and NPY) in the dorsolateral prefrontal cortex of psychosis patients. CONCLUSION: This study demonstrates the advantages of cross-study analysis in detecting consensus changes in gene expression across multiple microarray studies. Differential gene expression between individuals with and without psychosis suggests that psychosis may be a useful phenotypic variable to complement the traditional diagnosis categories.

The MacArthur Violence Risk Assessment Study revisited: two views ten years after its initial publication.

This article presents two views of the results of the MacArthur Violence Risk Assessment Study, which was conducted between 1992 and 1995 in order to ascertain the prevalence of community violence in a sample of people discharged from acute psychiatric facilities. The initial findings, which were published in 1998 in the Archives of General Psychiatry, have been cited by some advocates as proof that discharged psychiatric patients are not more dangerous than other persons in the general population. For the article presented here, Dr. Torrey and Mr. Stanley examined additional articles, book chapters, and a book about the MacArthur Study that have appeared since 1998 in order to ascertain whether the study's original conclusion should be modified and whether additional conclusions can be drawn from the subsequently published data. They present six points on which they disagree with the findings or fault the design of the MacArthur Study. After each point, Dr. Monahan, Dr. Steadman, and other authors of the MacArthur Study Group respond.

Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of filter paper blood samples obtained at birth.

BACKGROUND: Infections during fetal life or neonatal period, including infections with Toxoplasma gondii, may be associated with a risk for schizophrenia and other mental disorders. The objectives of this study were to study the association between serological markers for maternal and neonatal infection and the risk for schizophrenia, related psychoses, and affective disorders in a national cohort of newborns. METHODS: This study was a cohort-based, case-control study combining data from national population registers and patient registers and a national neonatal screening biobank in Denmark. Patients included persons born in Denmark in 1981 or later followed up through 1999 with respect to inpatient or outpatient treatment for schizophrenia or related disorders (ICD-10 F2) or affective disorders (ICD-10 F3). RESULTS: Toxoplasma gondii immunoglobulin G (IgG) levels corresponding to the upper quartile among control subjects were significantly associated with schizophrenia risk (odds ratio [OR] = 1.79, p = .045) after adjustment for urbanicity of place of birth, year of birth, gender, and psychiatric diagnoses among first-degree relatives. There was no significant association between any marker of infection and other schizophrenia-like disorders or affective disorders. CONCLUSIONS: Our study supports an association between Toxoplasma gondii and early-onset schizophrenia. Further studies are needed to establish if the association is causal and if it generalizes to cases with onset after age 18.

Meta-analysis of 12 genomic studies in bipolar disorder.

Multiple genome-wide expression studies of bipolar disorder have been published. However, a unified picture of the genomic basis for the disease has not yet emerged. Genes identified in one study often fail to be identified in other studies, prompting the question of whether microarray studies in the brain are inherently unreliable. To answer this question, we performed a meta-analysis of 12 microarray studies of bipolar disorder. These studies included >500 individual array samples, on a range of microarray platforms and brain regions. Although we confirmed that individual studies showed some differences in results, clear and striking regulation patterns emerged across the studies. These patterns were found at the individual gene level, at the functional level, and at the broader pathway level. The patterns were generally found to be reproducible across platform and region, and were highly statistically significant. We show that the seeming discordance between the studies was primarily a result of the following factors, which are also typical for other brain array studies: (1) Sample sizes were, in retrospect, too small; (2) criteria were at once too restrictive (generally focusing on fold changes >1.5) and too broad (generally using p < 0.05 or p < 0.01 as criteria for significance); and (3) statistical adjustments were not consistently applied for confounders. In addition to these general conclusions, we also summarize the primary biological findings of the meta-analysis, focusing on areas that confirm previous research and also on novel findings.

Schizophrenia and the inferior parietal lobule.

OBJECTIVE: Studies of the neuroanatomical localization of schizophrenia have not given sufficient attention to the inferior parietal lobule (IPL). METHODS: A search of the medical literature was carried out for links between schizophrenia and the IPL. RESULTS: Structural differences in the IPL in schizophrenia were reported by 10 recent neuroimaging studies, although the studies did not all agree with each other. Functional differences in the IPL in schizophrenia have been prominently reported in four areas: sensory integration, body image, concept of self, and executive function. CONCLUSION: The IPL appears to be an important, but relatively neglected, component of the frontal-limbic-temporal-parietal neural network involved in the schizophrenia disease process. To encourage histopathological research of this area, the Stanley Medical Research Institute is making available a new collection of sucrose-fixed IPL tissue from 25 individuals with schizophrenia and 25 matched controls. Additional imaging and functional studies are needed to better define the network and role of the IPL.

Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis.

Recent studies have linked infectious agents to schizophrenia. The largest number of studies has involved the analysis of Toxoplasma gondii; these studies were subjected to a meta-analysis. Published articles and abstracts were identified by searches of MEDLINE, Ovid, and Google Scholar; by a search of Chinese publications; through letters to researchers; and by visiting China. Published and unpublished controlled studies that used serological methods for measuring T. gondii antibodies to assess inpatients and/or outpatients diagnosed with schizophrenia were selected for analysis, and source documents were translated as needed. Forty-two studies carried out in 17 countries over 5 decades were identified; 23 of these (6 unpublished) met selection criteria. The combined odds ratio (OR) was 2.73 (95% confidence interval, 2.10 to 3.60; chi-square with 1 df 263; P < .000001). Seven studies that included only patients with first-episode schizophrenia (OR 2.54) did not differ significantly from 16 studies that included patients in all clinical phases (OR 2.79). The results suggest that individuals with schizophrenia have an increased prevalence of antibodies to T. gondii. This association is consistent with other epidemiological studies as well as with animal studies. Although the OR of 2.73 is modest, it exceeds that for genetic or other environmental factors identified to date and suggests that Toxoplasma is in some way associated with a large number of cases of schizophrenia. If an etiological association can be proven, it would have implications for the design of measures for the prevention and treatment of this disease.