E. Fuller Torrey

The Stanley Foundation brain collection and Neuropathology Consortium

The Stanley Foundation brain collection is an attempt to supplement existing brain collections for the purpose of promoting research on schizophrenia and bipolar disorder. Specimens are collected with the permission of the families in a standardized manner, with half of each specimen being frozen and half fixed in formalin. The Neuropathology Consortium is a subset of 60 specimens from the collection, well-matched groups of 15 each with diagnoses of schizophrenia, bipolar disorder, major depressive disorder without psychotic features, and normal controls. More than 75000 sections and blocks from the Consortium have been sent to over 50 research groups worldwide to carry out a wide variety of assessments. These data will be integrated to provide a more complete picture of the neuropathology of these disorders.

Neurochemical markers for schizophrenia, bipolar disorder, and major depression in postmortem brains.

BACKGROUNDnPrevious studies of postmortem neurochemical markers in severe psychiatric disorders have been carried out on different brain collections, making it difficult to compare results.nnnMETHODSnOne hundred RNA, protein, and other neurochemical markers were assessed in a single set of 60 postmortem brains (15 each with schizophrenia, bipolar disorder, major depression without psychosis, and unaffected control subjects) in relation to seven neurochemical systems. Quantitative measures of continuous variables for prefrontal, hippocampus, anterior cingulate, superior temporal cortex, or a combination of these were analyzed from published and unpublished studies by 56 research groups.nnnRESULTSnBefore correcting for multiple comparisons, 23% of markers (23/100) were abnormal in one or more regions, with most indicating decreased expression. The largest percentage were associated with the developmental/synaptic (10/22) and gamma-aminobutyric acid (GABA; 3/7) systems. Bipolar disorder (20) and schizophrenia (19) had the most abnormalities, with a 65% overlap. When all brain areas were considered together and corrected for multiple comparisons, reelin, parvalbumin, and GAD67 were the most abnormal.nnnCONCLUSIONSnConfirming other studies, the GABA and developmental/synaptic neurochemical systems are promising areas for research on schizophrenia and bipolar disorder. Research should include tissue from both diseases, and additional brain areas should be assessed.

Multivariate analysis of prefrontal cortical data from the Stanley Foundation Neuropathology Consortium

Prefrontal cortical tissue from the Stanley Foundation Neuropathology Consortium, which contains samples from patients with schizophrenia, bipolar disorder, non-psychotic depression, and normal controls (n = 15 per group), was studied in a blinded fashion in 14 different laboratories between 1997 and 2000. The results of 69 separate data sets were analyzed with univariate and multivariate techniques. A total of 17 abnormal markers were identified that pertained to a variety of neural systems and processes, including neuronal plasticity, neurotransmission, signal transduction, inhibitory interneuron function, and glial cells. Schizophrenia was associated with the largest number of abnormalities, many of which were also present in bipolar disorder. Major depression was associated with relatively few abnormalities. The majority of abnormal findings represented a decline in function and could not be easily explained by exposure to psychotropic or illicit drugs. It is argued that the abnormal findings are not simply due to stochastic processes but represent viable markers for independent replication and further study as candidate genes or targets for new treatments.

Cytomegalovirus and schizophrenia.

Several lines of evidence suggest that cytomegalovirus (CMV) may play an aetiological role in schizophrenia. Epidemiologically, both have a worldwide distribution and an increased prevalence in lower socioeconomic groups. Studies have reported that some patients experiencing initial episodes of schizophrenia have increased levels of IgG antibodies against CMV, but not other herpes viruses, in their sera and CSF. Treatment with antipsychotic medications may result in a decrease in CMV antibodies, while treatment with anti-herpes virus and anti-inflammatory medications may reduce symptoms in some individuals with schizophrenia. There is also some overlap in the genes that are thought to operate in CMV infections and schizophrenia.The strongest argument against the role of CMV in schizophrenia is the absence of the traditional CMV neuropathological changes in the brains of individuals with schizophrenia; however, neuropathological studies of CMV have mostly been conducted in immune-compromised individuals.Further studies on CMV and schizophrenia are needed and may lead to improved treatments for schizophrenia.

Serum antibodies reactive with non-human primate retroviruses identified in acute onset schizophrenia

Schizophrenia is a pervasive neuropsychiatric disease of uncertain etiology. Previous studies have postulated that retroviruses may contribute to the etiology of some cases of schizophrenia. We examined the possible relationship between retroviral infection and schizophrenia by measuring antibodies to a number of different primate retroviruses in the sera of individuals undergoing their first hospitalization for this disease. Sera from patients with first onset schizophrenia and matched healthy controls were analyzed by immunoblot and enzyme linked immunosorbent assays using purified retrovirus antigens to identify and quantify antibodies reactive with retrovirus proteins. A significantly increased incidence of antibodies reactive to gag encoded proteins of Mason-Pfizer monkey virus (MPMV), baboon endogenous virus (BaEV) and simian retrovirus type 5 (SRV-5) was observed in the sera of schizophrenia patients compared to controls. The reactivity of the cases and controls displayed the greatest differences in terms of antibodies to the proteins of Mason-Pfizer monkey virus. Employing an algorithm of enzyme linked immunosorbent assay reactivity followed by immunoblot confirmation, we found that MPMV antibodies in 28.9% of the individuals with first episode schizophrenia patients as compared to 3.7% of the unaffected controls (P<0.009, Fishers Exact Test). These studies are consistent with the occurrence of retrovirus replication in some individuals who are undergoing their first episode of schizophrenia.

Abnormalities of the cingulate gyrus in bipolar disorder and other severe psychiatric illnesss: postmortem findings from the Stanley Foundation Neuropathology Consortium and literature review

Abstract The cingulate gyrus is an important area of study for psychiatric disease because of its rich interconnectedness with prefrontal, limbic, and dopaminergic brain areas. A substantial literature that is briefly reviewed here has demonstrated subtle structural and functional abnormalities of the cingulate in severe mental illness. Postmortem data obtained from cingulate specimens from the Stanley Foundation Neuropathology Consortium (which contains matched specimens from subjects with schizophrenia, bipolar disorder, major depression, and controls) are also summarized. Using multiple analyses of variance (ANOVA), and the non-parametric Classification and Regression Tree (CART) technique, 58 data sets were examined. Six molecular markers (calbindin RNA, complexin 2, GAP-43, cytosolic phosphorylated protein kinase C (PKC) α, membrane-bound PKCα, and synaptophysin) were abnormal in at least one disease by ANOVA. Bipolar disorder was associated with four molecular abnormalities, schizophrenia with three and major depression with two. Cytosolic phosphorylated PKCα and glial density contributed to statistically significant disease classifications with CART. The abnormalities presented may serve as future targets for therapeutic intervention or candidate gene studies.

Deinstitutionalization and the rise of violence

The deinstitutionalization of individuals with serious mental illness was driven by 4 factors: public revelations regarding the state of public mental hospitals, the introduction of antipsychotic medications, the introduction of federal programs to fund patients who had been discharged, and civil libertarian lawyers. The result is approximately 3.2 million individuals with untreated serious mental illness living in the community. Beginning in the 1970s in the United States, there began to be reported increasing incidents of violent behavior, including homicides, committed by these untreated individuals. Such incidents became more numerous in the 1980s and 1990s, and have further increased since the turn of the century. Existing studies suggest that individuals with untreated severe mental illness are responsible for at least 10% of all homicides and approximately half of all mass killings. Studies have also shown that when these individuals are treated, the incidence of violent behavior decreases significantly. Examples of treatment mechanisms that have proven effective include assisted outpatient treatment (AOT), conditional release, and mental health courts.The deinstitutionalization of individuals with serious mental illness was driven by 4 factors: public revelations regarding the state of public mental hospitals, the introduction of antipsychotic medications, the introduction of federal programs to fund patients who had been discharged, and civil libertarian lawyers. The result is approximately 3.2 million individuals with untreated serious mental illness living in the community. Beginning in the 1970s in the United States, there began to be reported increasing incidents of violent behavior, including homicides, committed by these untreated individuals. Such incidents became more numerous in the 1980s and 1990s, and have further increased since the turn of the century. Existing studies suggest that individuals with untreated severe mental illness are responsible for at least 10% of all homicides and approximately half of all mass killings. Studies have also shown that when these individuals are treated, the incidence of violent behavior decreases significantly. Examples of treatment mechanisms that have proven effective include assisted outpatient treatment (AOT), conditional release, and mental health courts.

Controlled trial of hydroxychloroquine in schizophrenia.

Hydroxychloroquine is widely employed for the treatment of rheumatological diseases. A preliminary pilot study suggested that hydroxychloroquine may be a useful adjunct for the treatment of schizophrenia, which has been associated with abnormalities in several proinflammatory cytokines. Sixty-one patients were randomized to receive 200 mg/ day hydroxychloroquine or placebo in addition to standard typical antipsychotic treatment. After 8 weeks of double-blind treatment, there was no significant interaction between treatment status and length of treatment for positive, negative, or general symptoms according to the Positive and Negative Syndrome Scale, despite a hydroxychloroquine-associated decrease in serum interferon-γ levels. After completion of the 8-week study, all participants were offered open treatment with hydroxychloroquine for an additional 12 weeks. Open treatment produced no further improvement in Positive and Negative Syndrome Scale scores at weeks 12, 16, and 20. Further study will be required to determine the role of anti-inflammatory treatments for schizophrenia.

Summary of Prefrontal Molecular Abnormalities in the Stanley Foundation Neuropathology Consortium

Postmortem specimens from the Stanley Foundation Neuropathology Consortium, which contains matched samples from patients with schizophrenia, bipolar disorder, non-psychotic depression, and normal controls (n=15 per group), have been distributed to many research groups around the world. This chapter provides a summary of abnormal markers found in prefrontal cortical areas from this collection between 1997 and 2000. From 69 separate data sets, a total of 17 abnormal markers were identified that pertained to a variety of neural systems and processes including neuronal plasticity, neurotransmission, signal transduction, inhibitory interneuron function, and glial cells. Schizophrenia was associated with the largest number of abnormalities, many of which were also present in bipolar disorder. Major depression was associated with relatively few abnormalities. Most abnormal findings represented a decrease in protein or mRNA levels that could not be fully explained by exposure to psychotropic or illicit drugs or by other confounding variables. It is argued that the abnormal findings are not due to stochastic processes but represent viable markers for independent replication and further study as candidate genes or targets for new treatments.

Prenatal Infections and Schizophrenia in Later Life – Focus on Toxoplasma gondii

Schizophrenia and bipolar disorder are prevalent neuropsychiatric disorders that are major causes of morbidity and mortality in the United States and most other areas of the world. The etiology of these disorders remains obscure. Family studies have indicated that both have a high degree of heritability [1,2].