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(searched for: doi:10.1126/science.129.3362.1528)
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, Stephen W. Looney, Houlin Hong, Anilkumar Pillai, Wei Hou
Published: 10 July 2020
Psychiatry Research, Volume 291;

The publisher has not yet granted permission to display this abstract.
, , Matthew D. Puhl, Glenn T. Konopaske
Harvard Review of Psychiatry, Volume 24, pp 80-86;

Nearly 60 years ago Seymour Kety proposed that research on genetics and brain pathology, but not on neurochemistry, would ultimately lead to an understanding of the pathophysiology of schizophrenia. This article will demonstrate the prescience of Kety’s proposal; advances in our knowledge of brain structure and genetics have shaped our current understanding of the pathophysiology of schizophrenia. Brain-imaging techniques have shown that schizophrenia is associated with cortical atrophy and ventricular enlargement, which progresses for at least a decade after the onset of psychotic symptoms. Cortical atrophy correlates with negative symptoms and cognitive impairment, but not with psychotic symptoms, in schizophrenia. Studies with the Golgi-staining technique that illuminates the entire neuron indicate that cortical atrophy is due to reduced synaptic connectivity on the pyramidal neurons and not due to actual loss of neurons. Results of recent genetic studies indicate that several risk genes for schizophrenia are within two degrees of separation from the N-methy-D-aspartate receptor (NMDAR), a subtype of glutamate receptor that is critical to synapse formation and synaptic plasticity. Inactivation of one of these risk genes that encodes serine racemase, which synthesizes D-serine, an NMDAR co-agonist, reproduces the synaptic pathology of schizophrenia. Thus, widespread loss of cortical synaptic connectivity appears to be the primary pathology in schizophrenia that is driven by multiple risk genes that adversely affect synaptogenesis and synapse maintenance, as hypothesized by Kety.
Journal of the History of the Neurosciences, Volume 20, pp 106-122;

In 1956, Dr. Robert Galbraith Heath, Chair of Psychiatry and Neurology at Tulane University School of Medicine in New Orleans, announced that he and colleagues had discovered a protein they called taraxein in the blood of schizophrenic patients that caused symptoms of schizophrenia when injected into healthy volunteers. Heath's claim received wide public and professional attention. Researchers quickly tried to confirm the discovery. These efforts, which were rigorous and in some cases conducted in consultation with the Tulane researchers, failed. Nevertheless, for the next four decades Heath continued to defend his claim. This article recounts the scientific developments that led up to Heath's putative discovery and it explores the scientific findings for and against the taraxein theory of schizophrenia. 11The neologism “schizogen” refers to a substance that produces schizophrenia. Although use of the term is uncommon, it is not without precedent. Hoffer (1981) Hoffer, A . 1981. The adrenochrome hypothesis of schizophrenia revisited. Orthomolecular Psychiat, 10: 98–118. [Google Scholar] uses it in his review of the Adrenochrome Hypothesis of schizophrenia (p. 100). More widely use alternatives include schizophrenogenic compound, psychotomimetic, or endogenous schizophrenia-inducing agent. Schizogen is used in this article for its brevity. View all notes
Kenneth S. Kendler, Kenneth F. Schaffner
Philosophy, Psychiatry, & Psychology, Volume 18, pp 41-63;

The dopamine (DA) hypothesis of schizophrenia (DHS) has, since its inception over 30 years ago, been among the most prominent etiologic theories in psychiatry. This essay begins by summarizing the history of its emergence and efforts to empirically test it through the examination of (i) cerebrospinal fluid DA metabolites, (ii) neuroendocrine measures, (iii) clinical response to psychostimulants, (iv) brain levels of DA and its metabolites, (v) brain studies of DA receptors, and (vi) genetic association studies. We then examine how successful the DHS has been and by what criteria its performance should be evaluated. In this process, it is critical to distinguish the etiological DHS from the pharmacological DA hypothesis of neuroleptic action. Although the DHS stimulated much science, most efforts to empirically validate it have failed, in contrast with the well-supported pharmacological DA hypothesis of neuroleptic action. Nonetheless, the DHS has held the status of a scientific paradigm defended by some with great avidity. Like other temporally extended theories, the DHS in its most general form is relatively nonspecific and protean in nature. In its evolution through successive more specific forms, often embodying ad hoc modifications of subsidiary hypotheses, it became very difficult to falsify. Although stimulating much research, it has not produced a progressive research program generating various novel and confirmed predictions about schizophrenia. For most of its history, the DHS has lacked a viable competing alternative theory against which it could be incisively compared. Sociological factors, especially the rise to prominence of the biological psychiatry movement, and the conflation of the DHS and the DA theory of antipsychotic drug action have probably played an important role in its persistence. Psychiatry needs theories with higher levels of specificity and falsifiability. As the science of psychiatry matures, the field needs to become more self-critical about the validity of its theories.
Cullen L. Schmid,
The Journal of Neuroscience, Volume 30, pp 13513-13524;

Hallucinogens mediate many of their psychoactive effects by activating serotonin 2A receptors (5-HT2AR). Although serotonin is the cognate endogenous neurotransmitter and is not considered hallucinogenic, metabolites of serotonin also have high affinity at 5-HT2AR and can induce hallucinations in humans. Here we report that serotonin differs from the psychoactive N-methyltryptamines by its ability to engage a β-arrestin2-mediated signaling cascade in the frontal cortex. Serotonin and 5-hydroxy-l-tryptophan (5-HTP) induce a head-twitch response in wild-type (WT) mice that is a behavioral proxy for 5-HT2AR activation. The response in β-arrestin2 knock-out (βarr2-KO) mice is greatly attenuated until the doses are elevated, at which point, βarr2-KO mice display a head-twitch response that can exceed that of WT mice. Direct administration of N-methyltryptamines also produces a greater response in βarr2-KO mice. Moreover, the inhibition of N-methyltransferase blocks 5-HTP-induced head twitches in βarr2-KO mice, indicating that N-methyltryptamines, rather than serotonin, primarily mediate this response. Biochemical studies demonstrate that serotonin stimulates Akt phosphorylation in the frontal cortex and in primary cortical neurons through the activation of a β-arrestin2/phosphoinositide 3-kinase/Src/Akt cascade, whereas N-methyltryptamines do not. Furthermore, disruption of any of the components of this cascade prevents 5-HTP-induced, but not N-methyltryptamine-induced, head twitches. We propose that there is a bifurcation of 5-HT2AR signaling that is neurotransmitter and β-arrestin2 dependent. This demonstration of agonist-directed 5-HT2AR signaling in vivo may significantly impact drug discovery efforts for the treatment of disorders wherein hallucinations are part of the etiology, such as schizophrenia, or manifest as side effects of treatment, such as depression.
Pawel Kreczmanski, Helmut Heinsen, Valentina Mantua, Fritz Woltersdorf, Thorsten Masson, Norbert Ulfig, Rainald Schmidt-Kastner, Hubert Korr, Harry W. M. Steinbusch, , et al.
Published: 6 February 2009
Acta Neuropathologica, Volume 117, pp 409-421;

The publisher has not yet granted permission to display this abstract.
F. Vogel
Published: 28 June 2008
Clinical Genetics, Volume 36, pp 392-404;

Complex genetic diseases are often common: in most common diseases liability is influenced by genetic variation. The ways in which this variation is analyzed are discussed using diabetes, affective disorders and schizophrenia as examples. Molecular biology has opened new paths for a more incisive analysis of genetic heterogeneity and biological mechanisms. However, important population genetic aspects such as mutation and selection are largely unexplored. Therefore, predictions regarding possible increases or decreases in frequencies of susceptibility genes are hardly feasible. In many cases, however, the public health impact of such diseases can be alleviated and the quality of life of the individual can be improved, by appropriate adaptation of relevant environmental factors.
Alessandro Guidotti, William Ruzicka, , , Graziano Pinna, John M. Davis, Erminio Costa
NeuroReport, Volume 18, pp 57-60;

Prefrontal cortex (Brodmann's area 9) levels of the methyl donor S-adenosyl methionine were increased by about two-fold in schizophrenia and bipolar disorder patients, but not in unipolar depressed patients compared with nonpsychiatric subjects from the Stanley Foundation Neuropathology Consortium (Bethesda, Maryland, USA). Neither age, brain weight and pH, hemisphere, post-mortem interval, disease onset/duration, nor cumulative dose of fluphenazine affected S-adenosyl methionine content. In schizophrenia and bipolar disorder patients, the increase of S-adenosyl methionine is associated with an overexpression of DNA methyltransferase-1 mRNA in Brodmann's area 9 GABAergic neurons. Hence, the increased expression of S-adenosyl methionine and DNA methyltransferase-1 may contribute to promoter cytosine 5-methylation and to downregulation of the expression of mRNAs encoding for reelin and GAD67 in cortical GABAergic neurons of schizhophrenia and bipolar disorder patients.
Pawel Kreczmanski, Rainald Schmidt-Kastner, Helmut Heinsen, Harry W. M. Steinbusch, Patrick R. Hof,
Published: 10 May 2005
Acta Neuropathologica, Volume 109, pp 510-518;

The publisher has not yet granted permission to display this abstract.
Erik R Kandel
Published: 1 January 2002
L'Évolution Psychiatrique, Volume 67, pp 12-39;

The publisher has not yet granted permission to display this abstract.
Published: 20 November 2001
Schizophrenia Research, Volume 54, pp 95-103;

A personal review is presented of the functional basis of activation, withdrawal and unreality, individual differences in schizophrenia that Venables et al. pioneered. Activated and withdrawn syndromes were delineated from the totality of symptoms by classifying unmedicated patients on the basis of lateral asymmetries in electrodermal responses. A neuropsychological syndrome translation led to a syndrome hemispheric imbalance model supported by a literature review disclosing widespread cortical and infracortical involvement extending to motoneurone excitability, with validation from tests of learning, memory and evoked responses including the P300. It is contended that the centrality of arousal, the extensive substrate and the evidence of asymmetry modification with recovery and treatment all implicate specific and nonspecific thalamo-cortical systems whose uncoupling may lead to dysfunction of input, cognition and to unreality symptoms (found inconsistently related to asymmetry). The three syndromes have developmental associations including immune competence, ventricular changes and lateral asymmetry, putative regressive neuronal changes in connectivity and electrocortical measures of connectivity, as well as sensory gating and anomalies of P50 suppression and habituation. Replication of the syndromal structure in psychometric schizotypy indicates that syndrome expression is based on the premorbid personality, compatible with evidence of early determinants of the approach/withdrawal balance in social encounters. Functional considerations for the nature of schizophrenia support neurophysiological approaches to treatment such as neurofeedback.
Seymour S. Kety
Published: 1 October 1999
Nature Medicine, Volume 5, pp 1113-1116;

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Francine M. Benes
Published: 30 April 1997
Journal of Psychiatric Research, Volume 31, pp 257-275;

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K. Borch-Johnsen, T. I. A. Sørensen
Acta Psychiatrica Scandinavica, Volume 87, pp 73-78;

During the past 30 years, the Danish Adoption Registry has been used in the analysis of the effect of genes and family environment on the development of mental disorders. During the last 15 years, the registry has also been used for similar analyses of somatic disorders, including obesity and premature death from somatic disorders. This article discusses the potential problems generally related to inference on morbidity from mortality data and particularly when using mortality data in adoption studies. We conclude that further insight into the question of nature, nurture or both requires extending the studies to include morbidity data as well as mortality data. We suggest that expanding the study by including biological and adoptive siblings and by using recently developed statistical methods will considerably strengthen the adoption study of morbidity and mortality.
Rohan Ganguli, Jaspreet S. Brar, K. N. Roy Chengappa, Zan Wei Yang, V. L. Nimgaonkar, Bruce S. Rabin
Published: 1 January 1993
Annals of Medicine, Volume 25, pp 489-496;

The pathophysiology of psychotic and other symptoms in schizophrenia remains a mystery despite decades of research. Even though it has been suspected for many years that autoimmune mechanisms may play a role in the pathophysiology of schizophrenia, firm evidence for this hypothesis has been lacking. Our studies, over the last 10 years, have revealed that a subgroup of schizophrenics have several significant immunological abnormalities, including increased prevalence of autoimmune diseases and of antinuclear antibodies (ANA) and anticytoplasmic antibodies (ACA), decreased lymphocyte interleukin-2 (IL-2) production, increased serum IL-2 receptor concentration, increased serum IL-6 concentration, and an association with HLA antigens. These findings are characteristic of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis and insulin-dependent diabetes mellitus. We also found that some schizophrenics have antibodies to hippocampal antigens (AHA) in their serum, together with lowered IL-2 production. None of the above findings can be interpreted as definitely confirming the role of autoimmunity in schizophrenia. Nevertheless, taken together, the recent evidence points towards the existence of a subgroup of schizophrenics who have immunological findings consistent with that hypothesis. Further studies directed at finding the brain antigens targeted by the immune system in these patients, and longitudinal studies correlating clinical and immune changes over time, are needed.
F. Okada, T. J. Crow, G. W. Roberts
Published: 1 October 1990
Journal of Neural Transmission, Volume 79, pp 227-234;

We detected the existence of Gi (the inhibitory G-protein) or Go (a similar G-protein of unknown function) in the striatum of control and schizophrenic brains utilizing pertussis toxin-catalyzed ADP ribosylation. The level of Gi/Go was significantly decreased by 42% in the putamen of the left hemisphere in schizophrenics; caudate head and globus pallidus levels were unchanged. Decreased Gi or Go may underlie enhanced dopamine function in the schizophrenic brain.
J. L. Crammer
British Journal of Psychiatry, Volume 149, pp 337-345;

Specific questioning and frequent observation of a 69 year-old woman with cyclic bipolar manic-depressive illness showed that she had disturbances of thirst, appetite, bowel and bladder function and dramatic changes in body weight, in association with different phases of her mental illness. Examination of one manic phase under constant diet and inpatient control showed cardiovascular changes, sodium retention, body weight gain, with raised aldosterone secretion but steady vasopressin. There appears to be a sub-group of manic-depressive patients with evidence of disturbed hypothalamic functions as part of their mental illness, as shown particularly by changes in water and electrolyte metabolism.
Joan Murray-Jobsis
American Journal of Clinical Hypnosis, Volume 28, pp 34-42;

A brief summary of theories concerning the schizophrenic syndrome is presented within an historical perspective. The psychological theories of environmental/parental influences as well as physiological theories of genetic and biochemical influences are discussed. An interactional theory of both parental and genetic factors is then proposed as most useful for present exploration. An empathic view of the schizophrenic experience as perceived by the therapist utilizing the hypnotic trance is presented as a composite picture of schizophrenia. With this composite picture as a background, the author attempts to view and explore a possible interaction theory of the etiology of schizophrenia. A “model” of an interaction theory describing possible deviant parental patterns and possible genetic differences in empathic ability is discussed. The theory is proposed that genetic variations in empathie capacity interacting with a deviant environment contribute to the etiology of schizophrenia.
Martin Goldstein, Inge Goldstein
Published: 1 January 1984
The publisher has not yet granted permission to display this abstract.
, Joel E. Kleinman, Ingeborg Hanbauer
Science, Volume 221, pp 1304-1307;

Sodium fluoride, guanylimidodiphosphate, and the D1 dopamine receptor agonist SKF 38393 elicited a greater activation of adenylate cyclase in homogenates of caudate nucleus in schizophrenic than in nonschizophrenic subjects used as controls. Similarly, a greater activation of adenylate cyclase by sodium fluoride was observed in the nucleus accumbens of schizophrenics. These findings suggest that the coupling of dopamine D1 recognition sites with adenylate cyclase is more efficient in the brain of the schizophrenic, presumably because of an increased affinity of the G/F protein for guanosine 5'-triphosphate.
I. N. Ferrier, P. M. Cotes, T. J. Crow, E. C. Johnstone
Psychological Medicine, Volume 12, pp 263-273;

Synopsis LH, FSH, PRL and testosterone were estimated by radioimmunoassay in serial venous samples from 20 male chronic schizophrenic patients, 17 age-matched controls, 3 patients in remission from acute schizophrenia, and in single samples from age–sex matched populations. LH and FSH, but not testosterone or PRL, were significantly reduced in patients with chronic schizophrenia. There was an associated reduction in the frequency, but not amplitude, of LH secretory episodes in patients with chronic schizophrenia. No abnormalities of LH secretion were detected in those patients in remission from acute schizophrenia. Fourteen of the chronic schizophrenic patients were retested at a later date with similar results, except in the case of the few patients who had been started on neuroleptic medication. Some relationships were established between hormonal secretion and the clinical features of these patients. The possible significance of these findings is discussed in the context of the complex control of gonadotrophin secretion from the anterior pituitary and the natural history and nature of chronic schizophrenia.
Richard J. Wyatt, Farouk Karoum, David M. Stoff, Joel E. Kleinman, J. Christian Gillin, Dilip V. Jeste,
Published: 1 May 1981
Clinical Genetics, Volume 19, pp 437-442;

The publisher has not yet granted permission to display this abstract.
John S. Strauss, William T. Carpenter
Published: 1 January 1981
The publisher has not yet granted permission to display this abstract.
Irene J. Farley, Kathleen S. Price, Edward McCullough, John H. N. Deck, Walter Hordynski, Oleh Hornykiewicz
Science, Volume 200, pp 456-458;

In postmortem examination of brains of four patients with chronic paranoid schizophrenia, above-normal norepinephrine levels were measured in the ventral septum, the bed nucleus of the stria terminalis, the nucleus accumbens, and the mammillary bodies. No changes were detected in other limbic forebrain regions, including the hypothalamus and the medial olfactory (preoptic) area. The results point to the possibility of a malfunction of limbic noradrenergic mechanisms in schizophrenia, especially the paranoid variety.
J.B. Chassan
Pharmacology & Therapeutics. Part B: General and Systematic Pharmacology, Volume 1, pp 139-148;

H. R. Maricq
Published: 1 October 1975
Acta Psychiatrica Scandinavica, Volume 52, pp 264-282;

A two-gene model for the hereditary transmission of schizophrenia is presented involving two pairs of autosomal alleles Ss and Pp. It is hypothesized that the recessive gene can produce schizophrenia in homozygous state with a penetrance of .40. In the presence of the gene P schizophrenia can occur in the heterozygote Ss, resulting in a more serious form of the disease and having a manifestation rate of .70. The population frequencies best fitting the available data are estimated to be approximately .03 for P and .07 or .08 for s. It is also hypothesized that the reproductive fitness is .80 in manifest schizophrenics with genotype ss pp and .50 in overt schizophrenics carrying the modifier gene P. The model is proposed to cover only the so-called "process" or "nuclear" type of schizophrenia. The remaining schizophrenics of "reactive" and other types may belong to different genotypes or consist in phenocopies. The model is discussed in relation to literature observations and our own previous studies. The possibilities for increased fitness of non-schizophrenic carriers of P and s are also discussed.
Jack D. Barchas, Roland D. Ciaranello, Jerome A. Dominic, Takeo Deguchi, Elaine K. Orenberg, Jean Renson, Seymour Kessler
Published: 1 January 1975
Ira B. Black, Susan C. Geen
Archives of Neurology, Volume 32, pp 47-49;

Postmortem changes in the activities of tyrosine hydroxylase, dopa decarboxylase, and dopamine-β-hydroxylase were examined in various areas of rat brain. Tyrosine hydroxylase activity decreased in an exponential fashion with a half-time of two to four hours in caudate-putamen, substantia nigra, and locus ceruleus. Dopa decarboxylase activity remained within 20% of control values at five hours in these areas, but then decreased precipitously. Dopamine-β-hydroxylase activity remained within 20% of control for at least 20 hours after death.
Jack D. Barchas, Roland D. Ciaranello, Jerome A. Dominic, Takeo Deguchi, Elaine K. Orenberg, Jean Renson, Seymour Kessler
Published: 31 December 1974
Journal of Psychiatric Research, Volume 11, pp 347-360;

J. H. Gruzelier, P. H. Venables
Quarterly Journal of Experimental Psychology, Volume 26, pp 594-604;

Two-flash threshold, response criterion, and sensitivity (defined by the slope of the psychophysical ogive), were examined in schizophrenics and in normals under three conditions—a base-line condition, and during and after continuous white noise. Schizophrenics were subdivided into four groups on the basis of whether or not they exhibited paranoid symptomatology and electrodermal orienting responses. In general schizophrenics had more lenient two-flash response criteria than normal subjects. In the base-line condition schizophrenics with orienting responses had lower two-flash thresholds than those without orienting responses. Paranoid schizophrenics had more lenient criteria than non-paranoid schizophrenics and lower sensitivity than the non-paranoid group with orienting responses. Differential group effects were obtained during and after noise, especially with regard to sensitivity.
T. Hkfelt, A. Ljungdahl, , O. Johansson
Science, Volume 184, pp 177-179;

There is a 24-hour rhythm in the turnover of norepinephrine in sympathetic nerves innervating the pineal gland. This rhythm persists in blinded animals but is suppressed in normnal rats by light. The rhythm in norepinephrine turnover generates the rhythums in pineal indoleamines and N-acetyltransferase.
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