Poster Presentation PO-77-16 F1334
Encephalopathy by Antipsychotic,Malpractice and View of Schizophrenia
Satoshi HAYAMA
Department of Biophysics,Faculty of Science, Kyoto University

WCP 2002 Yokohama Aug24-29
Display Aug27 10:00am-Aug28 2:30pm
Session Time Aug28 1:00pm-2:30pm

ABSTRACT
Encephalopathy by Antipsychotic ,Malpractice and View of Schizophrenia

Pharmacopsychiatry today has 3 difficult themes .One is understanding and cure of irreversible encephalopathy caused by antipsychotics[1] .Another is malpractice[2]. The other is integration of many traditional views of schizophrenia for development of new antipsychotic[3].METHOD-interviewed patients,lawyers and reviewed literature.[1]HAYAMA'S DISEASE(I named)-Many of irreversible encephalopathies caused by antipsychotics are unclassifiable chronic disease rather than neuroleptic malignant syndrome and tardive dyskinesia.SYMPTOM- exhausted brain,prostration,epilepsy,dementia,sleep disorder.EXAMINATION-CT-cortical atrophy.EEG-abnormal. POTENTIALITY OF TARDIVE DISORDER- neurodegenerative diseases and brain tumors in later years.[2]Typical malpractice is misdiagnosis of uncommon personality as psychoses,and misinterpretation of paradox reaction due to antipsychotics as psychotic symptoms, leading to onset of encephalopathy.[3]HYPOTHESIS-biological pathology of schizophrenia.(a) .excessive dopamine secretion. (b).gene and cells (e.g.abnormal gene expression). (c). synapses, NORMAL-Keep inevitability all neuron selecting particular neuron on extension of neurites and brain controlling all combinations of synaptic transmission.SCHIZOPHRENIA-Extension of neurites that have lose their targets,selection of wrong synapses for signal transmission,abnormal combination of synaptic transmission.From thought about cause,I pay attention to ancient schizophrenia view without discriminaiton,too.
References
[1]Hyman SE,Nestler EJ(1993):The Molecular Foundations of Psychiatry:American Psychiatric Press
[2]Lader MH(1977):Psychiatry on Trial :Penguin Books
Introduction
In Japan ,hold this WPA congress,,,this is long-cherished wish of many conscientious psychiatrist. Without tear we remember many Japanese that can attend only mind from their tomb.Japanese psychiatry history is too dark to tell.If WCP held more early ,maybe more many patients saved. But God bless us,the light of WCP yokohama will save after Japanese psychiatry.
-"I found Bushido is doing death .Everyday dead and every morning and every evening we must live new death"(Hagakure by Tsunetomo Yamanoto Edo Age)-Hagakure mean hide under a leaf,and he wrote the mental life of Bushi this.Welcome to Japan.We hope master fencers of psychiatry from far get many thing.
In Psychiatry field three absolute commonsense and difficulty and prohibition exist.I try to cut all of them by Katana as Samurai.Firstly we think irreversible side effect are syndrome malin and tardive dyskinesia.Is it true? Secondly malpractice difficult case. Thirdly please do not laugh,Schizophrenia view of Bible is truly error? This work is very primitive and very sharp.But which do you choose complete print or a important nega-film ? If you are Bushi ,you choose after.I try to point all weak point of psychiatry that cannot know without my pointing to the peruse of advance of psychiatry.
[1] Encephalopathy by Antipsychotic
In drug induced diseases ,we must continue to use same drug,the mysterious illness happen that only the drug make ,the studying about the illness will be useful for understanding cause illnes,such disease have worth to study.For example haloperidol is one of such drug .Given to schizophrenia patients case ,Problem are few.But given to diagnosed wrongly personality disorder,eccentric person,as schizophrenia and dementia elder,problem children case have made many induced disease.They are abandoned by doctors,lawyers and citizen's group.Japanese situation is serious.Long term haloperidol given laboratory animal and patient's brain many finding exist.Though that finding is not more serious than mercury poisoning,carbon monoxide poisoning and another poisoning But about patient's impression haloperidol's patients is more serious.
Why? We have thought about schizophrenia main biological patology,it is polyrrhea of dopamine and about haoperidol's main role is D2 receptor blocking.The reason of many psychiatrists have treated this problem lightly is they have thought haloperidol's object is receptor.But is it true?We have thought about schizophrenia as catecholamine disorder and for catecholamine's control, drug is easy to make.But that thought discus schizophrenia as same level with melancholy and Parkinson's disease.Nearly young doctor scarcely look at their end stage.If our old memory is exact,schizophrenia must more serious and many-sided disease.Maybe schizophrenia's main biological pathorgy is abnormal of many gene expression.
For example ,the genes controlling thinking,affect.Some genes are activated and some genes are reprersed.Haloperidol's role is activating repressed gene and repressing activated genes.I think all major tranquilizer have common effect,exquisite gene controlling like this over producer's purpose. So ,though haloperidol's cell toxicity is weak,genes toxicity is strong in the case of given to normal brain.For treatment of halopeidol induced brain disease ,researching controlled gene by haloperidol and activating repressed genes and reprersing activated gene,produce such mew medicine.It is not impossible.
I think for example next experiment method . Without patients such studying do not give benefit to society.
But even how few patients they have the right studied for recover as the right of patients about not only drug induced disease but also all rare sick patients. United Nation order it as human right,WHO order researching institute that they have .Only one company product medicine for all world patients.And International Red Cross order one hospital in each nation.If world think more serious ,such rare sick patients treatment is not dream.About haroperidol political problem exist.At U.S.S.R age,many political offender given in mental hospital.After released the rich of them escape to Germany and U.S.A the poor of them still in Russia.Many of text book do not write .But I think typical irreversible brain disease by neuroleptica are not so much syndrome malin and tardive dyskinesia as "not apply taxon ,chronicity brain disease".Side effect studying need turning about central target .And about central purpose from contriving to program few medication to treat neuron and gene in it..After 30 years molecular biology and imaging enhance the possibility recognize such side effect and product recovery drug.
---------
The side effects to the brain of present antipsychotic medicine is mentioned below.
"Perkinsonism, dystonia,akathisia, rabbit syndrome ,reversibility dyskinesia, pisa syndrome,
tardive dyskinesia,tardive dystonia,tardive akathisia,tourette syndrome "
In these side effect irreversible- is a part of tardive dyskinesia and others. And lethality is malignant syndrome ,another will be recovered in several years after medication.
However, such side effects are limited the doctor can be checked in the clinical .
I check disease which is completely different from civic organizations, patients, and lawyers , and report it.
--Case 1--
. 15 -17 age. Diagnosed wrongly as "v.a schizotypal personality".The physician in charge misunderstand patient talk as idea of reference "I am like Dostoevsky's hero( mean resemble Dostevsky's hero)"at the first medical examination. Truely the aftereffect of meningitis then. symptoms was insomnia . Took major tranquilizer and antidepressants for example haloperidol 10mg /day for two years by doctor. After starting medicine,insomnia became worse,parkinsonism,catalepsy,fever,prodromal stage of syndrom malin,dyskinesia(syndrome oculaire,opisthotonus,glossal project),akathisia, uneasiness,unstable spirit condition,epilepsy(main tonicolonic in sleeping time)start one or two times for a month,intellect lowering,myotomia,dementia,forgot his name in short time,derangement of capacity to register,for disturbance of memorization mistake when count as chairman at majority decision,amnesia,etc.At 17 age changed hospital. New doctor corrected diagnose to neurosis ,stopped haloperidol and gave minor tranquilizer.But nobody can understand about his illness for long term.When patient said his illness was by medicine.Nobody approved and refused examination from some doctor in Japan. At 20 age , bedridden.Even watching TV brain tired soon.After long year gradually such symptoms have become normalize .After 5 years from stop Haloperidol,at examination still high tendon reflex. Now aftereffects are easy to tired(brain),epilepsy,insomnia ,headache(chronicity,not localized at after awake time do not exist,according to tired gradually increase,head heavy feeling,not psychogenic).and taking diazepam,triazolam.When stop this diazepam ,triazolam, circadian rhythm is into disorder. This case did not bring it trial.The next day gone to work his brain is tired, absentminded can not move.One day go to work and next day in bed. On Head-CT cortical atrophy existed at 23 age.On EEG spike wave , reversed phase,irregular in size wave,exist. neuron death ,degenerative atrophy,catecholamine disolder,abnomal proteingenesis from destroyed gene by medicine and another unknown pathology like Alzheimer's and Parkinson's disease exist.Of course another sick possibility for example melancholia ,but all another possibility have contradiction. On 35 age Head-MRI , some cortical atropy point recovered.Atropia neurons have recovered cell size by autotherapy.
On brain wave there are four stages sleeping.Brain wave's feature were appear sleeping time brain wave at awaking time.Usually human lose consciousness time are first stage .but in awaking time second stage's wave spindle,K-complex appear.This case patient decided that he do not bring it court.
--Case 2--
The 2nd case is took haloperidol , 2.4mg [ /day ] 100 days .48 years-old woman.chlorpromazine and diaxepam are used together. The first diagnosis is obstructive arteriosclerosis.
After useless prostaglandin medication, diagnosis of hysteromyoma was received, after the operation, and there was dehydration, and from anxiety hysteria haloperidol gave as stomach medicine explained for the patient.The extrapyramidal syndrome including the Parkinson syndrome appeared very strongly.hypermyotonia,sudoresis, dyspnea, and IQ decrease from standard to 60.
It was diagnosed as the 1st class of the physical disability of both the upper-limbs functional disorder by Parkinson's disease and obstructive arteriosclerosis, and a trunk functional disorder with difficult standing up.It has recovered to the state of the third class of a physical disability today 15 years after.
The headache which is extracted and another operation cannot be carried out simultaneously
There are cortical atrophy Head CT.The patient petitioned strongly to lawyer here and there chronic brain obstacle by haloperidol, and has received 10 million yen by mediation.It is famous case.
---------------
Both of these are haloperidol which the concentration difference in blood tends to produce, they are considered to be easy to generate such case.Otherwise, the case has not been well checked, although they are this disease potentially fairly. Consent of patients could not obtained the information is not clarified .They are misdiagnosed as the another illness which is different .Even if they consults.Or patient does not trust hospital and does not consult .There are common in the civic organization.On psychiatry, although there are no such disease, there are many medical malpractice victims who tell such self-diagnosis in civic organization in fact, and they live miserable life .
From these cases we cannot help judging antipsychotic induce chronic brain disease.Although recognized irreversible side effects also until now, it is condition which should give and consider 1 disease unit.Some of psychophamacologist deny the existence of such Encepharopaty by Antipsychotic,because of their clinical experience .They say "I have not examine such patient".But this is not demonstration of not-existence of them.All the better it is the proof of the difficulty of recognize them,and survival of such patients.From 1952 the first use of Chlorpromazine Encephalopaty by neuroleptica have been existed still now.It is the most important blot of the psychophamacology history.I think the name of disease is better another proper.But if do not use my name,suffer a loss persons by recognize this disease idea may try to change disease concept no relation with me from social benefit.e.g.change"irreversible" to "reversible" and deny possibility of tardive disorder.
<The next is the definition of this disease.>
Hayama's Disease is excessive extent ,chronic brain disease by irreversible antipsychotic induced encephalopathy.
-- HAYAMA'S DISEASE -
.The definition of the illness.
Although the idea it was presupposed that an irreversible brain disease by neuroleptica medicine appeared here and there on reference, and it had the long-term use history until today, but we can not construct the clear illness concept. Although tardive dyskinesia is accepted as an irreversible brain disease, it is only intelligible phenotype , the main part of brain disease by neuroleptica is still wrapped in darkness.
This illness concept is the general term of chronic and irreversible brain lesions by neuroleptica.
Condition is divided into three kinds and indicated below.Clinical condition
<The Symptom>
(1)Taking medicine term
parkinsonism,catalepsy,fever,prodrome of syndrom malin,dyskinesia(syndrome oculaire,opisthotonus,glossal project),akathisia, uneasiness,unstable spirit condition,epilepsy(e.g.main tonicolonic in sleeping time)start one or two times for a month,intellect lowering,myotomia,dementia,disturbance of memory(e.g.forgot his name in short time,)
(2)Some years after stopped medicine
light dementia,intellect lowering,epilepsy,hypomnesia,unstable spirit condition,
(3) Irreversible Sequela
exhausted brain,prostration,aftereffects are easy to tired(brain),epilepsy,insomnia ,headache(chronicity,not localized at after awake time do not exist,according to tired gradually encrease,head heavy feeling,not psychogenic). Without minor tranquilizer circadian rhythm is into disorder.
< The Diagnosis>
Judgment from integration of Symptom and examination, medication information
Cortex atrophy on Head CT is important ,this is key,but maybe all case slight.If it is possible that comparison with before took drugs,it is easy.But there are no Head CT and Head MRI case ,use MRA and watch blood vessel and if they are beautiful and perfect cortex atrophy is high possibility suggest this disease ,if they are awkwardness cortex atrophy is strong possibility of naturally.And if on Head CT after 20 years from stopped drug suggest recovery point of cortex atrophy,high possibility of disease. And use normal EEG and 24h EEG.Notice the slow wave, reversed phase,and difference of consciousness level on EEG and patient sence.If though EEG is sleep condition, the patient said "I was awaked perfectly", strong possibility of this disease.And primary patient intellect level is high and dementia,high possibility of disease.On 24 h EEG pattern is important point.
<The Criterion >
*use as rough idea about patients can not diagnose by anyway.
Group A---Almost Certain, total over 15 points
Group B---High Possibility, total over 10 points
Group C---Low Possibility, total under 5 points
(1) Basic Diagnosis
Schizophrenia ---- -2
Atypical Psychosis or manic-depressive psychosis--- -1
Borderline Case or neurosis or personality disorder-- 0
Normal(misdiagnosis)-- 2
(2) medication quantity
standard administration(if Haloperidol, 3-6mg/day)--- 0
twice of standard--- 1
three times of standard--- 2
(3) medication term
one-three year--- 0
three-ten years-- 1
over ten years-- 2
(4) medication age
10-14 age-- 2
15-19 age-- 1
20-49 age-- 0
over 50 age-- 1
(5) Head CT,Head MRI MRA
Cortex atrophy-- 1
Cortex atrophy(appear after take drug)-- 2
recovered cortex atrophy
(cortex atrophy after stopped drug ,recovered after 20 years from stoped drug)--- 5
lateral ventricle expansion---- -2
normal--- 0
beautiful blood vessel(and cortex atrophy) --- 1
awkwardness blood vessel (and cortex atrophy)--- 0
(6) PET glucose dysbolism
abnormal-- 2
normal-- 0
(7) EEG
slow wave(awaking time)-- 1
reversed phase--- 1
difference of consciousness level on EEG and patient sense
(pat say high ,EEG show low)-- 1
spike(appear after take drug )-- 1
(8) 24h EEG
normal-- 0
abnormal pattern-- 1
<What pathology can be considered?>
There are the following views in dissection for example death by the malignant syndrome , or clinical extensive medication and animal experiment by present.
<Pathology>
Long term neuroleptica given laboratory animal and patient's brain many finding exist.These are only anatomy findings.The most important pathology is neroleptica influence to gene in neuron and abnormal protein accumulation,(e.g.haloperidol and c-fos9,but it is not enough to clear yet.
-laboratory animal-
(Cerebral Cortex,and include Hippocampus)-- Nissl degeneration,Vacuolar degeneration,shrinkage,dicreaseor increase nidus chrommatin,nuclear membrane unclear,nucleorrhexis,disarranged laminar construction of cortex with growth glia cell, telangiectasia,blood bessel degeneration like vitreum,groth glia cell,tunicia vavasculosa hypertrophy,brainstem hemorrhage,cork-screw,satellitosis,neuronophagia,hyperchomia,(brainstem) cell to pallor,(prukine cell) degeneration
-human brain take neuroleptica-
brain congestion,brain edema,petechiae,chromosomalbreakage,satellitosis,neuronophagia
-Dead by syndrome malin human brain-
brain edema, (Cerebral Cortex and thalamus,hypothalamus ,pallidum),--destroyed cell construction,atrophy and deciduation of neuron,(ceruleus nucleus nigra)--melanin decrease
**It is not specified part , pathology occurs.
---------------SUMMARY FROM JAPANESE PAPER-----------------------
Long term haloperidol given laboratory animal and patient's brain many finding exist.
I summarized and translated Japanese papers next .
*Arioka,I 1976 "Brain Disease by Tranquilizer"
(A). Give Chlorpromazie to 4 groups rabbit 6 monthes,peroral
Group 1=11.3mg,Group2=10mg,Group3=6.7 ,Group4=3.3mg/day
After 3 month stopped giving,
1.Cerebral Cortex-- Nissl degeneration,Vacuolar degeneration,shrinkage,dicreaseor increase nidus chrommatin,nuclear membrane unclear,nucleorrhexis,disarranged laminar construction of cortex with growth glia cell,
2.Hippocampus-- same
3.Cerebellar Cortex--same
(B) to guinea Chlorpromazie 10mg/day peroral 3 month
telangiectasia,blood vessel degeneration like vitreum,Vacuolar degeneration,groth glia cell,
(C)to guinea reserpine 0.05mg /day peroral 3 month
tunicia vavasculosa hypertrophy,brainstem hemorrhage,vacuolar degeneration,cork-screw,
(D)to rat Chlorpromazine 1.25mg/kg 5day in a week,8 month injection
Cerebral Cortex--satellitosis,neuronophagia,
1.brainstem-- cell to pallor,
2.prukine cell degeneration
(E)to rat CPZ 5mg/kg injection a day in two days 2month
25% of cerebral cortex to hyperchomia,shrinkage

*Tsuyoshi Ishii "Neuropathology"
-After long term major tranquilizer human brain-
brain congestion,brain edema,petechiae,chromosomal breakage,satellitosis,neuronophagia

*Tsuyosi Ishii "Chemical Poisoning"
-Dead by syndrome malin human brain-
brain edema,
Cerebral Cortex--destroyed cell construction,atrophy and deciduation of neuron,
1.thalamus,hypothalamuspallidum,--same
2.ceruleus nucleus nigra--melanin decrease

-------------------------
Dementia is the central symptom in several years from the beginning -- it is the lacunal dementia, brain is exhausted and of lethargy state by a little work as last condition.The pathology of other poisoning nerve diseases is simply written for comparison examination below.
*Korsakoff Syndrome---mamillary body atrophy, In mamillary body ,under third ventvicle, thalamus arround cerebral aqneduct, increase thickness and number of
blood capillary, hemorrhage, increase of glia cells.
*Minamata disease(Japanese original pollution,mercurial poisoning)---Wide degeneration and lost of neuron, specialty calcar avis.lost of neuron in cerebellum cortex. degeneration of peripheral part.
*Carbon monoxide poisoning---brain edema,congestion,petechial hemorrhage(specialy globus pallddus),necrocis and Malacia of globus palldus, degeneration and lost cerebral cortex neuron demyelinatiny of whita matter.
*SMON disease(Japanese original medical harm by quinoform ,Subacute Myelo-Opico-Neuropathy)---degereration of medulla spinalis and optic nerve. degeneration of radix posterior neuron. degeneration of pyramidal tract. medulla spinalis. peripheral part.

These illnesses are starting problems to paripheral part and the synapse of central nerve system, and being easily recognized by the nerve physician, and views which are easy to check.Contrastively Hayama's Disease do not appear numbe, paralysis and arctation of visual field.However, the example of serious case of this illness is equal level to such illness enough.In Hayama's Disease, consideration is recommended on the assumption that it is pathological change in neuron, Because in the first lacunal dementia,character change with extrapyramidal syndrome ,and on chronic term exhausted brain are the most important feature.Aggravation will continue several years after medication end.Although changed to recovering after that, it is grade of feel just recovering earnestly just for half a year.The above-mentioned dissection pathological change do not express critical condition of Hayama's Disease enough.If view of this level, it is below the degree of middle of Minamata disease.
It is not so light.The main part will become clear by neuron cultivation of the patient who contracted ill.
Compared disease based on ingestion of the so-called strong chemistry substance of nerve toxicity.This disease induced by antipsychotic.Becouse we can not understand antipsychotic how to treat schizophrenia,we can not understand pathology of Hayama's Disease.
It does not clarify why cell death happens.
*In normal dopamine brain HPD too decrease the input ,and happen cell death.
--->Though HPD occupy 75% of D2reseptor,but many receptor there are.
*HPD directly destroy neuron.
*HPD injure gene and gene produce abnormal protein.

*HPD (increase or decrease) receptor,or destroy receptor site.
--->after end of taken decreased receptor will recover
*HPD (increase or decrease)catecholamines production.
--->maybe decrease
*HPD destroy gene,DNA fragmentation."
--->DNA fragmentation was few but destroy gene and change expression

"Hyman,S.E and Nestler,E.J/The Molecular Foundations of Psychiatry '93"give some opinions.They say,
Major Tranquilizer ---------------------------------------------->cell death
*Major Tranquilizer make poison for example free radical.
*Major Tranquilizer have derepressed glutamic acid receptor's cell toxicity.
Important Tranquilizer effect
*activate signal transmit in cell and controlling of gene expression
------STUDYING THEME------
I have studied next theme.
1.How mechanism exist about haloperidol happen brain lesion?
　*In normal dopamin brain HPD too decrease the input ,and happen cell death.
*HPD directly destroy neuron.
*HPD injure gene and gene produce abnormal protein.
*HPD (increase or decrease) receptor,or destroy receptor site.
*HPD (increase or decrease)catecholamines production.
*HPD destroy gene,DNA fragmentation.
2.How lesion exist in haloperidol dementia patient brain?
*there are many paper that long time take HPD dissect brain tissue But it is not observe HPD moving in living brain .If we hope to observe HPD moving ,we think how experimentation method by mice.
3.How treatment method or medicine can think in possibility?
*I think very difficult.
4.Which SNP relate this drug problem?
*The relation of CYP2D6 was already known in case of HPD.
5.Which check up can find abnormal most exactly?
for example PET, which choose? 1 saccharometabolism 2 bloodstream 3 oxygen consumption(Vo2) 4 receptor
MRI 1 perfusion imaging 2diffusion imaging 3 MRS
6 Possibility destoryed gene by HPD happen another illness.
I hope to hear advice specially this point. In Japan nobody can think this problem.
For example ,HPD and c-fos ,cancer.
Hapoperidol induce c-Fos ,jun,zif268 Gene expression.
If continue expression of them after stop drug,after 20 years brain cancer will happen.
Effect to cerebrovascular
Neuron degeneration and destroyed gene 、DNA fragmentation make more serious sick,specialy cancer in brain, Alzheimer's disease ,Parkinson's disease ..Haropridol and c-fos gene relation is famous.If that possibility is high what can we do to stop it?.On the contrary by using brain hard,patients may induce brain disease.For example add to PET tracer another drug may induce problem..Haloperidol's expression c-fos,jun,zif268,etc have how mechanism ? It is continue after stopping taken or not?
--------
<possibility of tardive disorder>
Cell death may be starting by excitotoxicity.The biggest problem is the gene toxicity in neuron.
I thought that the chromosome was damaged and unusual protein is generated.
I examined the possibility of generating of tardive disorder.
1. neuro-degeneration disease
Alzheimar's disease
little possibility
Parkinson's disease
slight high risk more than others
2.Cerebrovascular accident
little possibility.no cerebrovascular difference exist.
schizophrenia brain and normal brain.
3.carcinogenesis(without brain tumor)
little or very slight high risk more than others
4.Brain Tumor
difference exist by patients group.
Halperidol stimulate c-fos ,jun.The reason expression of c-fos by HPD are stopping of receptor.
If receptor do not recover enough after stopping continue little by little gradually.If continue effect catecholamines or another secretion for example Melatonin decrease ,suppression effect of Melatonin to carcinogenesis decrease .If schizophrenia drug therapy are activating repressed genes and repressing activated gene,given to normal brain case easy to have possibility to happen genotoxic ,damaged gene.
group A schizophrenia or nearly illness patient and little side effect in taken days.
little risk
group B schizophrenia or nearly illness patient and big side effect in taken days or after.
very slight high risk
group C normal brain and little side effect in taken days.
slight high risk
group D normal brain and big side effect in taken days.
high risk
The brain tumor start from glia cells mostly, it was mainly considered from there being the same problem also in glia cells.There was an announcement about SMON in Japanese Society of Neurology congress last year, and complications were increasing with aging although there is already few research not much about SMON disease.
The SMON disease patient whom I know cancer increase ,although relation with SMON is not clear.
From neuroleptica gives damage to DNA of neuroglia, patients may become glioma as tardive disorder.
Although it is not in brain ,in other poisoning nerve diseases recently , the patient of SMON disease, there are much carcinogenesis. It may be having resulted from fragmentation of DNA in the cell by quinoform through long time. It may be that there is significant difference.By other pollution medicals harm over a long period of time, Though it investigates is difficult by there being few mother groups of the person who survived and being hard to take statistics, The medicine which the damage of DNA is made to recover needs to be developed.
Thus, the problem of brain disease with neuroleptica has the difficulty which psychopharmacologist cannot process as problem on learning.
<It is difficult to recognize and treat Hayama's disease.>
Next, describes what difficulty there is.In a word, it is the difficulty of taking evidence.I hoped to get reliable proof.But only by reasoning and hypotheses, every way is cut on the way.Therefore, it did not become learning only by gossiping.Probably, the symptom of Hayama's Disease appears also as mental symptom, distinction with aggravation of mental disease cannot diagnose easily.There are few patients more than the Schizophrenia person who insists, "My illness was made cerebral illness with medicine."There is risk of inducing medical malpractice trial.Although it is easy to discover this in the civic organization that the patient itself talks freely, on the everyday medical examination of clinical , it is hard to discover .The sick anyway has the conditions which are the premise for discovering.
1 illness is with objective symptom,or it can check by the certain inspection.
2. It has the feature distinguished from other sick.
3. doctor do not want to deny the sick existence.
Hayama's Disease is disqualification at all these three conditions. There are three kinds of situation of sick existence, they are complicated.
1 -- it exists with mental illness from the first
2 -- it is misdiagnosed, although illness from the first healed up and only Hayama's Disease still exists .
3 -- primarily, from the first, there was no mental illness and patients became Hayama's Disease with medicine.
In addition to it, affirmation of "brain disease by neuroleptica" is forbidden to psychopharmacology from the political military problem.
There may be developing country where medication to the political offender .There are many nations government of each country have explained to "the medicine which is harmless to the body and takes distortion of thought", and people regard such government into crime .Advanced nation are fighting with terrorism now.And the politician may think that it is good to catch while carrying out nothing, and to give such medicine to terrorist . There is problem which the past political crime etc has been medicated, if medical science recognize the symptoms of irreversible brain disease may be happen, it will be hard to do. It becomes impossible to use the strategy " caught and given neuroleptica before committing" as the future measure against terrorism.
Make it mix in water service in the war execution occupied territory, being able to take enemy people's resistance easily, such strategy will become difficult and each country have suspicion about the existence of such past use. If majority of Soviet Union age political offenders charged damage compensation, the base of the Russian Administration was shaken. The doctor who examined them in the U.S. -- cannot announce"from consideration of friendship" .-.Russia government hide information that they gave neuroleptica to political offender.
We can not know that where they live and how health condition ?Maybe,there are many "encepharopathy by neuloreptica"patients.And if the information give us realization ,we will notice our knowledge of neuroleptica side effect was limited to give schizophrenia patients case ,we knew only a part of side effect and we did not know sufficiently about neuroleptica with giant surprise. Though this is important information we can not get again for considering about brain disease by neuroleptica.Without this information ,there are no in the world given to normal brain case except single malpractice. But if we gather these information,1 method is that requiring directly to Russia government ,this method is very difficult,.2 method is search such patients from Russia in Germany and USA.They escaped to USA or Germany ,though the poor is still live in Russia.But this is difficult .I know that such age WPA criticize Russia by book "Psychiatry on Trial".
<How to save patients?>
Medical treatment is summarized and writes below.The stop of antipsychotic medication.
When the prodrome of malignant syndrome is appear, the cold method, dantrolene, etc.
---chronic term-.
Recover spontaneously from illness.Cerebral quiet and sufficient sleep.
<Treatment>
-Misdiagnosis case----
Impossible by today medical science. Only allopathy and wait to autotheraphy.Need enough explain about illness.order to patient don't use brain hard excessively.
Use minor tranquilizer before go to bed if patient have irregular circadian rhythm.
Need caution to get sick about Parkinson's Disease,Alzheimar's Disease ,Brain vascular disase,and brain tumor.Check Head MRI T1 T2 and MRA one time for 5 years.
-schizophrenia and another mental illness case----
somewhat less dose.It cannot do at present .
<the strategy on future research medical examination is described below.>
where field does this illness belong primarily first? Although psychophamacology pursuing the state of the medication which made side effects the minimum, it did not treat the fixed brain obstacle .We seek to help to clinical neurology ,but it is too unique when nerve physician treats as one of the poisoning nerve diseases.
Even if it medicates mice with antipsychotic, the brain of mice are too much crude and quantity tough for destroy we must prescribes too much, and cannot think that the pathology which broke forcibly was same with a man's pathology.The mice brain is strong about neuroleptica ,and no problem unless give large quantity.
About clinical EBM ,there are difficult problem ,schizophrenia patients brain can withstand neuroleptica,though normal men misdiagnosised case harmed soon.Anatomy of NMS patients brain contain mixed pathology by neuloreptica and schizophrenia.But I think observation of gene and protein synthesis in neuron given neuroleptica will give many information and read such some papers .In many paper view according to the brain of the man who took medicine for a long period of time, and dead by the malignant syndrome .In such case the view with schizophrenia, and view with medicine may be intermingled.Moreover, the medicine continues taking which such toxicity is clear, and patient are a lot, such medicine was not exist, I researched of electromagnetic wave,and the food of radioactive contamination after nuclear power plant accident, continues being eaten in low dose contamination of the radiation which has gene toxicity by weak toxicity .But it will not progress in the stage which transposes this problem to medicine.I can not know how to replaces.If it is high level radiation, tumor is result in from fragmentation of DNA.In the case of electromagnetic wave, calcium ion leak.

< the way of research -- for example>

1 In the case cerebrovascular accident,schizophirenia patients need ope,get the neurons from each important parts and culture.
2 Gene analysis and compare it normal brain's .and find difference.
3Add Haloperidol both and observe about normalized gene in schizophrenia and destroyed gene in normal brain.
4 Analysis found gene's function.About normalized gene in schizophirenia .Research the relation them and controlling system about thinking and affection.About destroyed normal brain's gene,research chemical substance that can normalize them for treatment medicine studying.
　
It is useful to prevention that we know the patients whom the concentration in blood increase unusually from difference of medicine metabolism by SNPs.
　Although there is CYP2D6 suspected in the case of antipsychotic first , the announcement of the research which denies relevance is also seen ,too.
---------Molecular Biology of the Drug-Induced Disease--------------------
The understanding drug induced disease is difficult.Becouse many patients no problem,a few patients happen problem.For example Penicillin shock case is enough to understand his IgE.But happening from long term took irreversible disease case,the studying point is his genetic analisys.Use the result of human genome project.Only special man happen problem,genetic problem exist. I project a experimentation .I choice haloperidol .Because this drug is sometimes happen problem,very popular,useable to understand brain and mental illness.
First Step-finding problem gene-
1.Beforehand one hundred lineage mice genetic analysis need.
2.For half a year,give haloperidol
3.Make taxon
a.subclinical
b.parkinsonism at that time,but after stop HPD recover.
c. epilepsy mouse
d. like parkinson's disease mouse
e. syndrome malin mouse
f. circadian rhythm disorder mouse
g. tardive dyskinesia mouse
4 term stop to haloperidol ,and choice mice
5 genetic analysis and researching change point
6 assay catecholamines
7 count receptor,measure second messenger,G-protein
8.Analysis human genome though much given no problem man and happen problem man like such mice.
9. Analysis that man's parents .The happen problem man's genome before injured are same about
their parents.
10.Where does change exist? Find genomic locus, compare man's gene with same syndrome mice's gene.
11. After it confirm result by knockout mice and transgenic mice.
If we cann't get reasult,use Japanese monkey.By that method we can find so to speack,drug-induced disease gene and decide genomic transversion.
Second Step-making pathology-.
1.After that what does problem gene give effect to brain function ?
research this problem on molecular level.
2.Theoretical think inclusive pathology drug -induced brain disease.
3Confirm it by mice again.
Third Step-making therapeutic drug.
1.If it is need ,think about gene therapy.
(but maybe it is meaningless)
2.Think how to remove continuing accumulated protein that is cause of neuron death and degeneration one after another in neuron
3. Give mice possible chemical substances and research possibility as true therapeutic drug.
I think drug-induced disease disorder is special constitution who has some SNPs.In the case of some singular combination SNPs make abnormal reaction with a specific chemical substances in drug metabolite of the specific drug. This is "genetic drug-induced disease doctrine" that I insist in Kyoto Univ since1999.　The problem is Mice brain are strong and short life.Many of studying of haloperidol side effect use mice ,but it is different from long term taken patients.Specially after 20 years carcinogenicity from stop drug . Long life more higher animal are better.Monkey is the best. Now drug side effect research are only statistical enumeration from clinical announcement and tissue specimen by microscope. These studying is useful producing more few side effect drug ,medication fitted own constitution.And at last mankind can conquer drug-induced disease from both prophylaxis and therapy.
[2 ]Malpractice
moves to the 2nd theme medical malpractice.Next, was some medical malpractice incident　that brung to court in Japan recently,Case listing. there is the following the case of medicinal side effects.
(1)A 27-year-old male
hospitalized October 1, 1988
diagnosis schizophrenia .
Taking orally .. haloperidol 9mg chlorpromazine75mg
Oct 2 injection haloperidol 20mg 30mg 30mg
Oct 3 haroperidol 30mg 30mg 30mg
Oct 4 ,large quantity of sweatig,The feeling of exhaustion and fever,
Oct 5 rigidity of whole body, tremor
Oct 6 temperature 41, "malignant syndrome" muscle rigidity,transfusion, dantrolene
Oct 8 death
(2)26 years-old woman
November 15, 1983
schizophrenia
haloperidol 18mg trihexyphenidyl 6mg
taken 3 times a day
before sleeping vegetamin A(chlorpromazine,etc)
Dec 1 , zotepire300mg haloperidol18mg trihexyphenidyl 6mg alosen0.45g
before sleeping levomepromazine100mg prometazine25mg
Dec 3 found dead in bathing.
(3)14 years-old female refusal to attend school .
entered to hosp.
Apr 27 haloperidol -- 0.5%1ml ×2
4.28 -- haloperidol -- 0.5%1ml ×1
4.30 paroxysmal tachycardia
5.1 -- haloperidol -- 0.5%1ml --× 3
5.2 -- haloperidol -- 0.5%1ml -- ×4
5.8 liver-function abnormal
5.17MRSA
5.26 septicemia
5.27 high fever
5.29 malignant syndrome diagnosis
5.30 death
(4)September 18,1997
　at the time of the first medical examination (8 years old)Epilepsy, misdiagnosis, and antiepileptic medicine long-term medication(to 17 years old) and dead by leukemia .　In judgment, the causal relationship of the antiepileptic medicine and leukemia is denied.but reparations were ordered by negligence of misdiagnosis and have continued prescribing antiepileptic medicine to the patient 　The above is case of Japan.
<To others>
　the encephalopaty case which caused by medication ( a lot of unsuitable antipsychotic), the medical-harm type for example malignant syndrome , and the case that normalcy is misdiagnosed as the mental disease.　The reverse case exists,too.　And the case that patient is dead in traffic accident near the hospital by nurse carelessness.　
<IMPOTANT PATTERN>It is the case which we should think as most important is misdiagnosis of uncommon personality as psychoses,and misinterpretation of paradox reaction due to antipsychotics as psychotic symptoms, leading to onset of encephalopathy. This most important and typical medical malpractice of psychiatry not being judged, and not recognizing the existence by socially. In such case, though patient notices problem having happened to his own body and begins to say others, it is not trusted by anyone. And such cases die in mental hospital here and there with misdiagnosis.
Then, how can such misdiagnosis be prevented, about diagnosis of Schizophrenia?
How to relieve patients who were misdiagnosed as the Schizophrenia ?
<Definition>
Psychotic Diagnosed Wrongly (abbreviation PDW, a tentative name, by Hayama) --- it is the case in which it was misdiagnosed healthy person as Schizophrenia or its relative disease, received long-term antipsychotic medication, and became the irreversible illness of the brain. It is better for there are a name unified by something as an independent group of such case, because it is one condition of relief that we spread recognition that there is such cases.
<the cause and the background>
- It is the case of national crime like the Soviet Union.
- In the case of huge individuality people , unique child, and deterioration people, and truant child in super controlled society like Japan.
- In the case of bad mental hospital
- When based on the shortage of capability of the doctor
<. Problem>
Society does not know that there are such patients.It does not accept.Society gives the cause by discrimination trust throughout life, and hospital continues maintaining form.If the person set to PDW, even if they bear medicine and survives, life capability was lost, and they have high possibilities of death by continuation strain-related with society and discrimination.The most important thing is that society does not trust them.
In addition, psychiatry has another unsolvable medical malpractice, i.e., "and cannot cancel diagnosis and had been misdiagnosed as the mental disease, cannot return to work.". Can't make the system which can solve such things ?
.< Medical Relief>
Creation of the standard criterion of diagnostic release in the case that patients asserts misdiagnosis.Establishment of methodology.The unified form of the diagnostic release document .
. <Epidemiology>
It is about 0.01% of the whole as schizophrenia diagnostic person of all earth scales.
Although all medicals harm are saved, this victim are not ,and continue to produce without solving eternally.
---<If we misdiagnose normal person as psychosis, what is problem?>
Are there problems on the main part of the psychiatry itself or application of psychiatry diagnostic study?
It must be checked first that diagnosis of schizophrenia should not be aimlessly attached to accumulation of condition, and should be attached so much to the power of making a sick person changing to the last.It is the diagnosis name which should be given not to present but to the future. The problem is motion, is change and is whether to be able to say certainly that character is going to collapse. the power of collapsing character is in the inside of patient, and cannot explain it by the cerebral pathological change by analysis of human relations with his psychological, either. It should be attached to the inside of patient when it can be considered that exceeds the imaginative power of men and it is not generated also from society also from the mind such feature is fulfilled surely. Patients must be observed not in stationariness but in motion. Diagnostic standard should be devised to the each individual .The psychiatry got diagnostics with great difficulty, but psychiatry is still insufficient learning, and doesn't know the methodology which discovers many premises when we apply to patients?It is pathography that suggest clearly about problem on psychiatry contribution. There is problem in pathography which progressed with development of psychiatry.Although much genius are connected to mental disease and discussed, there cannot be no such thing.The weak point of psychiatry that it cannot respond to the diversity of individual characteristic is rather expressed.For example, it is better to think that there are many cracks in big-scale soul.
Person do various experiences which are not recorded by anyone, when living with the extraordinary soul.
There is bigger problem of psychiatry connecting genius to Schizophrenia. Two ends, the minimum, and the maximum of a number straight line of human group are tied up, and encircled.And the world image is shown closed itself style. People's imaginative power were prevented of its leaking out from dwarfish academic field of view simultaneously. It is the academic position which is going to build understanding of human soul on the assumption that negative of the existence of God .
------------------------SAVING MALPRACTICE -------------------
Japanese lawyers and many malpractice sufferers are too unripe to understand importance of thinking how to treat original pathology by medicine.I have been criticizing them saving sufferer is not trial but studying treatment method such difficult patient.The man rarely become the strange disease that nobody studying by medicine . In brain case we can understand only half of lesion by drug.Specialy the case of only brain functional disorder.I hope to establish researching such illness field as new field for example "pharmaco-induced-pathology" for more understanding drug induced brain patients systematically comprehensively and for making that patient treatment possible.Specialy major tranquilizer induced neuron illness.For clinical doctor standerd textbook need for example titled"The Practice of Drug-induced Inveterate Disease." In Japan I am lonely no cooperation. I request researching to Kyoto Univ some Prof.dept.of Pharmacology,dept of Medical Science.But it was difficult.They say we have no money.In Japan,pharmaceutical company's support need.If such knowledge popularize,company may decrease profit.I asked to the public researching institute got much money from Ministry of Education Japan.But they could not understand importance of problem.When his canvassing I talked with the Prime Minister,but he could not understand .Both hospital side lawyer and sufferer side lawyer do not help .Sufferer side lawyer fear "if many malpractice sufferer will possible to treat ,We may return money to hospital".Sufferer and their family do not help . I am the member of "The Medical Malpractice Information Center"(Headquarters office in Nagoya Japan,lawyer's group) and "The Citizen's Group to Establish The Law of Patient' Right in Japan"(headquarters office in Fukuoka Japan ,lawyer's group). I have sent letter to International Red Cross,WHO,and United Nations as only individual. I hope that studying for drug-induced brain disease become active.For example "Foundation of Drug-Induced Disease Research" ,international congress ,Journal"Drug-Indeced Disease" like Nature, I dream.I do not know such studying group.If man do not start now,even if the age Alzheimer's can treat come,only such disease can not treat.There is no method ,if I hope to create such studying group.In Neurology field doctor can diagnose only a half of patients.Another patients illness are unknown.I think this is the most important neurology's theme. World needs rare neurology sickes studying institute. It is difficult.Becouse if the doctor make rare illness treatment possible it is not big achievement in this world.If found treatment drug,company will be obliged to product it responsibility for a few patients. I feel importance of dialogue with company.
[3].View of Schizophrenia
the third theme.I arranged the Schizophrenia view until today.
130-200Galen.C
1896 Kraepelin,E "dementia praecox"
1896Freud.S"psychoanalyse"
1911 Bleuler,E "the group of schizophrenias"
1952 chlorpromazine
1960Laing.R"dividedself"anti-psychiatry 1963Carlsson&Lindqvist"dopamine hypothesis of schizophrenia"

I want to point out Schizophrenia view before modern was omitted with establish formation of modern psychiatry . The definition according to development of the antipsychotic which mainstream of Schizophrenia medical treatment is re-defining the Schizophrenia by the dopamine theory which is completely different from German psychopathology group's Schizophrenia definition. Thus, original pathology cannot hold connection to pharmacology, there is no other field in which the learning itself loses the integration and it is divided further.
for example, there are not anti- physical science , although the school which should use expression such name cannot be generated in the other learning field-- only in psychiatry -- having generated . Although it is this sick basis that character loses the integration and dissolves to the last, what pathology exist biologically?
<As hypothesis>
HYPOTHESIS-biological pathology of schizophrenia.(a) .excessive dopamine secretion. (b).gene and cells (e.g.abnormal gene expression). (c). synapses, NORMAL-Keep inevitability all neuron selecting particular neuron on extension of neurites and brain controlling all combinations of synaptic transmission.SCHIZOPHRENIA-Extension of neurites that have lose their targets,selection of wrong synapses for signal transmission,abnormal combination of synaptic transmission.
<Dopamine>
dopamine hypothesis of schizophrenia is proved, so that itself does not need to doubt. It does not simply clarify whether they are excessive dopamine secretion, or hypersensitivity, whether or up- regulation of receptor , or its the composite.It is problem. What importance does this have in the whole pathology of Schizophrenia?
We cannot understand whether it is in the cause of Schizophrenia or a result of Schizophrenia .
gene and cell
<gene >
The linkage analysis by the DNA marker
(announcement) (negation)
Xq26-27 Sherrington1988 Kennedy1988
6p24-22 Antonarakis.Straub -- 1995 multi-institution joint research 1997
22q12-11 Coon1994 Puluer1994
<cell>
Recently, there are researching which observed cell arrangement and stratified structure of schizophrenia patient brain like intercellular junction hypothesis.
<Synapse>
The hypothesis which explains Schizophrenia by the abnormalities of wiring of neuronetwork is proposed from before .
The problem is how to position and unify in the Schizophrenia research from such degree of multiple.
although it is each element which forms the Schizophrenia surely, we can not understand where we must place like the piece of jigsaw puzzle anywhere, and constituted whole .It is most important point to consider.
About the Schizophrenia view of Bible,
the Bible has connected the evil spirit with to the Schizophrenia clearly in the next part.Luke Gospels Chapter 8 [ Section 27- ]---A s Jesus stepped ashore, he was met by a man from the town who had demons in him. He had gone for a long time without clothes, and would not stay at home,but spent his time in the burial caves. W hen he saw Jesus he gave a loud cry, fell down before him , and said in a loud voice, "Jesus, Son of the Most High God! What do you want with me? I beg you , do not punish me!"He said this because Jesus had ordered the evil spirit to go out of him. Many times it had seized him, and even though he was kept a prisoner, his hands and feet tied with chains, he would break the chains and be driven by the demon out into the desert.---
I did not think that the Bible never connect all illnesses to evil spirit.Moreover, there is also no part which encouraged discriminating against mentally handicapped person. The Bible itself is the existence which became independent in the ancients' sick evil spirit theory and hunting subsequent Christianity society. Were the ancients people foolish, and did they exist in order to prepare our prosperity? Did the Bible tell what about schizophrenia? About healthy person, a brain and a soul correspond by 1 to 1. The Schizophrenia person corresponds by 1 to 2 , the man's soul and evil spirit are governing one brain. And it is the Schizophrenia view corresponded with the fundamental pathology of the Schizophrenia that character loses the integration nature .
The reality in which there are many people who do bad and few who do better after became schizophrenia,
　We felt the impression held intuitively " root is deep rather than they say that it is sick", and a certain moment, and "thirst for blood" which does not have the power in the patient himself holds it, and comes from that peculiar deep place.We can sympathy with schizophrenia view of Bible.There is no security that both God and the soul do not exists. We already get neuro-transmitter, gene expression, and synapse as biological view, and are also performing psychoanalysis and sociological consideration. Recently, imaging by the positron is intermediary .
We got all the methodology with imperfection that already once wanted . It already all the kind .The piece does not increase.However, our culture still cannot understand main part of schizophrenia,only by circling in the circumference of Schizophrenia. The works were much and already done to the end of efforts .But we feel circling focusing on it rather than we found out the way of understanding Schizophrenia. Isn't that because our culture and the view of the world itself turn behind Schizophrenia after modernization? A conclusion does not appear in such question. Although Schizophrenia can never be dispelled with man's wisdom, whatever the main part of Schizophrenia, we think that we fulfill the responsibility as a man by continuing efforts for symbiosis in the future.
CONGRESS(I learned this too original theme by the way of discussion on congress)
*5th international congress on progress in Alzheimer's and Parkinson's disease Mar31-Apr5 '01 Kyoto
*Societas Neurologica Japonica congress May11-13 Tokyo
*International Symposium on Radiation and Homeostasis Jul13-16 Kyoto
*4th International conference on Biological Physics Jul30-Aug3 '01 Kyoto
*Neuro2001 Sep26-28 Kyoto
*CINP regional meeting Oct2-5 2001 Hiroshima
*4th International Workshop on Advanced Genomics Nov13-14 '01 Kyoto
*3th World congress vascular factors in Alzheimer's disease Apr7-10 '02Kyoto
*26th International congress of internal medicine May26-30 '02Kyoto
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*Hyman SE,Nestler EJ(1993):The Molecular Foundations of Psychiatry:American Psychiatric Press
*Lader MH(1977):Psychiatry on Trial :Penguin Books
*Stephen M(1996):Essential Psychophamacology:Neuroscientific Basis and Practical Applications:Cambridge
*FAR ERSATTNING FOR SKADAR AV PSYKOFARMAKA　　LAKARTIDNINGEN
　Volum93,NR22,1996
*Levinson AJ:Haloperidol induces persistent down-regulation of tyrsine hydroxylase
immunoreactivity in substantia nigra but not ventral tegmental area in the rat.　　　　Neuroscience May'98
*Sagara Y:Induction of reactive oxygen species in neurons by haloperidol　 J Neurochem Sep '98
*Behl C:Haloperidol-induced cell death -mechanism and protection with vitamin E in vitro
Neuroreport Dec'95
*Post A:Induction of NF-kappaB activity during haloperidol-induced oxidative toxicity in
clonal hippocampal cells:suppression of NF-kappaB and neuroprotection by antioxidants.
J Neurosci Oct'98
*Mihara K:Effect of a genetic polymorphism of CYP1A2 inducibility on the steady state
plasma concentration of haloperidol and reduced haloperidol in Japanese patients
with schizophrenia. Ther Drug Monit Jun '00
*Andreassen OA:Oral dyskinesias and striatal lesions inrat after long-termco-treatment with
haloperidol and 3-nitropropionic acid. Neuroscience Dec'98