SIRT1 is a NAD
+-dependent deacetylase that governs a number of genetic programs to cope with changes in the nutritional status of cells and organisms. Behavioral responses to food abundance are ...important for the survival of higher animals. Here we used mice with increased or decreased brain SIRT1 to show that this sirtuin regulates anxiety and exploratory drive by activating transcription of the gene encoding the monoamine oxidase A (
MAO-A) to reduce serotonin levels in the brain. Indeed, treating animals with MAO-A inhibitors or selective serotonin reuptake inhibitors (SSRIs) normalized anxiety differences between wild-type and mutant animals. SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter. Both common and rare variations in the
SIRT1 gene were shown to be associated with risk of anxiety in human population samples. Together these data indicate that SIRT1 mediates levels of anxiety, and this regulation may be adaptive in a changing environment of food availability.
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► SIRT1 activity in the brain alters murine exploratory drive and anxiety ► SIRT1 activates
MAO-A and decreases serotonin via deacetylation of NHLH2 ► Common variants of
SIRT1 are associated with mood disorder prevalence in humans
The deacetylase SIRT1 modulates brain serotonin levels to impact anxiety behavior in mice, and in humans, genetic variants in the
SIRT1 gene are associated with the prevalence of mood disorders.
The year 1900 saw not only the rediscovery of Mendel's hybridization studies but also the publication by Karl Pearson of his newly developed tetrachoric correlation which he used to study the ...parent–offspring resemblance for the “insane diathesis” in 1905. This was followed by more detailed reports by two of his students/associates: Heron in 1907 and Goring in 1909. Both calculated the tetrachoric correlation for insanity in parent–offspring and Heron for sib–sib pairs. Estimates ranged from approximately +0.30 to +0.60. These papers were statistically sophisticated but demonstrated minimal interest in the phenotype being studied. They are of historical interest because they laid the groundwork for biometrical psychiatric genetics which emerged as a major research paradigm in latter third of the 20th century. In a biting critique of Heron's paper by a young Ernst Rüdin, we see the beginnings of a long‐running argument in psychiatric genetics about the relative value of detailed phenotyping versus novel statistical methods and of Mendelian versus Biometrical methods. While much interest has focused on the eugenic orientation of German psychiatric genetics in the early 20th century, these early British biometrical geneticists, like the majority of geneticists of that day, were also ardent advocates of the eugenic application of their research results.
Abstract While the origins of two of Kraepelin’s three subtypes of dementia praecox (DP), catatonic and hebephrenic, are well understood, no similar clear narrative exists for his concepts of ...paranoia and paranoid DP, which require a consideration of both German and French sources. An important milestone in the French literature is the massive 524 page monograph entitled “Le Délire Des Persécutions” published in 1871 by Henri Legrand du Saulle which contained extensive, clinically detailed descriptions of a wide range of cases with prominent, organized persecutory delusions. Many of his cases reported auditory hallucinations (AH), and some bizarre, Schneiderian delusions. The delusional content could evolve to include prominent somatic and/or grandiose themes. Using a symptomatic diagnostic framework, Legrand du Saulle proposed that this syndrome represented an independent “species” of mental illness. He sought to give a voice to the affected individuals, including a chapter devoted entirely to their writings. He described several clinically fascinating features of such patients including how often they moved residence to unsuccessfully flee their persecutors and how delusional beliefs could be communicated to spouses and relatives. Unlike Kraepelin, he was little interested in their course of illness or rates of deterioration, except to note that recoveries occurred in 20% of cases. The clinical richness of this work substantially exceeded that in the contemporaneous German literature. Most of the cases described by du Saulle would fit easily into the two major non-affective delusional syndromes articulated 28 years later in Kraepelin’s famous 6th edition of his textbook: paranoia and paranoid DP.
We investigated the functional classes of genomic regions containing SNPS contributing most to the SNP-heritability of important psychiatric and neurological disorders and behavioral traits, as ...determined from recent genome-wide association studies. We employed linkage-disequilibrium score regression with several brain-specific genomic annotations not previously utilized. The classes of genomic annotations conferring substantial SNP-heritability for the psychiatric disorders and behavioral traits differed systematically from the classes associated with neurological disorders, and both differed from the classes enriched for height, a biometric trait used here as a control outgroup. The SNPs implicated in these psychiatric disorders and behavioral traits were highly enriched in CTCF binding sites, in conserved regions likely to be enhancers, and in brain-specific promoters, regulatory sites likely to affect responses to experience. The SNPs relevant for neurological disorders were highly enriched in constitutive coding regions and splice regulatory sites.
Abstract
In 1916, Ernst Rüdin published the first modern family study in the history of psychiatric genetics, the major goal of which was to test whether the pattern of risk in the siblings of ...dementia praecox (DP) probands followed Mendelian expectations. He utilized systematic ascertainment of probands and multisourced diagnostic assessments of probands and relatives, applying the narrow Kraepelinian concept of DP. In a novel step, he collaborated closely with a statistical geneticist—Wilhelm Weinberg—and applied his sibling, proband, and age correction methods. In his key sample—701 sibships when neither parent had DP—the morbid risk for DP in siblings was 4.48%, much lower than 25% expected for a recessive disorder. Risk for DP was increased by alcoholism or other mental disorders in parents. Other non-DP psychoses were common in both siblings and parents of DP probands. Rüdin discussed several alternative genetic models for DP including a 2-locus recessive, incomplete penetrance, and an oligogenic model. The high rates of other psychoses and psychopathic personalities in relatives might arise, he suggested, because these disorders shared genetic risks with DP. Rüdin established that DP, when carefully studied, ran in families, did not have a simple Mendelian genetic transmission pattern, and appeared likely to be genetically related to other non-DP psychotic disorders and perhaps some kinds of psychopathic personalities. This study, the most important in Rüdin’s career, should be viewed in the context of his later extensive support of and collaboration with Nazi eugenic policies.
The Emergence of Psychiatry: 1650–1850 Kendler, Kenneth S; Tabb, Kathryn; Wright, John
The American journal of psychiatry,
05/2022, Letnik:
179, Številka:
5
Journal Article
Recenzirano
Western psychiatry emerged as a medical specialty caring for the mentally ill over the course of the late 18th and early 19th centuries. This emergence was a contingent process, dependent on the ...co-occurrence of three historical developments that together shaped the young discipline. The first was the rise of the mind as an entity with numerous active faculties in the conceptual space between the body and the Christian soul. Only by the latter half of the 18th century was it common to conceptualize conditions like mania or melancholy as mental illnesses. The second advance critical to psychiatry’s proto-specialty status, with its increasing focus on a mechanistic understanding of disease, was the rejection of humoral theories of insanity in favor of the brain and nerves as the seat of madness. The third development was the rise of the asylum. Only in dedicated institutions could mad-doctors be exposed to large numbers of the insane, permitting the development of a specialized clinical vocabulary grounded in faculties of mind, which led to new nosologic systems. The decline of humoral medicine, with its purges, bleeding, and emetics, and the urgent clinical need for care produced, in early asylums, the first novel treatment from the young specialty: moral therapy. We tell this story focusing mainly on the work of five philosophers and physicians: Descartes, Willis, Locke, Boerhaave, de Sauvages, and Cullen. Throughout its history, psychiatry has struggled with its sometimes disconjugate goals of understanding both mind and brain, with alternating efforts to expel one of these tasks from the profession. A historical perspective demonstrates that psychiatry is a profession inextricably linked to these two contrasting projects—and, indeed, jointly constituted by them.
Prosper Lucas (1808–1885) is a unique figure in the history of psychiatric genetics. A physician‐alienist, he authored one of the most important books on human genetics in the mid‐19th century cited ...frequently by Darwin: the 1,500 page treatise—Philosophical and Physiological Treatise on Natural Heredity (1847–1850). This book contained a novel theory of the nature of inheritance and a detailed review of the heredity of a range of human traits and disorders, including various forms of insanity. Lucas postulated four forms of heredity (direct, crossed, indirect, and atavistic), supported the importance of hereditary factors in insanity, accepted the inheritance of acquired characteristics, considered it important to examine both ancestors and collateral relatives, and recognized that heredity could influence both primary insanity and insanity secondary to other medical conditions. He reviewed the then available literature on most major forms of insanity including separate sections on hallucinations and suicidal monomania. The literature consisted of case reports of unusual families with high concentrations of illness. Lucas advocated for the homogeneity of transmission of forms of illness in families but recognized that—just as the form of illness could evolve within individuals over time—it could change forms when transmitted between relatives.
IMPORTANCE: Family and genetic approaches have traditionally been used to evaluate our diagnostic concepts. Using a novel method, the family genetic risk score (FGRS), can we validate the genetic ...architecture of major affective and psychotic disorders in a national Swedish sample? OBJECTIVE: To determine whether FGRSs, calculated for the entire Swedish population, can elucidate the genetic relationship between major affective and psychotic disorders and clarify the association of genetic risk with important clinical features of disease. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included the native Swedish population born from January 1, 1950, through December 31, 1995, and followed up through December 31, 2017. Data were collected from Swedish population-based primary care, specialist, and hospital registers, including age at first registration for a psychiatric diagnosis and number of registrations for major depression, bipolar disorder, and schizophrenia. Data were analyzed from October 15, 2020, to February 2, 2021. EXPOSURES: FGRSs for major depression, bipolar disorder, and schizophrenia calculated from morbidity risks for disorders in first- through fifth-degree relatives, controlling for cohabitation. MAIN OUTCOMES AND MEASURES: Diagnoses of major depression, bipolar disorder, schizophrenia, schizoaffective disorder, and other nonaffective psychoses (ONAPs), age at registration, and number of registrations for major depression, bipolar disorder, and schizophrenia. Diagnostic conversion of major depression to bipolar disorder and ONAPs to schizophrenia was assessed by Cox proportional hazards regression models. RESULTS: The cohort included 4 129 002 individuals (51.4% male) with a mean (SD) age at follow-up of 45.5 (13.4) years. Mean FGRSs for major depression, bipolar disorder, and schizophrenia produced distinct patterns for major depression, bipolar disorder, schizophrenia, schizoaffective disorder, and ONAPs with large separations between disorders. In major depression, bipolar disorder, and schizophrenia, high FGRSs were associated with early age at onset and high rates of recurrence: a high mean FGRS for bipolar disorder was associated with early age at onset (younger than 25 years, 0.11; 95% CI, 0.11-0.12) and higher recurrence (8 or more registrations, 0.11; 95% CI, 0.11-0.12) in major depression. The schizophrenia FGRS was separately associated with psychotic and nonpsychotic forms of major depression (0.10; 95% CI, 0.06-0.14 vs 0.03; 95% CI, 0.02-0.03) and bipolar disorder (0.22; 95% CI, 0.16-0.28 vs 0.11; 95% CI, 0.09-0.12). The bipolar disorder and schizophrenia FGRSs were associated with conversion from major depression to bipolar disorder (eg, hazard ratio, 1.70 95% CI, 1.63-1.78 for high vs low bipolar FGRS) and ONAP to schizophrenia (eg, hazard ratio, 1.38 95% CI, 1.27-1.51 for high vs low schizophrenia FGRS). CONCLUSIONS AND RELEVANCE: In this Swedish cohort study, the FGRSs for major depression, bipolar disorder, and schizophrenia for the Swedish population clearly separated major affective and psychotic disorders from each other in a larger and more representative patient sample than previously possible. These findings provide possible validation, from a genetic perspective, for these major diagnostic categories. These results replicated and extended prior observations on more limited samples of the association of FGRS with age at onset, recurrence, psychotic subtypes, and diagnostic conversions.
•At 65, Kraepelin wrote the final edition of Introduction to Clinical Psychiatry.”•This contained a mini-textbook and 9 new detailed case reports.•These provide an overview of his final ideas on ...manic-depressive insanity.
At the age of 65, 8 years after finishing his last textbook edition, Emil Kraepelin completed the final edition of his “Introduction to Clinical Psychiatry” which included a mini-textbook for students with a 7-page section on manic-depressive insanity (MDI), a disorder he had formally proposed 22 years earlier, and a series of new detailed case histories, 9 of which examined MDI. This text distills, near the end of his life, Kraepelin's perspective of the key features of MDI. The text and case histories are here translated into English for the first time. Kraepelin's views of the symptoms and signs of melancholia and mania closely aligned to those proposed by DSM-5. He emphasized the importance both of mixed features and the constitutional/personality foundations of MDI suggesting that a particular emotional disposition is often seen both inter-episodically in affected individuals (where they “fill the entire life”) and in their unaffected relatives. He illustrates both these points in his case reports. His cases also made clear that for Kraepelin, classical Schneiderian psychotic symptoms and a full catatonic syndrome were consistent with a diagnosis of MDI.
Four years before the rediscovery of Mendel's work in 1900, Karl Grassmann published a detailed, scholarly review of the heredity of psychosis which we here review. A full translation is in the ...appendix. We emphasize seven major conclusions from this review. First, while recognizing the key importance of heredity in the etiology of psychosis. Grassmann was critical of many of the highly speculative extant theories. Second, he reviewed most of the major methodologic concerns in the literature from what kinds of heredity to investigate to the problems with the global use of insanity as a diagnostic category. Third, he discussed in detail genetic theories associated with Degeneration theory, maintaining considerable skepticism. Fourth, he recognized nongenetic contribution to familial transmission. Fifth, he reviewed evidence for both homogeneous and heterogeneous transmission of forms of mental illness in families, suggesting that both were important. Sixth, while he noted that mania, melancholia, and cyclothymia commonly replaced each other in families, Verrücktheit (delusional psychoses) rarely co‐segregated in families with these mood disorders. Seventh, Grassmann, like other 19th century writers, saw relatives to be of value only in assessing the level of hereditary predisposition in patients and had limited appreciation of the need for controlled studies.
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