Talk:Causes of schizophrenia
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[edit] Hypoxia, as one option, in the neurodevelopmental model.
This scattergun approach to hypoxia is a small picture which fits in Dr Seeman's robust 1993 and more recent findings on dopamine. —Preceding unsigned comment added by Notpayingthepsychiatrist (talk • contribs) 02:50, 25 March 2008 (UTC)
In American Journal of Psychiatry' 160:1186, June 2003 - Letter to the editor 'Fetal Hypoxia, Genetic Risk and Schizophrenia, Dr Antonio Preti says: "Theo GM van Erp, MA and co-workers presented interesting data that link fetal hypoxia to smaller hippocampal volume and subsequent greater risk of schizophrenia" and entertains the possibility that hypoxia may be a contributing factor to schizophrenia risk.
I think the Wikipedia article could be improved by a discussion of hypoxia and reporting on the findings of Dr Seeman.
To get straight to the point: Molecular Psychiatry (2004)9,p684-697 in 'Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress', S Prabakaran, J E Swatton, M M Ryan, S J Huffaker, JT-J Huang, J L Griffin, M Wayland, T Freeman, F Dudbridge, K S Lilley, N A Karp, S Hester, D Tkachev, M L Mimmack, R H Yolken, M J Webster, E F Torrey and S Bahn search for 'disease signatures' and say: "Cluster analysis of transcriptional alterations showed that genes related to energy metabolism and oxidative stress differentiated almost 90% of schizophrenia patients from controls". The study rules out the effect of antipsychotics by using non-medicated patients partly, and controls for many other factors including brain pH, The article says microvasculature abnormalities could explain cellular hypoxia (for specific reasons the article names hypoxia as the probable cause of oxidative stress) and energy depletion, but p694 says an increase in oxygen deprivation causes an increase in glucose demands.Notpayingthepsychiatrist (talk) 17:15, 8 March 2008 (UTC)
"Glycogen is a brain energy source that can be quickly mobilised in response to abnormally high glucose demand or insufficient glucose supply (such as under hypoxic conditions)" p694. Notpayingthepsychiatrist (talk) 20:11, 9 March 2008 (UTC)
Archives of General Psychiatry, Vol 59, Jan 2002 p35 in "Fetal Hypoxia and Structural Brain Abnormalities in Schizophrenic Patients, Their Siblings and Controls", Tyrone D. Cannon, PhD; Theo G. M. van Erp, MA; Isabelle M. Rosso, PhD; Matti Huttunen, MD, PhD; Jouko Lönnqvist, MD; Tiia Pirkola, MA; Oili Salonen, MD, PhD; Leena Valanne, MD; Veli-Pekka Poutanen, MSc; Carl-Gustav Standertskjöld-Nordenstam, MD, conclude 'Fetal hypoxia is associated with greater structural brain abnormalities among schizophrenic patients and their nonschizophrenic siblings than among controls at low genetic risk for schizophrenia. This pattern of results points to a gene-environment interaction account of the disorder's neurodevelopmental pathogenesis'.
MINOR PHYSICAL ANOMALIES
These anomalies are thought to reflect changes in the brain as both are derived from the ectoderm.
Several minor physical anomalies are attributable in part by hypoxia. The most often cited minor physical anomaly: high arched palate, is described in articles as a microform of a cleft palate, Baher Ismail, Elizabeth Cantor-Graae, Thomas F McNeil."Minor physical anomalies in schizophrenic patients and their siblings" The American Journal of Psychiatry. Washington: Dec 1998. Vol. 155, Iss. 12; pg. 1695. Cleft palates are partly attributable to hypoxia: Guillermo Millicovsky, Malcolm C. Johnston, Proceedings of the National Academy of Sciences of the United States of America, Vol. 78, No. 9, [Part 2: Biological Sciences] (Sep., 1981), pp. 5722-5723
The vaulted palate caused by nasal obstruction and consequent mouth breathing, without the lateralising effect of the tongue can produce hypoxia at night but is not reported as contributing to schizophrenia.
Other malformations are reported only sporadicly. Capillary Malformation is induced by RASA1 mutation and can be changed by hypoxia: Rob Helton, Jiankun Cui, John R. Scheel, Julie A. Ellison, Chris Ames, Claire Gibson, Barbara Blouw, Ling Ouyang, Ioannis Dragatsis, Scott Zeitlin, Randall S. Johnson, Stuart A. Lipton, and Carrolee Barlow , April 20 2005, Brain-Specific knock- out of Hypoxia inducible factor -1alpha, reduces - rather than increases hypoxix-ischemic damage, The Journal of Neuroscience, pp4099-4107, http://www.jneurosci.org/cgi/content/full/25/16/4099/TBL2. A study in the American Journal of Psychiatry by Trixler et al: Mátyás Trixler, M.D., Ph.D., Tamás Tényi, M.D., Györgyi Csábi, M.D.,Gizella Szabó, M.D., and Károly Méhes, M.D., Ph.D., Sc.D,; 1997 Informative Morphogenetic Variants in Patients With Schizophrenia ,and Alcohol-Dependent Patients: Beyond the Waldrop Scale, 154:691–693 . http://ajp.psychiatryonline.org/cgi/reprint/154/5/691.pdf found hemangiomas to be highly significant in schizophrenia, and one of the authors said hemangiomas would include any birthmark which hadn't faded by adulthood - as this was suspected as abnormal (although he added the correlation wasn't high)(Pers. Comm).Realiseyourdignity (talk) 00:47, 13 December 2007 (UTC).
Exotropia is reported as having low correlation and high significance as well. See Toyota et. al, (2004) Vol 13(5) "Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B"; Human Molecular Genetics; p551; (http://hmg.oxfordjournals.org/cgi/content/abstract/13/5/551 as of 13-12-07). It can be caused by perinatal hypoxia: R. Huo, S.K. Burden, C.S. Hoyt and W.V. Good; "Chronic cortical visual impairment in children: aetioloy, prognosis and associated neurological deficits"; The British Journal Of Ophthalmology [Br J Ophthalmol], 1999 Jun; Vol. 83 (6).
However, using tests with significant MPAs often has a sensitivity of about 50%. The 'Gold Standard' is still presumably the psychiatrist's diagnosis.
DR SEEMAN'S PREVIOUS WORK
This work did not rely in any way on hypoxia. In 1993, Nature published Philip Seeman, Hong-Chang Guan & Hubert H. M. Van Tols work "Dopamine D4 receptors elevated in schizophrenia" (Vol 365, 30 September p441). In this work they found d4-like receptors to be elevated six times in schizophrenia. This result was replicated many times. Recently Dr Seeman said the most likely explanation for this is an alteration in the monomer:dimer ratio of the d2 receptor: "Dopamine Receptors: Clinical Correlates", http://www.acnp.org/G4/GN401000027/CH027.html Such alterations are caused by dopamine agonists or dopamine: Logan J; Fowler J. S.; Dewey S. L.; Volkow N. D.; GY S Gatley S J.; A consideration of the dopamine D2 receptor monomer-dimer equilibrium and the anomalous binding properties of the dopamine D2 receptor ligand, N-methyl spiperone: Short communication; 2001, vol. 108, no3, pp. 279-286, Journal of neural transmission, http://cat.inist.fr/?aModele=afficheN&cpsidt=911475. Dopamine itself can increase 1000% in striatal dialysates under hypoxia reversably provided (in part) the reuptake is not blocked.(Akiyama Y, Koshimura K, Ohue T, Lee K, Miwa S, Yamagata S, Kikachi H (1991) J Neurochem Sep; 57(3);997-1002 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1861163&dopt=Abstract. Notpayingthepsychiatrist (talk) 08:19, 25 March 2008 (UTC) Dr Seeman attributes the excess of monomers to "increased release of endogenous dopamine": Seeman P, Kapur S, Schizophrenia: more dopamine, more D2 receptors; Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7673-5; http://www.pnas.org/cgi/content/full/97/14/7673 a Google search reveals several possible causes of such release (as could be inferred from Philip Seeman, David Weinshenker, Remi Quirion, Lalit K. Srivastava, Sanjeev K. Bhardwaj, David K. Grandy, Richard T. Premont, Tatyana D. Sotnikova, Patricia Boksa, Mufida El-Ghundi, Brian F. O'Dowd, Susan R. George, Melissa L. Perreault, Pekka T. Männistö, Siobhan Robinson, Richard D. Palmiter, and Teresa Tallerico; Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis; PNAS, March 1, 2005, vol. 102 no. 9, pp 3513-3518 (in which hypoxia is considered too)). One of the cited cause of release is amphetamine exposure. It turns out that amphetamines work by means of a hypoxic process: Alberto Del Arco, Jose´ L. Gonza´lez-Mora, Vicente R. Armas, Francisco Mora, Amphetamine increases the extracellular concentration of glutamate in striatum of the awake rat Neuropharmacology 38 (1999) 943–954. Involvement of high affinity transporter mechanisms and "endogenous release of dopamine" is attributed to hypoxia in: P. William Conrad, David E. Millhorn and Dana Beitner-Johnson, Novel regulation of p38γ by dopamine D2 receptors during hypoxia ; Cellular Signalling, Volume 12, Issue 7, July 2000, Pages 463-467 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T2M-4164TXR-6&_user=62921&_coverDate=07/31/2000&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000005418&_version=1&_urlVersion=0&_userid=62921&md5=9d30ae53161c6bb3a9f72a27e2905be0 ; increase was also reported by Gary B. Freeman and Gary E. Gibson, Effect of Decreased Oxygen on In Vitro Release of Endogenous 3,4-Dihydroxyphenylethylamine from Mouse Striatum, Journal of Neurochemistry, Volume 47 Issue 6 Page 1924-1931, December 1986 and there is a natural period when the placenta is hypoxic: John D. Aplin, Hypoxia and human placental development, J Clin Invest. 2000 March 1; 105(5): 559–560: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=292460 besides dysfunctional reasons for hypoxia.
BUT HOW DOES HYPOXIA ALTER THE NEUROTRANSMITTER, DOPAMINE, IN THE BRAIN?
As Dr Seeman pointed out, the original dopamine hypothesis suggested that not only may dopamine be more highly expressed in the brains of psychotic people, but they might be more sensitive to it Philip Seeman and Shitij Kapur "Schizophrenia: More Dopamine, More D2 Receptors" PNAS http://www.pnas.org/cgi/content/full/97/14/7673 as at 2-01-08. He has written extensively and done many experiments with d2high, the highly sensitized receptor state for dopamine.
According to Dr Seeman et al, (SYNAPSE 60:319–346 (2006) p332 (full reference at the end of article)), The low affinity state of the receptor could be explained by the 'cooperativity model': when a dopamine-like chemical "binds to the vacant receptor, the occupied receptor interacts or 'cooperates' with the other receptors ... such that the affinity of the other receptors for the agonist is markedly reduced ..." - a 'negative cooperativity': the low state of the receptor. He says that, according to this model, increased d2high is a result of reduced 'negative cooperativity'.
So the question is: does hypoxia promote positive or negative cooperativity. Unfortunately Dr Seeman doesn't refer to hypoxia and cooperativity in just mentioned article. Notpayingthepsychiatrist (talk) 10:19, 2 January 2008 (UTC)
Nitric Oxide is often stimulated by hypoxia (nitric oxide is elevated at high altitudes http://en.wikipedia.org/wiki/Nitric_oxide).
Nitric oxide's use results in a guanine nucleotide exchange: http://www.jbc.org/cgi/content/abstract/270/13/7017 (as of 30-03-08). Dr Seeman says the role of guanine nucleotide is to alter the interreceptor cooperativity (332). The ability of some binding sites to bind with guanine nucleotides can "cooperatively increase their affinity" Paolo Migani, Rosamaria Fiorini, Ersilia Ferretti, Elena Manini, Stefano Chimichi, Gloriano Moneti (1997) Role of Guanine Nucleotides as Endogenous Ligands of a Kainic Acid Binding Site Population in the Mammalian Cerebellum Journal of Neurochemistry 68 (4) , 1648–1654 http://www.blackwell-synergy.com/doi/abs/10.1046/j.1471-4159.1997.68041648.x Notpayingthepsychiatrist (talk) 21:33, 2 January 2008 (UTC)
OTHER SCHIZOPHRENIC PHENOMENA, OTHER THAN DELUSIONS, CAN BE INFLUENCED BY HYPOXIA.
Hallucinations (widely reported in schizophrenia) may be generated by the Mirror Neuron System. Neuropsychologia 43 (2005) 268–280 Perspective "Schizophrenia and the mirror system: an essay" Michael A. Arbib, T. Nathan Mundhenk. —Preceding unsigned comment added by Notpayingthepsychiatrist (talk • contribs) 05:50, 25 April 2008 (UTC) The mirror system may play a role in delusions, but also in circumstances the schizophrenic feels are outside himself. Notpayingthepsychiatrist (talk) 05:55, 25 April 2008 (UTC) Hallucinations are related to serotonin Human Molecular Genetics, 1998, Vol. 7, No. 9 1507–1509 "5-HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer’s disease" Clive Holmes1, Maria J. Arranz, John F. Powell, David A. Collier and Simon Lovestone. High altitude mountain climbers can also get hallucinations - indicating a role for hypoxia.
OTHER REPORTS LINKING HYPOXIA
Many genes are triggered by hypoxia and have been listed as candidate genes for schizophrenia (Rainald Schmidt-Kastner, Jim van Os, Harry WM Steinbusch and Christoph Schmitz, Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia 'Schizophrenia Research' 84 2006 pp253-271).
Anecdotal evidence points to the importance of lack of oxygen to schizophrenia in that 53% of several of high altitude Peru's psychiatric hospital patients have schizophrenia (Cesar Sotillo, Claudia Rodriguez, Victor Salazar, 'Dissemination of a social skills training program for chronic schizophrenic patients in Peru, International Review of Psychiatry, Vol 10, Iss 1, pp51-53). The figure is some 20% in Australia: http://www.aihw.gov.au/mediacentre/2001/mr20010627.cfm. Indicating it may be maternal insufficiency in oxygen rather than nutrients which is crutial. It is known that maternal hypoxia leads directly to fetal hypoxia http://books.google.com.au/books?id=sfp-OzoU6X4C&pg=PA276&lpg=PA276&dq=maternal+hypoxia+mucus&source=web&ots=oupeVZNhaR&sig=qWrTvae82t-nb3jLDS6zoEGutEE&hl=en#PPA276,M1 Management of High-risk Pregnancy By John T. Queenan, Inc NetLibrary p276, Blackwell Publishing 1999. Maternal hypoxia is indicated by stomach mucus. Bulletin of Experimental Biology and Medicine, "Effect of hypoxia on gastric secretion and excretion. T. I. Selivanova and V. I. Gridneva 17 Aug 1984.
Sandra Rees et al have done experiments suggesting that placental or umbilical insufficiency may be responsible for many diseases including schizophrenia. Her experiments even show enlarged lateral ventricles - similar to 50% of schizophrenics: But the resultant animals were also growth restricted. Mallard, E C; Alexandra Rehn; Sandra Rees; Mary Tolcos and David Copolov; Schizophrenia Research, 1999, Vol40, 1, 9, pp11-21, "Ventriculomegaly and reduced hippocampal volume following interuterine growth restriction: implications for the aetiology of schizophrenia", Elselvier Science, . http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TC2-3XJTJCP-2&_user=10&_coverDate=11%2F09%2F1999&_alid=652131782&_rdoc=7&_fmt=summary&_orig=mlkt&_cdi=5158&_sort=v&_st=17&_docanchor=&view=c&_ct=1954&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a0f4c32a30c69587870ba0925fd9d9e3. (Keltner, Perspectives in psychiatric care, v32 iss2, pp32)
It is difficult to tease apart whether enlarged ventricles are due to hypoxia or nutrition. In one case of excessive birth weight (or macrosomia) a 4900g (over 10lb) baby as a fetus of 30 and 34 weeks had noted prominence of lateral ventricles, but at 40 weeks, after c-section delivery (so experiencing hypoxia) no noted ventricular enlargement and ventricles appeared normal on MRI as a child. The child was healthy concerning schizophrenia at that age, but preganacy had been complicated with psychoactive drugs. If the psychoactive drug used was amphetamine, it is an apetite suppressor as well as working by hypoxic mechanism. But the enlarged ventricles disappeared after birth and remained normal even after the c-section. Infact, Dr Rees uses the term growth-restriction in her title. And in the article on p17 says it is not clear which factor is responsible for the results, but entertains the probability that hypoxia or one of its consequences is influential: "In summary, we have found that intrauterine compromise involving hypoxia, malnutrition and an altered endocrine status, during the second half of gestation in the guinea pig, can result in several structural alterations similar to those seen in some schizophrenic patients." (p19) "Outcome in children with fetal mild ventriculomegaly:a case series" Schizophrenia Research (2001) p220 John H. Gilmore, Julia J. van Tol, Hellen Lewis Streicher, Kwanna Williamson, Sherry B. Cohen , Robert S. Greenwood, H. Cecil Charles, Mark A. Kliewer, J. Kenneth Whitt, Susan G. Silva, Barbara S. Hertzberg, Nancy C. Chescheir. Notpayingthepsychiatrist (talk) 15:47, 10 April 2008 (UTC)
That oxygenation and nutrition are independent has been demonstrated http://content.nejm.org/cgi/content/abstract/328/10/692. (New England Journal of Medicine, Volume 328:692-696, March 11, 1993, Number 10 Diagnostic Value of Blood Sampling in Fetuses with Growth Retardation Giorgio Pardi, Irene Cetin, Anna Maria Marconi, Antonella Lanfranchi, Patrizia Bozzetti, Enrico Farrazzi, Mauro Buscaglia, and Frederick C. Battaglia )
The placenta originates as cells in the embryo. Notpayingthepsychiatrist (talk) 04:56, 1 January 2008 (UTC)
In 1993, Gross, J. Lun, A. and Berndt, Ch ('Early postnatal hypoxia induces long-term changes in the dopaminergic system in rats', Journal of Neural Transmission, Springer Wein, concluded hypoxia at critical times resulted in: "The postsynaptic part lets expect a supersensitivity because of the long term dopaminergic hypoactivity due to hypoxia ...' p119.
Realiseyourdignity (talk) 08:55, 22 November 2007 (UTC)
IN THE BELOW SECTION - Notpayingthepsychiatrist, is the same person as Realiseyourdignity, only forgot password.
A Japanese case study of monozygotic twins with discordant schizophrenia draws attention to their different weights at birth and concludes hypoxia may be the differentiating factor: http://www.blackwell-synergy.com/doi/pdf/10.1046/j.1440-1819.2003.01116.x Notpayingthepsychiatrist (talk) 07:16, 22 January 2008 (UTC)
In "Invited Commentary: Gaining Traction on the Epidemiologic Landscape of Schizophrenia", John McGrath reports studies in which high birth weight is associated with schizophrenia. (American Journal of Epidemiology (2003) V158,4). Notpayingthepsychiatrist (talk) 22:41, 9 April 2008 (UTC)
Astoundingly, a report shows an actually increased density or high density of D2R in the striatum after hypoxia: " It has been shown that the D2R density in the striatum in infants might be upregulated after hypoxia (Tranquart et al 2001)"Reduced Midbrain Dopamine Transporter Binding in Male Adolescents with Attention-Deficit/Hyperactivity Disorder: Association Between Striatal Dopamine Markers and Motor Hyperactivity", Aurelija Jucaite, Elisabeth Fernell, Christer Halldin, Hans Forssberg, and Lars Farde. Biological Psychiatry, Volume 57, Issue 3, 1 February 2005, Pages 229-238.
Golan, H and Huleihel, M report that, "Contrary to what has been found for sensory reflexes, impairment in motor function and coordination remained. Thus impairment of motor performance may be considered a hallmark of prenatal hypoxia" (Developmental Science 9:4 (2006) p341). Apgar scores have shown to be unreliable (Marrin, M and Paes, B A; Obstetrics and Gynecology 1988 72:120-123). "A history of low Apgar scores at 1 and 5 minutes is commonly used as an indicator of HIE and subsequent morbidity, but this index has several drawbacks" (http://www.emedicine.com/neuro/topic696.htm as of 02-06-08) and "an infant with significant prepartum injury to the brain in this period may be entirely asymptomatic in the neonatal period" (http://www.emedicine.com/neuro/topic696.htm#target3 as of 02-06-08) Notpayingthepsychiatrist (talk) 19:24, 20 February 2008 (UTC)Notpayingthepsychiatrist (talk) 01:13, 2 June 2008 (UTC)
What determines delusional themes?
GIVEN IDENTITY - and a possible role for hypoxia.
The striatum being a social organ, and the region where d2 receptors are most frequent, means these delusions have to be seen in cultural context http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6V5W-48JK0CW-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=9a9aa8603c0270bef3d0c796d8e22dc8. Behaviour Research and Therapy Volume 41, Issue 7, July 2003, Pages 755-776 Assessment of psychopathology across and within cultures: issues and findings, Juris G. Draguns and Junko Tanaka-Matsumi For example, delusions of guilt and punishment are frequesnt in a Western, Christian country like Austria, but not in Pakistan - where it is more likely persecution. It says cultural factors have a decisive influence in shaping delusions: http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=224276&Ausgabe=226529&ArtikelNr=29094 Comparison of Delusions among Schizophrenics in Austria and in Pakistan T. Stompea, A. Friedmana, G. Ortweinb, R. Strobla, H.R. Chaudhryc, N. Najamc, M.R. Chaudhryc, Psychopathology Vol. 32, No. 5, 1999 . This report shows frequesnt delusions of guilt and punishment in Austria as well and this is with Parkinson's patients treated with l-dopa, showing the delusion in schizophrenia is not necessarily due to narcissism, guilt, homosexuality or any other psychoanalytic reason http://www.springerlink.com/index/N11474QQ25R5U236.pdf The balance of biogenic amines as condition for normal behaviour W. Birkmayer, W. Danielczyk, E. Neumayer and P. Riederer, Journal of Neural Transmission, Volume 33, Number 2 / June, 1972.
Narcissism could be manifest though and is correlated to schizotypal personality disorder (schizophrenia was exclusded from the study) and according to a growing body of research has two factors: covert/vulnerable or overt/grandiose (Miller, JD, Hoffman, B J, Campbell, W K, Pilkonis, PA' Comprehensive Psychiatry, 2008 Vol 49, pp141-145). ("Schizophrenia: a very short introduction" presents a case study of a man given amphetamine. The patient said that the first thing he felt was that "everything changed" and now he was the centre of attention C Frith EC Johnstone Oxford University Press 2003). Similarly, in "Cognitive Therapy for Delusions, Voices and Paranoia"2001 John Wiley and Sons Ltd by P Chadwick, M Birchwood and P Trower the authors make a distinction between persecuation and punishment paranoia. But narcisstic regression is reported amongst drug users, perhaps implicating dopamine (Bulletin On Narcotics, 1983 Jul-Sep Vol 35(3) pp81-86, Dias CA, Polvora FF 'Drug addiction among adolescents'). http://www.addictioninfo.org/articles/534/1/Theory-of-Drug-Use/Page1.html Confirming Chadwick et al's dichotomy of paranoia is the Schizophrenia Bulletin article "Hypothesis: Grandiosity and Guilt Cause Paranoia; Paranoid Schizophrenia is a Psychotic Mood Disorder; a Review" by Charles Raymond Lake, December 1997.
Then there are focus' within themes. The Pastoral Psychology article "John Nash's Delusional Decade: A case of paranoid schizophrenia" Jan 2004 describes several of John Nash's: homosexuality, religion and guilt.
Also, coincidentally, when amphetamine or l-dopa intake are converted to dopamine, the rarer delusions like Gender Identity Disorder delusion require more dopamine whereas the more frequent ones like jealousy require less. —Preceding unsigned comment added by Notpayingthepsychiatrist (talk • contribs) 21:48, 4 April 2008 (UTC) As previously shown hypoxia can increase dopamine up to 1000% - this is the percentage required for gender identity delusions. This might explain why neuroleptics are only partially effective in some cases, if nearly all d2 receptors are converted to d2high SYNAPSE 49:209 –215 (2003) Dopamine Displaces [3H]Domperidone From High-Affinity Sites of the Dopamine D2 Receptor, But Not [3H]Raclopride or [3H]Spiperone in Isotonic Medium:Implications for Human Positron Emission Tomography PHILIP SEEMAN, TERESA TALLERICO, AND FRANCOISE KO ̧, because the d2high receptors which aren't blocked are still at a very sensitive state - so the same delusional message is signalled. Notpayingthepsychiatrist (talk) 08:38, 25 April 2008 (UTC)
While it would be convenient for patients like myself to have simple answers to the questions of schizophrenia, Table 2 of Philip Seeman et al's Dopamine Pathways Converge via D2high, shows this disease has multiple pathways certainly in some cases without hypoxia. —Preceding unsigned comment added by Notpayingthepsychiatrist (talk • contribs) 23:51, 30 December 2007 (UTC) P Seeman, J Schwarz, J Chen, H Szechtman, M Perreault, S McNight, J.C. Roder, R Quirion, P Boska L Srivastava, K Yanai, D Weinshenker and T Sumiyoshi, (2006) Synapse 60, pp319-346 Notpayingthepsychiatrist (talk) 11:39, 11 March 2008 (UTC) It seems that unless there is some intervention the d2high population is permancent. Proof that Dr Seeman is right comes from his own work and the correlation between the 600% increase in d2 monomers (caused as shown above by the reversal of negative cooperativity and resulting in the release of micromole concentrations of dopamine in place of the nanomole concentration needed for d2high p331) in 1993 and lately a similar percentage increase in D2high caused by most contributing factors.Notpayingthepsychiatrist (talk) 00:23, 2 January 2008 (UTC). Excess hypoxia is surely prevenable? Notpayingthepsychiatrist (talk) 02:16, 24 February 2008 (UTC)
Notpayingthepsychiatrist (talk) 06:46, 1 January 2008 (UTC)
Notpayingthepsychiatrist (talk) 14:25, 30 December 2007 (UTC)
Permanence of the schizophrenia as a unique potential - perhaps caused by many things.
"A Prospective Cohort Study of Childhood Behavioural Deviance and Language Abnormalities as Predictors of Adult Schizophrenia" by CE Bearden, IM Rosso, JM Hollister, LE Sanchez, T Hadley and TD Cannon; Schizophrenia Bulletin, V 26, No 2, 2000, p396 says "Thus it has been suggested that there is a distinct "neurodevelopmental" form of the dosorder, involving early language, behavioural and neuromotor abnormalities, early onset and poor prognosis that may stem from heterogeneity in etiologic factors (eg obstetric complications)" also, " ... a history of fetal hypoxia predicted schizophrenia".
In FASEB Philip Seeman showed a photograph of abnormal d2 schizophrenic receptors and said it deserved further genetic examination (figure 6 in P Seeman and HB Niznik "Dopamine receptors and transporters in Parkinson's disease and schizophrenia" FASEB J. 1990 4:2737-2744. So, according to this, the change in d2 receptor could be genetic, however Dr Seeman says in the sentences above it that the protein structure may be altered during the course of schizophrenia. He does however, call it a 'unique peptide fragment' and did use controls too. So schizophrenics have a unique potential.
The caption for the photograph describes the difference as an additional fragment in the peptide map. Hypoxia is considered as underpinning the 'schizophrenic process' according to the Molecular Psychiatry article at the beginning of this discussion. Hypoxia can quantitatively alter the d2 receptor: http://www.ncbi.nlm.nih.gov/pubmed/9545180 as at 20-05 (Neuropathological characteristics and alteration of the dopamine D2 receptor in hypoxic-ischemic basal ganglia necrosis Meng SZ, Isumi H, Takashima S. Brain Dev. 1998 Mar;20(2):98-104,
Alterations to the actual receptor would explain why genetic evidence is not forthcoming. I have checked to see if anyone currently holds this opinion and couldn't find positive or negative information. If this 'unique' peptide is actually another receptor number or d2long or short I assume Philip Seeman would have noticed that in the control population. Soon after - in 1993 - Dr Seeman and his team explored the d2r gene for abnormalities and concluded there was nothing that would affect the protein - the study was presumable done from a blood sample (Neuropsychopharmacology. 1993 Feb;8(2):137-42. Schizophrenia: normal sequence in the dopamine D2 receptor region that couples to G-proteins. DNA polymorphisms in D2. Seeman P, Ohara K, Ulpian C, Seeman MV, Jellinger K, Van Tol HH, Niznik HB.)
Perhaps hypoxia could be added as a third option. In "Proteomics profiling of nuclear proteins for kidney fibroblasts suggests hypoxia, meiosis and cancer may meet in the nucleus" by K Shakib, JT Norman, LG Fine, LR Brown and J Godovac-Zimmermann, in Proteomics, 2005, 5, pp2822, 2827, they say: "Although different mechanisms might be operative for different proteins, several observations speak against generalised proteolysis as part of an apoptitic response to prolonged hypoxia. First, for all of these proteins, only a single truncated isoform was observed, ie no change in the amount of an aditional fragment was observed for any of them .... Indicating an additional fragment is perhaps indicative of prolonged hypoxia. Notpayingthepsychiatrist (talk) 15:45, 27 May 2008 (UTC)
Dr Seeman proved the link between d1 and d2 receptors was broken in schizophrenics: "In post-mortem schizophrenia tissue, however, the D1-blocking drug is not able to reverse the action of such high concentrations of dopamine (400 nM) (9; Seeman et al., 1989)" ("Dopamine and Schizophrenia" Dr Philip Seeman, http://www.scholarpedia.org/article/Dopamine_and_schizophrenia as at 2-06-08). Notpayingthepsychiatrist (talk) 06:38, 2 June 2008 (UTC). He also said that the d1-d2 link may be mediated by guanine nucleotide, and as said before, nitric oxide's use results in a guanine nucleotide exchange. The guanine nucleotide link is also insensitive in schizophrenia (Nature 365, 441 - 445 (30 September 1993); Dopamine D4 receptors elevated in schizophrenia Philip Seeman, Hong-Chang Guan & Hubert H. M. Van Tol), Presumably the d2 receptor variant mentioned from FASEB is the reason - pointing to genetic, peptide variant or hypoxia.
To the uneducated reader, it seems that alterations in peptide structure due to flexibility will not prevent its functionality in major areas (so perhaps too as to prevent binding to G-protein, in the d2 case), so hypoxia seems a valid alternative: "...flexibility contributes ~18 kT to the stabilization of an ion at the center of the channel...". "Role of Protein Flexibility in Ion Permeation: A Case Study in Gramicidin A" Biophysical Journal, Apr 1, 2006 by Bastug, Turgut, Gray-Weale, Angus, Patra, Swarna M, Kuyucak, Serdar (http://findarticles.com/p/articles/mi_qa3938/is_200604/ai_n17184191/pg_1 as at 04-06-08). —Preceding unsigned comment added by Notpayingthepsychiatrist (talk • contribs) 18:54, 3 June 2008 (UTC)
Some indications you may have had prenatal hypoxia...
As mentioned before, lack of motor coordination is the hallmark of prenatal hypoxia. Also, there is some consistency in results showing those with prenatal hypoxia may have lower than average nitric oxide, which results in several symptoms which can be found on a Google search. ((example, The FASEB Journal. 2007;21:894.14 Long term effects of prenatal hypoxia on endothelium-dependent relaxation responses in pulmonary vessels of adult sheep Jie Liu1, Yuansheng Gao1,2, Lawrence D Longo3 and J. Usha Raj1)
But everyone is to some degree schizophrenic. As the authors (previously cited) show in 'More Dopamine, More D2' everyone has some degree of endogenous dopamine (even if only 5%) and free dopamine. In 'The Madness of Adam and Eve', David Horrobin, Bantam Press 2001, suggests schizophrenia may have been present before the division of races of mankind and given us a creative edge. On p181 he repeats: "James Joyce's daughter was schizophrenic. Albert Einstein's son was schizophrenic. Carl Gustav Jung's mother was probably schizophrenic. Several of philosopher Bertrand Russell's relatives were schizophrenic. The children of several recent Nobel Laureates ... are schizophrenic...". Nevertheless, the film 'A Beautiful Mind' shows John Nash as saying goodbye to his hallucinations and delusions. Notpayingthepsychiatrist (talk) 06:47, 13 April 2008 (UTC)
[edit] lack of holistic approach and structual approach
Neurotransmitters are only modulators of 'trigger level' of specific autosopher or perceptron network. i would like to point out @ A.Jakubik's findings about how information processing disorders are related to psychoses.
factors like infecteous damage of limbic system (i.e. due to viral, bacterial or parastic infection) which is usually rich supported by blood (so also circulatory system issues can contribute) and 'draws' lot of blood for quick enough information processing might be the 'key' to understand schizophrenia, which was afterall described as 'information metabolism' disorder by A.Kepinski.
also perserveration of perception and perserveration of emotional state can be put into this model nicely, as emotional system exists in limbic system structures, which are very prone to perserveration, due to their structural design.
so , reorganising the problem : schizophrenia is disorder of information metabolism in individual, with core axis symptom - autism - which is disorder of relation of individual with environment.
causes of either of disorders can be easily spot then (i.e. information/social memory overload, organic damage of information processing structures or tracts connecting them with other parts of the brain, or repetative (or very intense) environmental influences. separate section could include modelling of limbic system in early childchood, altrough this could be aswell accounted into organic damage.
83.12.255.234 (talk) 06:22, 4 April 2008 (UTC)
