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<head><title>Thyroid, insomnia, and the insanities: Commonalities in disease</title></head>
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<h1>
Thyroid, insomnia, and the insanities: Commonalities in disease
</h1>
<p></p>
<p><strong>SOME FACTORS IN STRESS, INSOMNIA AND THE BRAIN SYNDROMES:</strong></p>
<p>
Serotonin, an important mediator of stress, shock, and inflammation, is a vasoconstrictor that impairs
circulation in a great variety of circumstances.
</p>
<p>
Stress impairs metabolism, and serotonin suppresses mitochondrial energy production.
</p>
<p>
Stress and shock tend to increase our absorption of bacterial endotoxin from the intestine, and endotoxin
causes the release of serotonin from platelets in the blood.
</p>
<p>
Schizophrenia is one outcome of stress, both cumulative and acute. Prenatal stress commonly predisposes a
person to develop schizophrenia at a later age.
</p>
<p>
Serotonin"s restriction of circulation to the uterus is a major factor in toxemia of pregnancy and related
complications of pregnancy.
</p>
<p>
Hypothyroidism increases serotonin activity in the body, as it increases estrogen dominance.
</p>
<p>
Estrogen inhibits the enzyme monoamino oxidase (MAO), and is highly associated with increased serotonin
activity. Progesterone has the opposite effect on MAO.
</p>
<p>
The frontal lobes of the brain are hypometabolic in schizophrenia. Serotonin can cause vasoconstriction in
the brain.
</p>
<p>Serotonin release causes lipid peroxidation.</p>
<p>Schizophrenics have high levels of lipid peroxidation.</p>
<p>
Antioxidants, including uric acid, are deficient in schizophrenics.
</p>
<p>
Therapies which improve mitochondrial respiration alleviate the symptoms of schizophrenia.
</p>
<p>
Energy depletion leads to brain atrophy, but with normal stimulation and nutrition even adult brains can
grow.
</p>
<p>
Schizophrenics and depressed people have defective sleep.
</p>
<p>
Increasing the body"s energy level and temperature improves the quality of sleep.
</p>
<p><span style="font-size: 14pt; font-weight: normal"><hr /></span></p>
<p>
Everyone is familiar with the problem of defining insanity, in the case of people who plead innocent by
reason of insanity. The official definition of insanity in criminal law is "the inability to tell right from
wrong." Obviously, that can"t be generalized to everyday life, because any sane person realizes that
certainty is impossible, and that most situations, including elections, offer you at best the choice of "the
lesser of two evils," or the opportunity to "do the right thing," and to "throw your vote away." People who
persist in doing what they know is really right are "eccentric," in the sense that they don"t adapt to
society"s norms. In a society that chooses to destroy ecosystems, rather than adapting to them, the question
of sanity should be an everyday political issue.
</p>
<p>
The use of medical terms tends to give authority to the people who are in charge of defining the terms, and
it can give the impression of objectivity when there really isn"t any scientific validity behind the terms.
In their historical senses, "crazy" (flawed) and "insane" (unsound) are probably more objective terms than
the medically-invented terms, dementia praecox (premature idiocy) or schizophrenia (divided mind).
</p>
<p>
"Odd Speech" is one of the dimensions used in the diagnosis of insanity. I am reminded of William
Wordsworth"s dismissal of William Blake as insane after failing to understand some of Blake"s
poems--Wordsworth was conventional enough to become England"s Poet Laureate, and to his limited perspective,
Blake"s clear verses were incomprehensibly odd.
</p>
<p>
Whenever a trusted government employee decides to blow the whistle on criminal activities, his agency
invariably puts out the information that this now discharged employee is psychologically unbalanced.
Dissent, in other words, is easy to dispose of by psychiatric tainting.
</p>
<p>
If we are going to speak of mental impairment, then we should have objective measures of what we are talking
about. Blake unquestionably could do anything better than Wordsworth, because he was neither stupid nor
dishonest, and it"s almost a rule that ordinary employees are more competent than the administrators who
evaluate their work. Objective standards of mental impairment would be more popular among patients than
among diagnosticians, judges, and lawmakers.
</p>
<p>
In a famous test of the objectivity of diagnosis, a filmed interview with a patient was shown to British and
U.S. psychiatrists. 69% of the Americans diagnosed the patient as schizophrenic, but only 2% of the British
psychiatrists did.
</p>
<p>
The strictly medical/psychological definition of insanity is still, despite the existence of the
International Classification of Diseases, and in the U.S. the Diagnostic and Statistical Manual, which
enumerate a large number of "mental disorders," a crazily indefinite grouping of symptoms, and hasn"t made
diagnosis more objective.. For example, in the last 30 years autism has been separated from childhood
schizophrenia, but now the tendency is for both of them to be called developmental brain disorders. Both
schizophrenia and autism are now often described in terms of a "spectrum of conditions," which hardly
matters, since they are not understood in terms of cause, prevention, or cure.
</p>
<p>
The problem is in the history of psychosis as a medical idea. About 100 years ago, attempts were made to
classify psychoses by their symptoms, unifying a great variety of old diagnostic categories into two groups,
manic-depressive mood disorders, and "dementia praecox," or schizophrenia, which (as indicated by its name,
premature dementia) was considered to be progressive and incurable. Several kinds of mental disorder were
found to have clear causes, including vitamin deficiencies and various poisons and infections, but the idea
of a certain thing called schizophrenia still persists.
</p>
<p>
The unitary concept of psychosis grew up in a culture in which "endogenous insanity" was a "hereditary
taint," that for a time was "treated" by imprisonment, and that more recently has been treated with
sterilization or euthanasia to eliminate the "insanity genes."
</p>
<p>
The idea that the disease is "in the genes" now serves the drug industry well, since they offer chemicals
that will correct the specific "chemical error."
</p>
<p>
Not all psychiatrists and psychologists subscribed to the idea of a unitary psychosis, defined by a variety
of symptoms. A positive contribution of Freudian psychoanalysis (and its congeners and competitors) was that
it made people think in terms of causes and the possibility of cures, instead of hopelessness,
stigmatization, isolation and eradication. Although Freud expressed the thought that biological causes and
cures would eventually be found, the profession he founded was not sympathetic to the idea of physiological
therapies.
</p>
<p>
Looking for general physiological problems behind the various symptoms is very different from the practice
of classifying the insanities according to their symptoms and the hypothetical "brain chemicals" that are
believed to "cause the symptoms." The fact that some patients hallucinate caused many psychiatrists to
believe that hallucinogenic chemicals, interfering with nerve transmitter substances such as dopamine or
serotonin, were going to provide insight into psychotic states. The dopamine excess (or serotonin
deficiency) theories developed at a time when only a few "transmitter substances" were known, and when they
were thought to act as very specific on/off nerve switches, rather than as links in metabolic networks. The
drug industry helps to keep those ideas alive.
</p>
<p>
The idea that the brain is like a computer, and that the nerves are like wires and switches, is behind all
of the theories about transmitter substances and synapses. If this metaphor about the nature of the brain
and the organism is fundamentally wrong, then the theories of schizophrenia based on nerve transmitter
substances can hardly be right. Another theory of schizophrenia based on the computer metaphor has to do
with the idea that nerve cells" wire-like and switch-like functions depend on their membranes, and, in the
most popular version, that these all-important membranes are made of fish oil. The supporting evidence is
supposed to be that the fish-oil-like fatty acids are depleted from the tissues of schizophrenics. Just
looking at that point, the "evidence" is more likely to be the result of stress, which depletes unsaturated
fatty acids, especially of the specified type, in producing lipid peroxides and other toxic molecules.
</p>
<p>
In one of its variations, the "essential fatty acid deficiency" doctrine suggests that a certain
prostaglandin deficiency is the cause of schizophrenia, but experiments have shown that an <span
style="font-style: italic"
>excess</span>
<span style="font-style: normal"> of that prostaglandin mimics the symptoms of psychosis.</span>
</p>
<p>
<span style="font-style: normal">The drug industry"s effect on the way the organism is commonly understood
has been pervasively pathological. For example, the dogma about "cell surface receptors" has sometimes
explicitly led people to say that the "brain chemicals" are active
</span>
<span style="font-style: italic">only</span>
<span style="font-style: normal"> at the surface of cells, and not inside the cells. </span>
</p>
<p>
<span style="font-style: normal">The consequences of this mistake have been catastrophic. For example,
serotonin"s precursor, tryptophan, and the drugs called "serotonin reuptake inhibitors," and other
serotonergic drugs, and serotonin itself, are carcinogenic and/or tumor promoters. Excessive serotonin
is a major factor in kidney and heart failure, liver and lung disease, stroke, pituitary abnormalities,
inflammatory diseases, practically every kind of sickness, at the beginning, middle, and end of life. In
the brain, serotonin regulates circulation and mitochondrial function, temperature, respiration and
appetite, alertness and learning, secretion of prolactin, growth hormones and stress hormones, and
participates in the most complex biochemical webs. But the pharmaceutical industry"s myth has led people
to believe that serotonin is the chemical of happiness, and that tryptophan is its benign nutritional
precursor, and that they are going to harmlessly influence the "receptors on nerve membranes."
</span>
</p>
<p>
<span style="font-style: normal"
>A particular drug has many effects other than those that are commonly recognized as its "mechanism of
action," but when an "antidepressant" or a "tranquilizer" or a "serotonin reuptake inhibitor" alleviates
a particular condition, some people argue that the condition must have been caused by the "specific
chemistry" that the drug is thought to affect. Because of the computer metaphor for the brain, these
effects are commonly thought to be primarily in the synapses, the membranes, and the transmitter
chemicals.</span>
</p>
<p>
<span style="font-style: normal"
>The argument for a "genetic" cause of schizophrenia relies heavily on twin studies in which the frequency
of both twins being schizophrenic is contrasted to the normal incidence of schizophrenia in the
population, which is usually about 1%. There is a concordance of 30% to 40% between monozygotic
(identical) twins, and a 5% to 10% concordance between fraternal twins, and both of these rates are
higher than that of other siblings in the same family. That argument neglects the closer similarity of
the intrauterine conditions experienced by twins, for example the sharing of the same placenta, and
experiencing more concordant biochemical interactions between fetus and mother.</span>
</p>
<p>
<span style="font-style: normal"
>Defects of the brain, head, face, and even hands and fingerprints are seen more frequently in the
genetically identical twin who later develops schizophrenia than the twin who doesn"t develop
schizophrenia. Of the twins, it is the baby with the lower birth weight and head size that is at a
greater risk of developing schizophrenia.</span>
</p>
<p>
<span style="font-style: normal">Oliver Gillie (in his book, </span>
<span style="font-style: italic">Who Do You Think You Are?)</span>
<span style="font-style: normal">
discussed some of the fraud that has occurred in twin studies, but no additional fraud is needed when
the non-genetic explanation is simply ignored and excluded from discussion. The editors of most medical
and scientific journals are so convinced of the reality of genetic determination that they won"t allow
their readers to see criticisms of it.</span>
</p>
<p>
<span style="font-style: normal"
>Prenatal malnutriton or hormonal stress or other stresses are known to damage the brain, and especially its
most highly evolved and metabolically active frontal lobes, and to reduce its growth, relative to the
rest of the body.</span>
</p>
<p>
<span style="font-style: normal">The standard medical explanation for the association of pregnancy toxemia
and eclampsia with birth defects has been, until recently, that both mother and child were genetically
inferior, and that the defective child created the pregnancy sickness. The same "reasoning" has been
invoked to explain the association of birth complications with later disease<span
style="font-weight: bold"
>:</span><span style="font-weight: normal">
The defective baby was the
</span></span>
<span style="font-weight: normal; font-style: italic">cause</span>
<span style="font-weight: normal; font-style: normal">
of a difficult birth. That argument has recently been discredited (McNeil and Cantor-Graae, 1999).</span
>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>Schizophrenics are known to have had a higher rate of obstetrical complications, including oxygen
deprivation and Cesarian deliveries, than normal people. Like people with Alzheimer"s disease, the
circumference of their heads at birth was small, in proportion to their body weight and gestational
age.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>Animal studies show that perinatal brain problems tend to persist, influencing the brain"s metabolism and
function in adulthood.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>Like the other major brain diseases, shizophrenia involves a low metabolic rate in crucial parts of the
brain. In schizophrenics, "hypofrontality," low metabolism of the frontal lobes, is characteristic,
along with abnormal balance between the hemispheres, and other regional imbalances.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>A very important form of prenatal stress occurs in toxemia and preeclampsia, in which estrogen is dominant,
and endotoxin and serotonin create a stress reaction with hypertension and impaired blood circulation to
the uterus and placenta.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>The brain, just like any organ or tissue, is an energy-producing metabolic system, and its oxidative
metabolism is extremely intense, and it is more dependent on oxygen for continuous normal functioning
than any other organ. Without oxygen, its characteristic functioning (consciousness) stops instantly
(when blood flow stops, blindness begins in about three seconds, and other responses stop after a few
more seconds). The concentration of ATP, which is called the cellular energy molecule, doesn"t decrease
immediately. Nothing detectable happens to the "neurotransmitters, synapses, or membrane structures" in
this short period</span>
<span style="font-weight: bold; font-style: normal">;</span>
<span style="font-weight: normal; font-style: normal">
consciousness is a metabolic process that, in the computer metaphor, would be the flow of electrons
itself, under the influence of an electromotive force, a complex but continuous sort of electromagnetic
field. The computer metaphor would seem to have little to offer for understanding the brain.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal">In this context, I think it"s necessary, for the
present, to ignore the diagnostic details, the endless variety of qualifications of the idea of
"schizophrenia," that fill the literature. Those diagnostic concepts seem to tempt people to look for
"the precise cause of this particular subcategory" of schizophrenia, and to believe that a specific drug
or combination of drugs will be found to treat it, while encouraging them to ignore the patient"s
physiology and history.
</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>If we use the standard medical terms at all, it should be with the recognition that they are, in their
present and historical form, not scientifically meaningful.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>The idea that schizophrenia is a disease in itself tends to distract attention from the things it has in
common with Alzheimer"s disease, autism, depression, mania, the manic-depressive syndrome, the
hyperactivity-attention deficit syndrome, and many other physical and mental problems. When brain
abnormalities are found in "schizophrenics" but not in their normal siblings, it could be tempting to
see the abnormalities as the "cause of schizophrenia," unless we see similar abnormalities in a variety
of sicknesses.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>For the present, it"s best to think first in the most general terms possible, such as a "brain stress
syndrome," which will include brain aging, stroke, altitude sickness, seizures, malnutrition, poisoning,
the despair brought on by inescapable stress, and insomnia, which are relatively free of culturally
arbitrary definitions. Difficulty in learning, remembering, and analyzing are objective enough that it
could be useful to see what they have to do with a "brain stress syndrome."</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>Stress damages the energy producing systems of cells, especially the aerobic mitochondria, in many ways,
and this damage can often be repaired. The insanities that are most often called schizophrenia tend to
occur in late adolescence, or around menopause, or in old age, which are times of stress, especially
hormonal stress. Post-partum psychosis often has features that resemble schizophrenia.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>Although the prenatal factors that predispose a person toward the brain stress syndrome, and those that
trigger specific symptoms later in life, might seem to be utterly different, the hormonal and
biochemical reactions are probably closely related, involving the adaptive responses of various
functional systems to the problem of insufficient adaptive ability and inadequate energy.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>By considering cellular energy production, local blood flow, and the systemic support system, we can get
insight into some of the biochemical events that are involved in therapies that are sometimes
successful. A unified concept of health and disease will help to understand both the origins and the
appropriate treatments for a great variety of brain stress syndromes.</span>
</p>
<p></p>
<p>
<span style="font-weight: normal; font-style: normal"
>The simple availability of oxygen, and the ability to use it, are regulated by carbon dioxide and
serotonin, which act in opposite directions. Carbon dioxide inhibits the release of serotonin. Carbon
dioxide and serotonin are regulated most importantly by thyroid function. Hypothyroidism is
characterized by increased levels of both noradrenalin and serotonin, and of other stress-related
hormones, including cortisol and estrogen. Estrogen shifts the balance of the "neurotransmitters" in the
same direction, toward increased serotonin and adrenalin, for example by inhibiting enzymes that degrade
the monoamine "neurotransmitters."</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal">When an animal such as a squirrel approaches
hibernation and is producing less carbon dioxide, the decrease in carbon dioxide releases serotonin,
which slows respiration, lowers temperature, suppresses appetite, and produces torpor.
</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>But in energy-deprived humans, increases of adrenalin oppose the hibernation reaction, alter energy
production and the ability to relax, and to sleep deeply and with restorative effect.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal">In several ways, torpor is the opposite of sleep.
Rapid eye movement (REM), that occurs at intervals during sleep and in association with increased
respiration, disappears when the brain of a hibernating animal falls below a certain temperature. But
torpor isn"t like "non-REM" deep sleep, and in fact seems to be
</span>
<span style="font-weight: normal; font-style: italic">like wakefulness,</span>
<span style="font-weight: normal; font-style: normal"> in the sense that a sleep-debt is incurred</span>
<span style="font-weight: bold; font-style: normal">:</span>
<span style="font-weight: normal; font-style: normal">
Hibernating animals periodically come out of torpor so they can sleep, and in those periods, when their
temperature rises sharply, they have a very high percentage of deep "slow wave sleep."</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>Although it is common to speak of sleep and hibernation as variations on the theme of economizing on energy
expenditure, I suspect that nocturnal sleep has the special function of minimizing the stress of
darkness itself, and that it has subsidiary functions, including its now well confirmed role in the
consolidation and organization of memory. This view of sleep is consistent with observations that
disturbed sleep is associated with obesity, and that the torpor-hibernation chemical, serotonin,
powerfully interferes with learning.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>Babies spend most of their time sleeping, and during life the amount of time spent sleeping decreases, with
nightly sleeping time decreasing by about half an hour per decade after middle age. Babies have an
extremely high metabolic rate and a stable temperature. With age the metabolic rate progressively
declines, and as a result the ability to maintain an adequate body temperature tends to decrease with
aging.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>(The simple fact that body temperature regulates all organic functions, including brain waves, is
habitually overlooked. The actions of a drug on brain waves, for example, may be mediated by its effects
on body temperature, but this wouldn"t be very interesting to pharmacologists looking for
"transmitter-specific" drugs.)</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>Torpor is the opposite of restful sleep, and with aging, depression, hypothyroidism, and a variety of brain
syndromes, sleep tends toward the hypothermic torpor.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>An individual cell behaves analogously to the whole person. A baby"s "high energy resting state" is
paralleled by the stable condition of a cell that is abundantly charged with energy</span>
<span style="font-weight: bold; font-style: normal">;</span>
<span style="font-weight: normal; font-style: normal">
ATP and carbon dioxide are at high levels in these cells. Progesterone"s effects on nerve cells include
favoring the high energy resting state, and this is closely involved in progesterone"s "thermogenic"
effect, in which it raises the temperature set-point.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>The basal metabolic rate, which is mainly governed by thyroid, roughly corresponds to the average body
temperature. However, in hypothyroidism, there is an adaptive increase in the activity of the
sympathetic nervous system, producing more adrenalin, which helps to maintain body temperature by
causing vasoconstriction in the skin. In aging, menopause, and various stressful conditions, the
increased adrenalin (and the increased cortisol production which is produced by excess adrenalin) causes
a tendency to wake more easily, and to have less restful sleep.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>While the early morning body temperature will sometimes be low in hypothyroidism, I have found many
exceptions to this. In protein deficiency, sodium deficiency, in menopause with flushing symptoms, and
in both phases of the manic depression cycle, and in some schizophrenics, the morning temperature is
high, corresponding to very high levels of adrenalin and cortisol. Taking the temperature before and
after breakfast will show a reduction of temperature, the opposite of what occurs in simple
hypothyroidism, because raising the blood sugar permits the adrenalin and cortisol to fall.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>The characteristic sleep pattern of hypothyroidism and old age is similar to the pattern seen in
schizophrenia and depression, a decrease of deep slow wave sleep. Serotonin, like torpor, produces a
similar effect. In other words, a torpor-like state can be seen in all of these brain-stress states.
Several studies have found that anti-serotonin drugs improve sleep, and also reduce symptoms of
schizophrenia and depression. It is common for the "neuroleptic" drugs to raise body temperature, even
pathologically as in the "neuroleptic malignant syndrome."</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>In old people, who lose heat easily during the day, their extreme increase in the compensatory nervous and
hormonal adrenalin activity causes their night-time heat regulation (vasoconstriction in the
extremities) to rise to normal.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>Increased body temperature improves sleep, especially the deep slow wave sleep. A hot bath, or even warming
the feet, has the same effect as thyroid in improving sleep. Salty and sugary foods taken at bedtime, or
during the night, help to improve the quality and duration of sleep. Both salt and sugar lower the
adrenalin level, and both tend to raise the body temperature.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>Hypothyroidism tends to cause the blood and other body fluids to be deficient in both sodium and glucose.
Consuming salty carbohydrate foods momentarily makes up to some extent for the thyroid deficiency.</span
>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>In the peiodic table of the elements, lithium is immediately above sodium, meaning that it has the chemical
properties of sodium, but with a smaller atomic radius, which makes its electrical charge more intense.
Its physiological effects are so close to sodium"s that we can get clues to sodium"s actions by watching
what lithium does.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>Chronic consumption of lithium blocks the release of adrenalin from the adrenal glands, and it also has
extensive antiserotonin effects, inhibiting its release from some sites, and blocking its actions at
others.</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>Lithium forms a complex with the ammonia molecule, and since the ammonia molecule mimics the effects of
serotonin, especially in fatigue, this could be involved in lithium"s antiserotonergic effects. Ammonia,
like serotonin, impairs mitochondrial energy production (at a minimum, it uses energy in being converted
to urea), so anti-ammonia, anti-serotonin agents make more energy available for adaptation. Lithium has
been demonstrated to restore the energy metabolism of mitochondria (Gulidova, 1977).</span>
</p>
<p>
<span style="font-weight: normal; font-style: normal"
>Therapies that have been successful in treating "schizophrenia" include penicillin, sleep therapy,
hyperbaric oxygen, carbon dioxide therapy, thyroid, acetazolamide, lithium and vitamins. These all make
fundamental contributions to the restoration of biological energy. Antibiotics, for example, lower
endotoxin formation in the intestine, protect against the induction by endotoxin of serotonin,
histamine, estrogen, and cortisol. Acetazolamide causes the tissues to retain carbon dioxide, and
increased carbon dioxide acidifies cells, preventing serotonin secretion.</span>
</p>
<p></p>
<p></p>
<p><span style="font-size: 10pt"> <span style="font-weight: bold"><h3>REFERENCES</h3></span></span></p>
<p></p>
<p>
<span style="font-weight: normal">Gen Pharmacol 1994 Oct;25(6):1257-1262.</span>
<span style="font-weight: bold">
Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of
plasma hemoglobin; the protective action of calmodulin antagonists.</span>
<span style="font-weight: normal">
Koren-Schwartzer N, Chen-Zion M, Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan
University, Ramat Gan, Israel.
</span>
<span style="font-weight: bold"
>1. Injection of serotonin (5-hydroxytryptamine) to rats, induced a dramatic fall in brain ATP level,
accompanied by an increase in P(i). Concomitant to these changes, the activity of cytosolic
phosphofructokinase, the rate-limiting enzyme of glycolysis, was significantly enhanced. Stimulation of
anaerobic glycolysis was also reflected by a marked increase in lactate content in brain. 2. Brain
glucose</span>
<span style="font-weight: normal">
1,6-bisphosphate level was decreased, whereas fructose 2,6-bisphosphate was unaffected by serotonin. 3.
All these serotonin-induced changes in brain, which are characteristic for cerebral ischemia, were
prevented by treatment with the calmodulin (CaM) antagonists, trifluoperazine or thioridazine. 4</span>
<span style="font-weight: bold"
>. Injection of serotonin also induced a marked elevation of plasma hemoglobin, reflecting lysed
erythrocytes,</span>
<span style="font-weight: normal"> which was also prevented by treatment with the CaM antagonists. 5.</span>
<span style="font-weight: bold">
The present results suggest that CaM antagonists may be effective drugs in treatment of many
pathological conditions and diseases in which plasma serotonin levels are known to increase.</span>
</p>
<p>
<span style="font-weight: normal">WMJ 1990 Nov-Dec;62(6):93-7.</span>
<span style="font-weight: bold">
[Effect of inflammatory mediators on respiration in rat liver mitochondria].</span>
<span style="font-weight: normal"> Semenov VL.</span>
</p>
<p>
<span style="font-weight: bold"
>Vopr Med Khim 1990 Sep-Oct;36(5):18-21 [Regulation by biogenic amines of energy functions of
mitochondria].</span>
<span style="font-weight: normal">
Medvedev A.E. Biogenic amines (phenylethylamine, tyramine, dopamine, tryptamine,
</span>
<span style="font-weight: bold"
>serotonin and spermine) decreased activities of the rotenone-insensitive NADH-cytochrome c reductase, the
succinate cytochrome c reductase and the succinate dehydrogenase</span>
<span style="font-weight: normal">.</span>
</p>
<p>
<span style="font-weight: normal">Vopr Med Khim 1991 Sep-Oct;37(5):2-6.</span>
<span style="font-weight: bold">
[The role of monoamine oxidase in the regulation of mitochondrial energy functions].</span>
<span style="font-weight: normal"> Medvedev AE, Gorkin VZ.</span>
</p>
<p>
<span style="font-weight: normal">Lik Sprava 1997 Jan-Feb;(1):61-5.</span>
<span style="font-weight: bold">
[Microhemodynamics and energy metabolism in schizophrenia patients].</span>
<span style="font-weight: normal"><hr /></span>
<span style="font-weight: bold">
showed lowering of ATP level and rise in the content of cathodic LDG4-LDG5 fractions, accumulation in
blood of lactic and pyruvic acids.</span>
</p>
<p>
<span style="font-weight: normal">Schizophr Res 1996 Oct 18;22(1):41-7. </span>
<span style="font-weight: bold"
>Are reduced head circumference at birth and increased obstetric complications associated only with
schizophrenic psychosis? A comparison with schizo-affective and unspecified functional psychoses.</span>
<span style="font-weight: normal">
McNeil TF, Cantor-Graae E, Nordstrom LG, Rosenlund T.</span>
</p>
<p>
<span style="font-weight: normal">Schizophr Res 1993 Jun;10(1):7-14. </span>
<span style="font-weight: bold">Puberty and the onset of psychosis.</span>
<span style="font-weight: normal">
Galdos PM, van Os JJ, Murray RM Department of Child and Adolescent Psychiatry, Bethlem Royal Hospital,
London, UK. According to the neurodevelopmental hypothesis of schizophrenia, maturational events in the
brain at puberty interact with congenital defects to produce psychotic symptoms. As girls reach puberty
at a younger age than boys, we predicted that (i) females would show earlier onset of psychotic illness
arising around puberty, and (ii)</span>
<span style="font-weight: bold">
onset of psychosis in females would be related to menarche.</span>
<span style="font-weight: normal">
Analysis of epidemiological data regarding admission to psychiatric units in (a) England over the period
1973-1986, (b) France over the period 1975`-1980, as well as examination of 97 psychotic adolescents
referred to an adolescent unit over a 14 year period, supported both these propositions.
</span>
</p>
<p>
<span style="font-weight: normal">Int J Psychophysiol 1999 Dec;34(3):237-47.</span>
<span style="font-weight: bold">
Timing of puberty and syndromes of schizotypy: a replication.</span>
<span style="font-weight: normal">
Kaiser J, Gruzelier JH. "Active syndrome findings were confined to the male subsample with late maturing
males showing higher scores on the
</span>
<span style="font-weight: bold">Cognitive Failures and Odd Speech </span>
<span style="font-weight: normal"
>subscales than early maturers. As in the previous study, there was no relationship between a global
psychosis proneness scale and maturational rate. These findings support a neurodevelopmental model of
psychosis-proneness and show the importance of adopting a syndromal view."</span>
</p>
<p>
<span style="font-weight: normal">Am J Physiol 1978 Mar;234(3):H300-4. </span>
<span style="font-weight: bold"
>Potentiation of the cerebrovascular response to intra-arterial 5-hydroxytryptamine.</span>
<span style="font-weight: normal">
Eidelman BH, Mendelow AD, McCalden TA, Bloom DS. Infusion of 5-hydroxytryptamine (5HT) into the internal
carotid artery of normal baboons was not accompanied by alteration of gray matter cerebral blood flow.
</span>
<span style="font-weight: bold"
>In animals pretreated with depot estrogen and progesterone (dosage equivalent to oral contraceptive
preparations), infusion of 5HT produced a marked decrease in gray matter blood flow.</span>
<span style="font-weight: normal">
A similar decrease in flow was obtained when the 5HT was infused with a concentrate of beta-lipoprotein.
Steroid substances appear to enhance the cerebrovascular constrictor responses to 5HT. A further series
of six experiments has shown that the monoamine oxidase inhibitor tranylcypromine similarly produced
constrictor responses to 5HT. It is possible that the steroids, the beta-lipoprotein, and the
tranylcypromine produced constrictor responses to 5HT by the same mechanism (inhibition of
cerebrovascular monoamine oxidase).</span>
</p>
<p>
<span style="font-weight: normal">FASEB J 1989 Apr;3(6):1753-9. </span>
<span style="font-weight: bold"
>Steroid regulation of monoamine oxidase activity in the adrenal medulla.</span>
<span style="font-weight: normal">
Youdim MB, Banerjee DK, Kelner K, Offutt L, Pollard HB. "Administration of different steroid hormones in
vivo has distinct and specific effects on the MAO activity of the adrenal medulla." "As in the intact
animal, we found that</span>
<span style="font-weight: bold">
endothelial cell MAO activity was stimulated 1.5- 2.5-fold by 10 microM progesterone, hydrocortisone,
and dexamethasone, inhibited by ca. 50% by 17-alpha-estradiol,</span>
<span style="font-weight: normal">
but unaffected by testosterone." ". . . steroid-induced changes in total cell division ([14C]thymidine
incorporation) and total protein synthesis ([14C]leucine incorporation) were seen after changes in MAO
A."</span>
</p>
<p>
<span style="font-weight: normal">J Pharmacol Exp Ther 1984 Apr;229(1):244-9 </span>
<span style="font-weight: bold"
>Mechanisms of specific change by estradiol in sensitivity of rat uterus to serotonin.</span>
<span style="font-weight: normal"> Ichida S, Oda Y, Tokunaga H, Hayashi T, Murakami T, Kita T.</span>
</p>
<p>
<span style="font-weight: normal">Neuroendocrinology 1983;36 (3): 235-41. </span>
<span style="font-weight: bold"
>Gonadal hormone regulation of MAO and other enzymes in hypothalamic areas.</span>
<span style="font-weight: normal">
Luine VN, Rhodes JC. "Activities of type A monoamine oxidase (MAO), acetylcholine esterase (AChE), and
glucose-6-phosphate dehydrogenase (G6PDH) were differentially altered in hormone-sensitive areas of the
preoptic-hypothalamic continuum after administration of estrogen and progesterone."
</span>
<span style="font-weight: bold">"Estrogen decreased activity of MAO in the PVE of the anterior hypothalamus,
pars lateralis of the ventromedial nucleus and in the Ar-ME. Acute administration of progesterone (1 h)
to estrogen-treated females did not further alter estrogen-dependent changes in AChE or G6PDH; however,
MAO activity in the ventromedial nucleus and Ar-ME was rapidly increased after progesterone."
</span>
<span style="font-weight: normal">"Administration of the protein synthesis inhibitor anisomycin prior to
progesterone
</span>
<span style="font-weight: bold"
>did not antagonize progesterone-dependent increases in MAO. Progesterone added in vitro to homogenates from
estrogen-treated but not from untreated females increased MAO activity."</span>
<span style="font-weight: normal"> </span>
</p>
<p>
<span style="font-weight: normal">J Neurochem 1981 Sep;37(3):640-8. </span>
<span style="font-weight: bold"
>Gonadal influences on the sexual differentiation of monoamine oxidase type A and B activities in the rat
brain.</span>
<span style="font-weight: normal">
Vaccari A, Caviglia A, Sparatore A, Biassoni R</span>
<span style="font-weight: bold">
"When masculinization was prevented by neonatal administration of estradiol (E)</span>
<span style="font-weight: normal">
to males, hypothalamic MAO-A and MAO-B activities increased in both control and MAO-inhibited rats." ".
. . single, high doses of steroids to adult, but not to newborn rats, did acutely affect the kinetics of
MAO-A.
</span>
<span style="font-weight: bold"
>The activity of MAO-A was also decreased by high concentrations of E or TS in vitro. The imprinting for
patterns</span>
<span style="font-weight: normal">
of hypothalamic MAO-A and MAO-B in the two sexes results, probably, from genetic predetermination."
</span>
</p>
<p>
<span style="font-weight: normal">Gynecol Obstet Invest 2000;49(3):150-5.</span>
<span style="font-weight: bold">
Transport and metabolism of serotonin in the human placenta from normal and severely pre-eclamptic
pregnancies.</span>
<span style="font-weight: normal">
Carrasco G, Cruz MA, Gallardo V, Miguel P, Dominguez A, Gonzalez C. "These findings suggest that the
higher plasma-free serotonin levels observed in severe pre-eclampsia
</span>
<span style="font-weight: bold">are mainly due to a reduction in MAO-A activity</span>
<span style="font-weight: normal"> and not limited by the rate of serotonin uptake into the cells."</span>
</p>
<p>
<span style="font-weight: normal">Psychiatry Res 1989 Jun;28(3):279-88.</span>
<span style="font-weight: bold">
Acetazolamide and thiamine: an ancillary therapy for chronic mental illness.</span>
<span style="font-weight: normal">
Sacks W, Esser AH, Feitel B, Abbott K Cerebral Metabolism Laboratory, Nathan S. Kline Institute for
Psychiatric Research, Orangeburg, NY 10962. Twenty-four chronic schizophrenic patients were treated
successfully with the addition of acetazolamide and thiamine (A + T) to their unchanged existing
therapies in a double-blind, placebo-controlled crossover study. Therapeutic effects were measured by
the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms.
</span>
<span style="font-weight: bold"
>Overall, 50% of the patients showed improvement on all assessment scales.</span>
<span style="font-weight: normal">
No untoward effects occurred in these patients or in patients in previous studies who have been treated
continuously with A + T therapy for as long as 3 years.</span>
</p>
<p>
<span style="font-weight: normal">J Neural Transm 1998;105(8-9):975-86. </span>
<span style="font-weight: bold"
>Role of tryptophan in the elevated serotonin-turnover in hepatic encephalopathy.</span>
<span style="font-weight: normal">
Herneth AM, Steindl P, Ferenci P, Roth E, Hortnagl H. "The increase of the brain levels of
5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased turnover of
serotonin (5-HT)."</span>
</p>
<p>
<span style="font-weight: normal">J Neurosci Res 1981;6(2):225-36 </span>
<span style="font-weight: bold"
>A difference in the in vivo cerebral production of [1-14C] lactate from D-[3-14C] glucose in chronic mental
patients.</span>
<span style="font-weight: normal">
Sacks W, Schechter DC, Sacks S. "Previously unpublished whole-blood lactate determinations in these
experiments indicated a cerebral production of much higher specific activity of [1-14C]-lactate from the
D-[3-14C] glucose by mental patients."
</span>
</p>
<p>
<span style="font-weight: normal">Ther Umsch 2000 Feb;57(2):76-80.</span>
<span style="font-weight: bold"> [Antidepressive therapy by modifying sleep].</span>
<span style="font-weight: normal"> Haug HJ, Fahndrich E.</span>
</p>
<p>
<span style="font-weight: normal">Schizophr Res 1998 Jun 22;32(1):1-8. </span>
<span style="font-weight: bold">Reduced status of plasma total antioxidant capacity in schizophrenia.</span>
<span style="font-weight: normal"> Yao JK, Reddy R, McElhinny LG, van Kammen DP.</span>
</p>
<p>
<span style="font-weight: normal">FASEB J 1998 Dec;12(15):1777-83. </span>
<span style="font-weight: bold"
>Increased F2-isoprostanes in Alzheimer's disease: evidence for enhanced lipid peroxidation in vivo.</span>
<span style="font-weight: normal">
Pratico D, MY Lee V, Trojanowski JQ, Rokach J, Fitzgerald GA.</span>
</p>
<p>
<span style="font-weight: normal">Dis Nerv Syst 1976 Feb;37(2):98-103. </span>
<span style="font-weight: bold">Glucose-insulin metabolism in chronic schizophrenia.</span>
<span style="font-weight: normal">
Brambilla F, Guastalla A, Guerrini A, Riggi F, Rovere C, Zanoboni A, Zanoboni-Muciaccia W.
</span>
</p>
<p>
<span style="font-weight: normal">Psychiatr Clin (Basel) 1975;8(6):304-13. </span>
<span style="font-weight: bold"
>Blood flow and oxidative metabolism of the brain in patients with schizophrenia.</span>
<span style="font-weight: normal"> Hoyer S, Oesterreich K.</span>
</p>
<p>
<span style="font-weight: normal">Zh Nevropatol Psikhiatr Im S S Korsakova 1977;77(8):1179-86 </span>
<span style="font-weight: bold">[Effect of lithium on the energy metabolism of nervous tissue].</span>
<span style="font-weight: normal"> Gulidova GP, Khzardzhian VG, Mikhailova NM</span>
<span style="font-weight: bold">. </span>
<span style="font-weight: normal"
>"Lithium (0.5--4 mM) either significantly increase, either completely normalizers the intensity of the
oxidative and energy metabolism of the brain mitochondria, decreased by the influence of the blood serum
of patients with manic-depressive psychosis and attack like schizophrenia." "Processes of
phosphorilation become normalized in a joint action on the mitochondria by lithium and antioxidants."
"It is assumed that an increase in the intensity of the energy metabolism is one of the mechanisms of
therapeutical and prophylactic action of lithium."</span>
</p>
<p>
<span style="font-weight: normal">Ateneo Parmense Acta Biomed 1975 Jan-Apr;46(1-2):5-19.</span>
<span style="font-weight: bold">
[Clinical significance of changes in tryptophan metabolism].</span>
<span style="font-weight: normal">
Ambanelli U, Manganelli P. "The oxidative pathway is most important of the metabolic pathway of the
amino acid; the degredation of tryptophan is</span>
<span style="font-weight: bold"> </span>
<span style="font-weight: normal">particularly influenced by steroid hormones and vitamins' want. The
metabolic anomalies are demonstrable both in malignant tumors (mostly in bladder cancer and Hodgkin's
disease), both during psychiatric diseases (such as depression and schizophrenia) and in the diseases of
connective tissue in addition to congenital errors of the degradation of tryptophan (such as Hartnup's
disease, tryptophanuria and 3-hydroxychinureninuria)."
</span>
</p>
<p>
<span style="font-weight: normal">Acta Neurol Scand Suppl 1977;64:534-5.</span>
<span style="font-weight: bold">
Blood flow and oxidative metabolism of the brain in the course of acute schizophrenia.</span>
<span style="font-weight: normal"> Hoyer S, Oesterreich K. </span>
</p>
<p>
<span style="font-weight: normal">Med Hypotheses 1994 Dec;43(6):420-35</span>
<span style="font-weight: bold">
Schizophrenia is a diabetic brain state: an elucidation of impaired neurometabolism.</span>
<span style="font-weight: normal"> Holden RJ, Mooney PA.</span>
</p>
<p>
<span style="font-weight: normal">Neuropsychobiology 1990-91;24(1):1-7. </span>
<span style="font-weight: bold"
>Frontality, laterality, and cortical-subcortical gradient of cerebral blood flow in schizophrenia:
relationship to symptoms and neuropsychological functions.</span>
<span style="font-weight: normal"> Sagawa K, Kawakatsu S, Komatani A, Totsuka S. </span>
</p>
<p>
<span style="font-weight: normal">Schizophr Res 1989 Nov-Dec;2(6):439-48.</span>
<span style="font-weight: bold">
Effect of attention on frontal distribution of delta activity and cerebral metabolic rate in
schizophrenia.</span>
<span style="font-weight: normal">
Guich SM, Buchsbaum MS, Burgwald L, Wu J, Haier R, Asarnow R, Nuechterlein K, Potkin S. "Analysis
confirmed increased delta activity in the frontal region of patients with schizophrenia in comparison to
normal controls, and a significant correlation between increased frontal delta and relative reduction in
frontal</span>
<span style="font-weight: bold">
lobe metabolism among patients with schizophrenia. This finding of increased delta is consistent with
PET, blood flow and topographic EEG studies of schizophrenia, suggesting reduced frontal
activity."</span>
</p>
<p>
<span style="font-weight: normal">Br J Psychiatry 1990 Feb;156:216-27.</span>
<span style="font-weight: bold">
Glucose metabolic rate in normals and schizophrenics during the Continuous Performance Test assessed by
positron emission tomography.</span>
<span style="font-weight: normal">
Buchsbaum MS, Nuechterlein KH, Haier RJ, Wu J, Sicotte N, Hazlett E, Asarnow R, Potkin S, Guich S "When
the group of schizophrenic patients was divided into deficit and nondeficit types, a preliminary
exploratory analysis suggested</span>
<span style="font-weight: bold">
thalamic, frontal, and parietal cortical hypometabolism in the deficit subgroup, with normal metabolism
in the nondeficit patient group in those areas; in contrast, hippocampal and anterior cingulate cortical
metabolism was reduced in both deficit and nondeficit subtypes. These results suggest that the limbic
system, especially the hippocampus, is functionally involved in schizophrenic psychosis and that
different manifestations of schizophrenia may involve different neuronal circuits."</span>
</p>
<p>
<span style="font-weight: normal">Psychol Med 1994 Nov;24(4):947-55.</span>
<span style="font-weight: bold">
Patterns of cortical activity in schizophrenia.</span>
<span style="font-weight: normal">
Schroeder J, Buchsbaum MS, Siegel BV, Geider FJ, Haier RJ, Lohr J, Wu J, Potkin SG.
</span>
<span style="font-weight: bold"
>"Schizophrenics were significantly more hypofrontal than the controls,</span>
<span style="font-weight: normal">
with higher values on the 'parietal cortex and motor strip' factor and a trend towards higher values in
the temporal cortex.
</span>
<span style="font-weight: bold">A canonical discriminant analysis confirmed that the 'hypofrontality' and
'parietal cortex and motor strip' factors accurately separated the schizophrenic group from the healthy
controls."
</span>
</p>
<p>
<span style="font-weight: normal">Schizophr Res 1996 Mar;19(1):41-53</span>
<span style="font-weight: bold"
>. Cerebral metabolic activity correlates of subsyndromes in chronic schizophrenia.</span>
<span style="font-weight: normal">
Schroder J, Buchsbaum MS, Siegel BV, Geider FJ, Lohr J, Tang C, Wu J, Potkin SG. "The delusional</span>
<span style="font-weight: bold"> </span>
<span style="font-weight: normal">cluster showed a significantly reduced hippocampal activity, while the
negative symptoms cluster presented with a prominent hypofrontality and significantly increased left
temporal cortex values."
</span>
</p>
<p>
<span style="font-weight: normal">Psychiatry Res 1997 Oct 31;75(3):131-44.</span>
<span style="font-weight: bold">
Cerebral glucose metabolism in childhood onset schizophrenia.</span>
<span style="font-weight: normal">
Jacobsen LK, Hamburger SD, Van Horn JD, Vaituzis AC, McKenna K, Frazier JA, Gordon CT, Lenane MC,
Rapoport JL, Zametkin AJ. "Decreased frontal cortical glucose metabolism has been demonstrated in adult
schizophrenics both at rest and while engaging in tasks that normally increase frontal metabolism, such
as the Continuous Performance Test (CPT).". "These findings suggest that childhood onset schizophrenia
may be associated with a similar, but not more severe, degree of hypofrontality relative to that seen in
adult onset schizophrenia."</span>
</p>
<p>
<span style="font-weight: normal">Pharmacol Biochem Behav 1990 Apr; 35(4):955-62. </span>
<span style="font-weight: bold"
>The effects of ondansetron, a 5-HT3 receptor antagonist, on cognition in rodents and primates.</span>
<span style="font-weight: normal">
Barnes JM, Costall B, Coughlan J, Domeney AM, Gerrard PA, Kelly ME, Naylor RJ, Onaivi ES, Tomkins DM,
Tyers MB. "The selective 5-HT3 receptor antagonist, onansetron, has been assessed in three tests of
cognition in the mouse, rat and marmoset. In a habituation test in the mouse, ondansetron facilitated
performance in young adult and aged animals, and inhibited an impairment in habituation induced by
scopolamine, electrolesions or ibotenic acid lesions of the nucleus basalis magnocellularis." "In an
object discrimination and reversal learning task in the marmoset, assessed using a Wisconsin General
Test Apparatus, ondansetron improved performance in a reversal learning task. We</span>
<span style="font-weight: bold">
conclude that ondansetron potently improves basal performance in rodent and primate tests of cognition
and inhibits the impairments in performance caused by cholinergic deficits."</span>
</p>
<p>
<span style="font-weight: normal"
>Pharmacol Biochem Behav 1992 May;42(1):75-83. Ondansetron and arecoline prevent scopolamine-induced
cognitive deficits in the marmoset.</span>
<span style="font-weight: bold">
Carey GJ, Costall B, Domeney AM, Gerrard PA, Jones DN, Naylor RJ, Tyers MB
</span>
<span style="font-weight: normal">School of Pharmacy, University of Bradford, UK. </span>
<span style="font-weight: bold">The cognitive-enhancing potential of the 5-hydroxytryptamine (5-HT)
selective 5-HT3 receptor antagonist, ondansetron, was investigated in a model of cognitive impairment
induced by the muscarinic receptor antagonist, scopolamine.
</span>
</p>
<p>
<span style="font-weight: normal">J Comp Physiol Psychol 1977 Jun;91(3): 642-8. </span>
<span style="font-weight: bold"
>Tryptophan and tonic immobility in chickens: effects of dietary and systemic manipulations.</span>
<span style="font-weight: normal">
Gallup GG Jr, Wallnau LB, Boren JL, Gagliardi GJ, Maser JD, Edson PH.
</span>
<span style="font-weight: bold">"Systemic injections of tryptophan, the dietary precursor to serotonin, led
to a dose-dependent increase in immobility, with optimal effects being observed within 30 min after
injection. Dietary depletion of endogenous tryptophan served to attenuate the duration of immobility,
and a diet completely free of tryptophan, but supplemented with niacin, practically abolished the
reaction.
</span>
<span style="font-weight: normal">Dietary replacement served to reinstate the response." </span>
<span style="font-weight: bold"
>"The data are discussed in light of evidence showing serotonergic involvement in tonic immobility."</span>
</p>
<p>
<span style="font-weight: normal">J Neurosci Res 1995 Feb 15;40(3):407-413. </span>
<span style="font-weight: bold"
>Endotoxin administration stimulates cerebral catecholamine release in freely moving rats as assessed by
microdialysis.</span>
<span style="font-weight: normal"> Lavicky J, Dunn AJ. </span>
</p>
<p>
<span style="font-weight: normal">J Neurosci Res 1998 Feb 15;51(4):517-525. </span>
<span style="font-weight: bold">Lipopolysaccharide regulates both serotonin- and thrombin-induced
intracellular calcium mobilization in rat C6 glioma cells: possible involvement of nitric oxide
synthase-mediated pathway.
</span>
<span style="font-weight: normal">Tawara Y, Kagaya A, Uchitomi Y, Horiguchi J, Yamawaki S.
</span>
</p>
<p>
<span style="font-size: 9pt">Infect Immun 1996 Dec;64(12):5290-5294..<span
style="font-weight: bold"
>Biphasic, organ-specific, and strain-specific accumulation of platelets induced in mice by a
lipopolysaccharide from Escherichia coli and its possible involvement in shock.
</span><span style="font-weight: normal"
>Shibazaki M, Nakamura M, Endo Y. "Platelets contain a large amount of 5-hydroxytryptamine (5HT,
serotonin). Intravenous injection into BALB/c mice of a Boivin's preparation of lipopolysaccharide
(LPS) from Escherichia coli induced rapid 5HT accumulation in the lung (within 5 min) and slow 5HT
accumulation in the liver (2 to 5 h later)." "A shock, which was</span><span
style="font-weight: bold"
>
</span><span style="font-weight: normal">manifested by crawling, convulsion, or prostration, followed
shortly after the rapid accumulation of 5HT in the lung. On the other hand, the slow accumulation of
5HT in the liver could be induced by much lower doses of LPS (1 microg/kg or less), even when given
by intraperitoneal injection."
</span></span>
</p>
<p>
<span style="font-weight: normal">Life Sci 1997;61(18):1819-1827. </span>
<span style="font-weight: bold"
>Serotonin 5HT2A receptor activation inhibits inducible nitric oxide synthase activity in C6 glioma
cells.</span>
<span style="font-weight: normal"> Miller KJ, Mariano CL, Cruz WR.</span>
</p>
<p>
<span style="font-weight: normal">Harefuah 2000 May 15;138(10):809-12, 910.</span>
<span style="font-weight: bold">
[Jet lag causing or exacerbating psychiatric disorders].</span>
<span style="font-weight: normal">
Katz G, Durst R, Zislin J, Knobler H, Knobler HY. We presume, relying on the literature and our
accumulated experience, that in predisposed individuals jet lag may play a role in triggering
exacerbation of, or de novo affective disorders, as well as, though less convincing, schizophreniform
psychosis or even schizophrenia. An illustrative case vignette exemplifies the possible relationship
between jet lag following eastbound flight and psychotic manifestations.</span>
</p>
<p>
<span style="font-weight: normal">Life Sci 1987 May 18;40(20):2031-9.</span>
<span style="font-weight: bold">
Dysfunction in a prefrontal substrate of sustained attention in schizophrenia.</span>
<span style="font-weight: normal">
Cohen RM, Semple WE, Gross M, Nordahl TE, DeLisi LE, Holcomb HH, King AC, Morihisa JM, Pickar D.
Regional brain metabolism was measured in normal subjects and patients with schizophrenia while they
performed an auditory discrimination task designed to emphasize sustained attention. A direct
relationship was found in the normal</span>
<span style="font-weight: bold"> </span>
<span style="font-weight: normal"
>subjects between metabolic rate in the middle prefrontal cortex and accuracy of performance. The metabolic
rate in the middle prefrontal cortex of patients with schizophrenia, even those who performed as well as
normals, was found to be significantly lower than normal and unrelated to performance. The findings
point to a role of the mid-prefrontal region in sustained attention and to dysfunction of this region in
schizophrenia.</span>
</p>
<p>
<span style="font-weight: normal">Acta Psychiatr Scand 1987 Dec;76(6):628-41. </span>
<span style="font-weight: bold"
>Regional brain glucose metabolism in drug free schizophrenic patients and clinical correlates.</span>
<span style="font-weight: normal">
Wiesel FA, Wik G, Sjogren I, Blomqvist G, Greitz T, Stone-Elander S. "Thus, the lower the metabolic rate
was, the more autistic the patient. Metabolic rates were not correlated to atrophic changes of the
brain. No basis for a specific alteration in frontal cortical metabolism of schizophrenics was obtained.
Changes in regional metabolic rates in schizophrenia are suggested to reflect disturbances in more
general mechanisms which are of importance in neuronal function."</span>
</p>
<p>
<span style="font-weight: normal">Chung Hua Shen Ching Ching Shen Ko Tsa Chih 1991 Oct;24(5):268-71, 316-7.
</span>
<span style="font-weight: bold"
>[Developments observation of serum thyrohormone level in schizophrenics.</span>
<span style="font-weight: normal">
Wang X. "The authors reported that abnormal levels of T4, FT4I in 16 cases patients relate to disease
course and severe symptoms and suggested that the change of serum T4, FT4I in some cases was related to
the disease in itself."</span>
</p>
<p>
<span style="font-size: 10pt">Biol Psychiatry 1991 Mar 1;29(5):457-66.<span style="font-weight: bold">
Multidimensional hormonal discrimination of paranoid schizophrenic from bipolar manic
patients.</span><span style="font-weight: normal"> Mason JW, Kosten TR, Giller EL. </span></span>
</p>
<p>
<span style="font-weight: normal">Zh Nevropatol Psikhiatr Im S S Korsakova 1991;91(1):122-3 </span>
<span style="font-weight: bold">[Status of the thyroid gland in patients with schizophrenia].</span>
<span style="font-weight: normal">
Turianitsa IM, Lavkai IIu, Mishanich II, Margitich VM, Razhov KF. "The rise of TTH concentration
represents one of the mechanisms of correction, aimed at the attainment of the physiological content of
T4 at the expense of its additional output for its level in the blood serum is appreciably
reduced."</span>
</p>
<p>
<span style="font-weight: normal">Can J Psychiatry 1990 May;35(4):342-3. </span>
<span style="font-weight: bold">Increased detection of elevated TSH using immunoradiometric assay.</span>
<span style="font-weight: normal">
Little KY, Kearfott KS, Castellanos X, Rinker A, Whitley R. Using a highly sensitive immunoradiometric
assay, the authors detected an increased rate of elevated thyrotropin in 2,099 patients vs 1,789
patients examined with radioimmunoassay. Closer scrutiny of mood disorder patients with elevations found
confirmatory evidence of thyroid dysfunction in most.</span>
</p>
<p>
<span style="font-weight: normal">Metabolism 1990 May;39(5):538-43.</span>
<span style="font-weight: bold">
Serum thyrotropin in hospitalized psychiatric patients: evidence for hyperthyrotropinemia as measured by
an ultrasensitive thyrotropin assay.</span>
<span style="font-weight: normal"> Chopra IJ, Solomon DH, Huang TS. </span>
</p>
<p>
<span style="font-weight: normal">J Nerv Ment Dis 1989 Jun;177(6):351-8.</span>
<span style="font-weight: bold">
Serum thyroxine levels in schizophrenic and affective disorder diagnostic subgroups.</span>
<span style="font-weight: normal"> Mason JW, Kennedy JL, Kosten TR, Giller EL Jr</span>
<span style="font-weight: bold"
>. "For TT4, 75% of the PS group showed a rise during recovery in contrast to 4% of the remaining groups;
for FT4, 50% of the PS group showed a rise compared with 14% of the other groups." "This study
emphasizes the importance of exploring more fully the psychiatric significance of thyroxine levels
within the endocrinological normal range and of doing longitudinal assessments of thyroxine and symptom
changes during clinical recovery in psychiatric disorders."</span>
</p>
<p>
<span style="font-weight: normal">Biol Psychiatry 1989 Jan;25(1):67-74. </span>
<span style="font-weight: bold"
>Serum thyroxine change and clinical recovery in psychiatric inpatients.</span>
<span style="font-weight: normal">
Southwick S, Mason JW, Giller EL, Kosten TR. "A strong correlation between the range values for BPRS
[Brief Psychiatric Rating Scale] sum and for FT4 (p less than 0.005) and TT4 (p less than 0.001) levels
indicated that change in overall symptom severity was linked to change in thyroxine levels during
clinical recovery." "These findings suggest that a "normalizing" principle underlies the relationship
between clinical recovery and thyroxine levels and that both FT4 and TT4 levels within the normal range
appear to have clinical significance in either reflecting or contributing to the course of a variety of
psychiatric disorders and possibly having a role in pathogenesis."</span>
</p>
<p>
<span style="font-weight: normal">J Clin Psychiatry 1980 Sep;41(9):316-8. </span>
<span style="font-weight: bold">Myxedema psychosis--insanity defense in homicide.</span>
<span style="font-weight: normal"> Easson WM. </span>
</p>
<p>
<span style="font-weight: normal">Int J Psychiatry Med 1988;18(3):263-70.</span>
<span style="font-weight: bold">
The diagnostic dilemma of myxedema and madness, axis I and axis II: a longitudinal case report.</span>
<span style="font-weight: normal">
Darko DF, Krull A, Dickinson M, Gillin JC, Risch SC. "A patient with presumed chronic paranoid
schizophrenia had chronic thyroiditis and Grade I hypothyroidism. Psychosis cleared following treatment
with thyroid replacement." "The differential diagnosis among hypothyroidism and primary axis I psychotic
and depressive psychopathology has always been problematic."</span>
</p>
<p>
<span style="font-size: 10pt">P R Health Sci J 1993 Jun;12(2):85-7.<span style="font-weight: bold">
[Alzheimer's disease: the untold story].</span><span style="font-weight: normal">
Pico-Santiago G. After considering the potential relationship between amyloid deposits and
myxedematous infiltrations, the hypothesis is formulated that Alzheimer's disease may be due to
functional hypothyroidism and may thus respond to thyroid therapy.</span></span>
</p>
<p>
<span style="font-weight: normal">Psychiatry Res 1998 Jul 27;80(1):29-39.</span>
<span style="font-weight: bold">
Reduced level of plasma antioxidant uric acid in schizophrenia.</span>
<span style="font-weight: normal"><hr /></span>
<span style="font-weight: bold">
and inversely correlated with psychosis. There was a trend for lower uric acid levels in relapsed
patients relative to clinically stable patients. Smoking, which can modify plasma antioxidant capacity,
was not found to have prominent effects on uric acid levels. The present finding of a significant
decrease of a</span>
<span style="font-weight: normal">
selective antioxidant provides additional support to the hypothesis that oxidative stress in
schizophrenia may be due to a defect in the antioxidant defense system."</span>
</p>
<p>
<span style="font-size: 9pt">Zh Nevropatol Psikhiatr Im S S Korsakova 1989; 89(5):108-10.<span
style="font-weight: bold"
>
[Lipid peroxidation processes in patients with schizophrenia].</span><span
style="font-weight: normal"
>
Kovaleva ES, Orlov ON, Tsutsu'lkovskaia MIa, Vladimirova TV, Beliaev BS.
</span></span>
</p>
<p>
<span style="font-weight: normal">Zh Nevropatol Psikhiatr Im S S Korsakova 1991;91(7):121-4. </span>
<span style="font-weight: bold"
>[Significance of disorders of the processes of lipid peroxidation in patients with persistent paranoid
schizophrenia resistant to the treatment].</span>
<span style="font-weight: normal">
Govorin NV, Govorin AV, Skazhutin SA.</span>
</p>
<p>
<span style="font-weight: normal">Patol Fiziol Eksp Ter 1999 Jul-Sep;(3):19-22. </span>
<span style="font-weight: bold"
>[The biogenic amine content of rat tissues in the postresuscitation period following hemorrhagic shock and
the effect of the preparation semax].</span>
<span style="font-weight: normal">
Bastrikova NA, Shestakova SV, Antonova SV, Krushinskaia IaV, Goncharenko EN, Kudriashova NIu,
Novoderzhkina IS, Sokolova NA, Kozhura VL. "Early after resuscitation the trend was noted to higher LPO
products concentration in plasma and serotonin in the brain stem." "It is suggested that biogenic
amines, especially serotonin system, are involved in mechanisms of postresuscitation disorders, in
cerebral defects in particular, through prolongation of secondary hypoxia early after hemorrhagic shock
and activation of hypothalamo-hypophyso-adrenal system late after the shock."</span>
</p>
<p>
<span style="font-weight: normal">Prostaglandins Leukot Essent Fatty Acids 1996 Aug;55(1-2):33-43.
</span>
<span style="font-weight: bold">Free radical pathology in schizophrenia: a review.</span>
<span style="font-weight: normal">
Reddy RD, Yao JK.
</span>
</p>
<p>
<span style="font-weight: normal">Schizophr Res 1996 Mar;19(1):19-26. </span>
<span style="font-weight: bold">Impaired antioxidant defense at the onset of psychosis.</span>
<span style="font-weight: normal">
Mukerjee S, Mahadik SP, Scheffer R, Correnti EE, Kelkar H.</span>
</p>
<p>
<span style="font-weight: normal">Biol Psychiatry 1998 May 1;43(9):674-9. </span>
<span style="font-weight: bold"
>Elevated plasma lipid peroxides at the onset of nonaffective psychosis.</span>
<span style="font-weight: normal">
Mahadik SP, Mukherjee S, Scheffer R, Correnti EE, Mahadik JS.</span>
</p>
<p>
<span style="font-weight: normal">Brain Res 1999 Aug 21;839(1):74-84.</span>
<span style="font-weight: bold">
Psychological stress-induced enhancement of brain lipid peroxidation via nitric oxide systems and its
modulation by anxiolytic and anxiogenic drugs in mice.</span>
<span style="font-weight: normal">
Matsumoto K, Yobimoto K, Huong NT, Abdel-Fattah M, Van Hien T, Watanabe H. "The effects of diazepam and
FG7142 were abolished by the BZD receptor antagonist flumazenil (10 mg/kg, i.p.). These results indicate
that psychological stress causes oxidative damage to the brain lipid via enhancing constitutive
NOS-mediated production of NO, and that drugs with a BZD or 5-HT(1A) receptor agonist profile have a
protective effect on oxidative brain membrane damage induced by psychological stress."</span>
</p>
<p>
<span style="font-weight: normal">Anesteziol Reanimatol 1998 Nov-Dec; (6):20-5. </span>
<span style="font-weight: bold"
>[Role of hyperbaric oxygenation in the treatment of posthypoxic encephalopathy of toxic etiology].</span>
<span style="font-weight: normal">
Ermolov AS, Epifanova NM, Romasenko MV, Luzhnikov EA, Ishmukhametov AI, Golikov PP, Khvatov VB, Kukshina
AA, Davydov BV, Kuksova NS, et al. Hyperbaric oxygenation (HBO) was used in the treatment of 475
patients with toxic encephalopathy (TE) developing as a result of exo- and endotoxicosis. HBO promoted
correction of all components of homeostasis,
</span>
<span style="font-weight: bold"
>decreased endotoxicosis, reduced psychopathological and neurological disorders, and promoted social
adaptation.</span>
</p>
<p>
<span style="font-weight: normal">J Neurochem 2000 Jan; 74(1): 114-24. </span>
<span style="font-weight: bold"
>Metabolic impairment elicits brain cell type-selective changes in oxidative stress and cell death in
culture.</span>
<span style="font-weight: normal">
Park LC, Calingasan NY, Uchida K, Zhang H, Gibson GE. "Abnormalities in oxidative metabolism and
inflammation accompany many neurodegenerative diseases. Thiamine deficiency (TD) is an animal model in
which chronic oxidative stress and inflammation lead to selective neuronal death, whereas other cell
types show an inflammatory response." "Among the cell types tested, only in neurons did TD induce
apoptosis and cause the accumulation of 4-hydroxy-2-nonenal, a lipid peroxidation product. On the other
hand, chronic lipopolysaccharide-induced inflammation significantly inhibited cellular dehydrogenase and
KGDHC activities in microglia and astrocytes but not in neurons or endothelial cells. The results
demonstrate that the selective cell changes during TD in vivo reflect inherent properties of the
different brain cell types."</span>
</p>
<p>
<span style="font-weight: normal">Psychol Med 1976 Aug;6(3):359-69.</span>
<span style="font-weight: bold">
Possible association of schizophrenia with a disturbance in prostaglandin metabolism: a physiological
hypothesis.</span>
<span style="font-weight: normal">
Feldberg W. Schizophrenia may be associated with increased prostaglandin synthesis in certain parts of
the brain. This hypothesis is based on the following findings: (1) Catalepsy, which is the nearest
equivalent in animals to human catatonia,</span>
<span style="font-weight: bold"> </span>
<span style="font-weight: normal"
>develops in cats when prostaglandin E1 is injected into the cerebral ventricles and when during endotoxin
or lipid A fever the prostaglandin E2 level in cisternal c.s.f. rises to high levels; however, when
fever and prostaglandin level are brought down by non-steroid anti-pyretics which inhibit prostaglandin
synthesis, catalepsy disappears as well. (2) Febrile episodes are a genuine syndrome of
schizophrenia.</span>
</p>
<p>
<span style="font-weight: normal">Zh Nevropatol Psikhiatr Im S S Korsakova 1966;66(6):912-7. </span>
<span style="font-weight: bold"
>[Treatment of acute schizophrenia with antibiotics, gamma-globulin and vitamins].</span>
<span style="font-weight: normal">
Neikoya M.</span>
</p>
<p>
<span style="font-weight: normal">Prostaglandins Med 1979 Jan;2(1):77-80. </span>
<span style="font-weight: bold">Penicillin and essential fatty acid supplementation in schizophrenia.</span>
<span style="font-weight: normal">
Vaddadi KS.
</span>
</p>
<p>
<span style="font-weight: normal">Psychiatr Dev 1989 Spring;7(1):19-47.</span>
<span style="font-weight: bold">
Positron emission tomography in psychiatry.</span>
<span style="font-weight: normal">
Wiesel FA. "Schizophrenia is the most extensively studied psychiatric disorder. Most studies have
demonstrated decreased metabolic rates in wide areas of the brain. It is proposed that the metabolic
changes observed in the brains of schizophrenic patients are due to a fundamental change in neuronal
function." "Bipolar depressed patients probably have a decreased brain metabolism." "Alcohol dependent
subjects with a long duration of abuse may have a decreased brain metabolism."</span>
</p>
<p>
<span style="font-weight: normal">Arch Gen Psychiatry 1976 Nov;33(11):1377-81. </span>
<span style="font-weight: bold"
>Platelet monamine oxidase in chronic schizophrenia. Some enzyme characteristics relevant to reduced
activity.</span>
<span style="font-weight: normal">
Murphy DL, Donnelly CH, Miller L, Wyatt RJ. "These findings suggest that the reduced MAO activity found
in chronic schizophrenic patients is apparently not accounted for by nonspecific changes in platelets or
platelet mitochondria."</span>
</p>
<p>
<span style="font-weight: normal">Exp Neurol 1997 May;145(1):118-29.</span>
<span style="font-weight: bold">
Long-term reciprocal changes in dopamine levels in prefrontal cortex versus nucleus accumbens in rats
born by Caesarean section compared to vaginal birth.</span>
<span style="font-weight: normal">
El-Khodor BF, Boksa P. "Epidemiological evidence indicates a higher incidence of pregnancy and birth
complications among individuals who later develop schizophrenia, a disorder linked to alterations in
mesolimbic dopamine (DA) function. Two birth</span>
<span style="font-weight: bold"> </span>
<span style="font-weight: normal"
>complications usually included in these epidemiological studies, and still frequently encountered in the
general population, are birth by Caesarean section (C-section) and fetal asphyxia." "At 2 months of age,
in animals born by rapid C-section, steady state levels of DA were decreased by 53% in the prefrontal
cortex and increased by 40% in both the nucleus accumbens and striatum, in comparison to the vaginally
born</span>
<span style="font-weight: bold"> </span>
<span style="font-weight: normal"
>group. DA turnover increased in the prefrontal cortex, decreased in the nucleus accumbens, and showed no
significant change in the striatum, in the C-section group. Thus, birth by a Caesarean procedure
produces long-term reciprocal changes in DA levels and metabolism in the nucleus accumbens and
prefrontal cortex." "Although appearing robust at birth on gross observation, more subtle measurements
revealed that rat pups born by C-section show altered respiratory rates and activity levels and
increased levels of whole brain lactate, suggestive of low grade brain hypoxia, during the first 24 h of
life, in comparison to vaginally born controls." "It is concluded that C-section birth is sufficient
perturbation to produce long-lasting effects on DA levels and metabolism</span>
<span style="font-weight: bold"> </span>
<span style="font-weight: normal">in the central nervous system of the rat."</span>
</p>
<p>
<span style="font-weight: normal">Rehabilitation (Stuttg) 1983 May;22(2):81-5 </span>
<span style="font-weight: bold">[Physical capacity of schizophrenic patients]. </span>
<span style="font-weight: normal">Deimel H, Lohmann S.</span>
<span style="font-weight: bold"> </span>
<span style="font-weight: normal">"Reduced physical capacity in schizophrenic illness has been described in
medical literature, but so far not been substantiated empirically. The findings of progressive bicycle
ergometry confirm the assertion, with the following main results having been obtained: 1. As opposed to
a matched comparison group of untrained healthy clients, the schizophrenically ill patients demonstrated
significantly lower endurance levels
</span>
<span style="font-weight: bold">in respect of the aerobic-anaerobic threshold. </span>
<span style="font-weight: normal">2. Relative to the load maximum attainable highly significant differences
existed between the groups. Particularly noteworthy had been early exercise termination already at
submaximal loads by the schizophrenic patients. 3. The patients under study obtained values one third
below standard compared to the maximum load target for untrained persons, with age and weight being
taken into account."
</span>
</p>
<p>
<span style="font-weight: normal">Folia Psychiatr Neurol Jpn 1984;38(4):425-36 </span>
<span style="font-weight: bold"
>Antipsychotic and prophylactic effects of acetazolamide (Diamox) on atypical psychosis.</span>
<span style="font-weight: normal">
Inoue H, Hazama H, Hamazoe K, Ichikawa M, Omura F, Fukuma E, Inoue K, Umezawa Y We investigated the
antipsychotic and prophylactic effects of acetazolamide (Diamox) on atypical psychosis. Acetazolamide
was given to 30 patients: Type I, puberal periodic psychosis, a psychosis whose onset occurs during the
period of puberty and which appears repetitively with psychosis-like condition at about the same
interval as the menstrual cycle (6 cases); Type II, a) presenile atypical psychosis which initially
appears in patients in their 20s or 30s accompanied by manic-depressive cycles and shows acute
confusional and dreamy states in the presenile period, incurable cases (7), b) atypical psychosis, in
the narrow sense, cases which show acute hallucination, delusion, confusional and dreamy states
accompanied by affective symptoms (8 cases); Type III, repetitively the atypical manic and depressive
states, and atypical manic-depressive psychosis, and transient changes in consciousness, refractory
cases (2); Type IV, atypical schizophrenia, which is considered to be schizophrenia but shows the
abnormalities in electroencephalogram and emotional disorders (7 cases). Among these cases,</span>
<span style="font-weight: bold">
some extent of the therapeutic effects of acetazolamide (500-1,000 mg/day) was obtained in about 70%.
The high therapeutic effects were particularly observed in Types I, II and III. It was less effective
against atypical schizophrenia. Acetazolamide showed the effectiveness in 10 cases out of 13 cases to
which lithium carbonate and carbamazepine were ineffective.</span>
<span style="font-weight: normal">
The high therapeutic effects of acetazolamide were shown in the cases whose
</span>
<span style="font-weight: bold">symptoms were aggravated at the interval of the menstrual cycle.</span>
<span style="font-weight: normal">
No correlation was observed between the electroencephalographic abnormalities and the therapeutic
effects. In addition, the prophylactic effects of acetazolamide on the periodic crisis were observed in
9 cases. From these results, acetazolamide was considered to have the antipsychotic and prophylactic
effects on atypical psychosis.
</span>
<span style="font-weight: bold"
>Since side effects due to acetazolamide were rarely observed, the present drug was considered to have a
high safety margin.</span>
</p>
<p>
<span style="font-weight: normal">Am J Psychiatry 1999 Apr;156(4):617-23 </span>
<span style="font-weight: bold"
>Minor physical anomalies, dermatoglyphic asymmetries, and cortisol levels in adolescents with schizotypal
personality disorder.</span>
<span style="font-weight: normal">
Weinstein DD, Diforio D, Schiffman J, Walker E, Bonsall R. "The schizotypal personality disorder group
showed more minor physical anomalies and dermatoglyphic asymmetries than the normal comparison group and
higher cortisol levels than both of the other groups."
</span>
</p>
<p>
<span style="font-weight: normal">Am J Psychiatry 1992 Jan;149(1):57-61 </span>
<span style="font-weight: bold"
>Congenital malformations and structural developmental anomalies in groups at high risk for psychosis.</span
>
<span style="font-weight: normal"> McNeil TF, Blennow G, Lundberg L. "The inferred genetic risk for</span>
<span style="font-weight: bold"> </span>
<span style="font-weight: normal"
>psychosis does not appear to be associated with greater rates of early somatic developmental anomalies,
suggesting that early developmental anomalies do not represent an expression of genetic influence toward
psychosis."</span>
</p>
<p>
<span style="font-weight: normal">Schizophr Bull 1984;10(2):204-32.</span>
<span style="font-weight: bold">
Psychophysiological dysfunctions in the developmental course of schizophrenic disorders.</span>
<span style="font-weight: normal">
Dawson ME, Nuechterlein KH. "Two electrodermal anomalies are identified in different subgroups of
symptomatic</span>
<span style="font-weight: bold"> </span>
<span style="font-weight: normal">patients: (1) an abnormally high sympathetic arousal and (2) an abnormal
absence of skin conductance orienting responses to innocuous environmental stimuli."
</span>
</p>
<p>
<span style="font-weight: normal">Behav Brain Res 2000 Jan;107(1-2):71-83. </span>
<span style="font-weight: bold"
>Changes in adult brain and behavior caused by neonatal limbic damage: implications for the etiology of
schizophrenia.</span>
<span style="font-weight: normal">
Hanlon FM, Sutherland RJ. ."This study contributes to our understanding of the pathogenesis of
schizophrenia by showing that early damage to limbic structures produced behavioral, morphological, and
neuropharmacological abnormalities related to pathology in adult schizophrenics."</span>
</p>
<p>
<span style="font-weight: normal">Neurochem Res 1996 Sep; 21(9):995-1004. </span>
<span style="font-weight: bold"
>Mitochondrial involvement in schizophrenia and other functional psychoses.</span>
<span style="font-weight: normal">
Whatley SA, Curti D, Marchbanks RM. "Gene expression has been studied in post-mortem frontal cortex
samples from patients who had suffered from schizophrenia and depressive illness." "We conclude that
changes in mitochondrial gene expression are involved in schizophrenia and probably other functional
psychoses."</span>
</p>
<p>
<span style="font-size: 9pt">Eur J Pharmacol 1994 Aug 11;261(1-2):25-32.<span style="font-weight: bold">
The effect of alpha 2-adrenoceptor antagonists in isolated globally ischemic rat hearts.</span><span
style="font-weight: normal"
>
Sargent CA, Dzwonczyk S, Grover GJ. "The alpha 2-adrenoceptor antagonist, yohimbine, has been
reported to protect hypoxic myocardium. Yohimbine has
</span><span style="font-weight: bold"
>several other activities, including 5-HT receptor antagonism, at the concentrations at which protection
was found."</span><span style="font-weight: normal">
"The</span><span style="font-weight: bold">
cardioprotective effects of yohimbine were partially reversed by 30 microM 5-HT. These results
indicate that the mechanism for the cardioprotective activity of yohimbine may involve 5-HT receptor
antagonistic activity."
</span></span>
</p>
<p>
<span style="font-weight: normal">J Cardiovasc Pharmacol 1993 Oct;22(4):664-672. </span>
<span style="font-weight: bold"
>Protective effect of serotonin (5-HT2) receptor antagonists in ischemic rat hearts.</span>
<span style="font-weight: normal">
Grover GJ, Sargent CA, Dzwonczyk S, Normandin DE, Antonaccio MJ.</span>
</p>
<p>
<span style="font-weight: normal">J Appl Physiol 1994 Jul;77(1):277-284.</span>
<span style="font-weight: bold">
Aerobic muscle contraction impaired by serotonin-mediated vasoconstriction.</span>
<span style="font-weight: normal">
Dora KA, Rattigan S, Colquhoun EQ, Clark MG.</span>
</p>
<p>
<span style="font-weight: normal">J Cereb Blood Flow Metab 1995 Jul;15(4):706-13. </span>
<span style="font-weight: bold"
>Enhanced cerebrovascular responsiveness to hypercapnia following depletion of central serotonergic
terminals.</span>
<span style="font-weight: normal">
Kelly PA, Ritchie IM, McBean DE, Sharkey J, Olverman HJ.</span>
</p>
<p>
<span style="font-weight: normal">Arch Gen Psychiatry 1984 Mar;41(3): 293-300. </span>
<span style="font-weight: bold"
>Regional brain glucose metabolism in chronic schizophrenia. A positron emission transaxial tomographic
study.</span>
<span style="font-weight: normal">
Farkas T, Wolf AP, Jaeger J, Brodie JD, Christman DR, Fowler JS.
</span>
<span style="font-weight: bold">". . . schizophrenics had significantly lower activity in the frontal lobes,
relative to posterior regions."
</span>
</p>
<p>
<span style="font-weight: normal">Semin Nucl Med 1986 Jan;16(1):2-34. </span>
<span style="font-weight: bold"
>Positron emission tomography imaging of regional cerebral glucose metabolism.</span>
<span style="font-weight: normal">
Alavi A, Dann R, Chawluk J, Alavi J, Kushner M, Reivich M. "In patients with Alzheimer's disease . . .
parietal, temporal, and to some degree, frontal glucose metabolism is significantly diminished even in
the early stages of the disease. Patients with Huntington's disease and those at risk of developing this
disorder have a typical pattern of diminished CMRglu in the caudate nuclei and putamen. In patients with
stroke, PET images with FDG have demonstrated abnormal findings earlier than either XCT or MRI and with
a wider topographic distribution. FDG scans have revealed interictal zones of decreased LCMRglu in
approximately 70% of patients with partial epilepsy. The location of the area of hypometabolism
corresponds to the site of the epileptic focus as determined by electroencephalography and microscopic
examination of the resected tissue."</span>
</p>
<p>
<span style="font-weight: normal">Schizophr Bull 1988; 14(2): 169-76.</span>
<span style="font-weight: bold">
From syndrome to illness: delineating the pathophysiology of schizophrenia with PET.</span>
<span style="font-weight: normal">
Cohen RM, Semple WE, Gross M, Nordahl TE. "In normal controls, the metabolic rate in the middle
prefrontal cortex, measured during the ongoing performance of auditory discrimination, is associated
with their accuracy of performance. In unmedicated patients with</span>
<span style="font-weight: bold"> </span>
<span style="font-weight: normal">schizophrenia, even those who performed as well as normals, the metabolic
rate in the mid-prefrontal cortex was found to be significantly lower than normal. Further, this
decreased metabolic rate was unrelated to performance." "The mid-prefrontal cortex and its dopamine
neurotransmitter pathway input are important biological determinants of sustained attention."
</span>
</p>
<p>
<span style="font-weight: normal">Biol Psychiatry 1989 Apr 1;25(7):835-51. </span>
<span style="font-weight: bold"
>Increased temporal lobe glucose use in chronic schizophrenic patients.</span>
<span style="font-weight: normal">
DeLisi LE, Buchsbaum MS, Holcomb HH, Langston KC, King AC, Kessler R, Pickar D, Carpenter WT Jr,
Morihisa JM, Margolin R, et al. Temporal lobe glucose metabolic rate was assessed in 21 off-medication
patients with schizophrenia and 19 normal controls by positron emission tomography with
18F-deoxyglucose. Patients with schizophrenia had significantly greater</span>
<span style="font-weight: bold">
metabolic activity in the left than the right anterior temporal lobe, and the extent of this
lateralization was in proportion to the severity of</span>
<span style="font-weight: normal"> psychopathology.</span>
</p>
<p>
<span style="font-weight: normal">Am J Obstet Gynecol 1999 Dec;181(6):1479-84.</span>
<span style="font-weight: bold">
Stimulated nitric oxide release and nitric oxide sensitivity in forearm arterial vasculature during
normotensive and preeclamptic pregnancy.</span>
<span style="font-weight: normal">
Anumba DO, Ford GA, Boys RJ, Robson SC. "Alterations in serotonin receptor coupling to nitric oxide
synthase, or a limitation of availability of the substrate for nitric oxide synthase (L-arginine) during
pregnancy, could account for the reduction in stimulated nitric oxide release."</span>
</p>
<p>
<span style="font-weight: normal">J Hypertens 1999 Mar;17(3):389-96.</span>
<span style="font-weight: bold">
U46619-mediated vasoconstriction of the fetal placental vasculature in vitro in normal and hypertensive
pregnancies.</span>
<span style="font-weight: normal">
Read MA, Leitch IM, Giles WB, Bisits AM, Boura AL, Walters WA.
</span>
</p>
<p>
<span style="font-weight: normal">Am J Obstet Gynecol 1999 Feb;180(2 Pt 1):371-7. </span>
<span style="font-weight: bold"
>Ketanserin versus dihydralazine in the management of severe early-onset preeclampsia: maternal
outcome.</span>
<span style="font-weight: normal">
Bolte AC, van Eyck J, Kanhai HH, Bruinse HW, van Geijn HP, Dekker GA. "Ketanserin [a selective serotonin
2 receptor blocker] is an attractive alternative in the management of severe early-onset
preeclampsia."</span>
</p>
<p>
<span style="font-weight: normal">Am J Obstet Gynecol 1996 Dec;175(6):1543-50</span>
<span style="font-weight: bold"
>. Novel appearance of placental nuclear monoamine oxidase: biochemical and histochemical evidence for
hyperserotonomic state in preeclampsia-eclampsia.</span>
<span style="font-weight: normal">
Gujrati VR, Shanker K, Vrat S, Chandravati, Parmar SS. "Placental serotonin increases with severity
(rsystolic 0.84, rdiastolic 0.83) and monoamine oxidase decreases (rsystolic 0.86, rdiastolic 0.79).
Placental monoamine oxidase showed marked changes in preeclampsia-eclampsia." ."A severity-dependent
decrease was present in the nuclei of placentas with preeclampsia-eclampsia." "The study delineates an
impaired catabolism of placental serotonin in preeclampsia-eclampsia." "The novel appearance of
monoamine oxidase in nuclei in proximity to its normal site and low activity resulting in a
hyperserotonomic state may lead to preeclampsia-eclampsia."</span>
</p>
<p>
<span style="font-weight: normal">Chung Hua Fu Chan Ko Tsa Chih 1996 Nov;31(11):670-2 </span>
<span style="font-weight: bold"
>[Changes of plasma levels of monoamines in normal pregnancy and pregnancy-induced hypertension women and
their significance].</span>
<span style="font-weight: normal">
Lin B, Zhu S, Shao B. "Compared with NP [normal pregnant], the contents of DA in moderate and severe PIH
[pregnancy-induced hypertension] were markedly and very markedly decreased respectively (P < 0.05 and
P < 0.01), while the levels of 5-HT in PIH increased significantly (P < 0.05)." "The changes of
monoamines may be one of the causes of small artery spasm in PIH."</span>
</p>
<p>
<span style="font-weight: normal">Lancet 1997 Nov 1;350(9087):1267-71. </span>
<span style="font-weight: bold"
>Randomised controlled trial of ketanserin and aspirin in prevention of pre-eclampsia.</span>
<span style="font-weight: normal"><hr /></span>
</p>
<p>
<span style="font-weight: normal">Osaka City Med J 1989 Jun;35(1):1-11.</span>
<span style="font-weight: bold">
Serotonin and tryptamine metabolism in the acute hepatic failure model: changes in tryptophan and its
metabolites in the liver, brain and kidney.</span>
<span style="font-weight: normal">
Kodama C, Mizoguchi Y, Kawada N, Sakagami Y, Seki S, Kobayashi K, Morisawa S.
</span>
</p>
<p>
<span style="font-weight: normal">Br J Pharmacol 1984 Apr;81(4):645-650.</span>
<span style="font-weight: bold">
Induction of hypoglycaemia and accumulation of 5-hydroxytryptamine in the liver after the injection of
mitogenic substances into mice.
</span>
<span style="font-weight: normal">Endo Y</span>
<span style="font-weight: bold">.</span>
</p>
<p>
<span style="font-weight: normal">Eur J Pharmacol 1983 Aug 5;91(4):493-499.</span>
<span style="font-weight: bold">
A lipopolysaccharide and concanavalin A induce variations of serotonin levels in mouse tissues.</span>
<span style="font-weight: normal"> Endo Y. </span>
</p>
<p>
<span style="font-weight: normal">Brain Res 1986 Jul 16;378(1):164-8 </span>
<span style="font-weight: bold">5-Hydroxytryptamine-2 antagonist increases human slow wave sleep.</span>
<span style="font-weight: normal">
Idzikowski C, Mills FJ, Glennard R Ritanserin, a specific 5-HT2 antagonist, was given to volunteers in a
double-blind placebo controlled sleep study. Slow wave sleep doubled in duration at the expense of stage
2. The finding that a serotonin antagonist changed the architecture of sleep without producing insomnia
is of fundamental importance and calls for a re-examination of traditional theories of sleep control
which assign a facilitatory role to serotonin.</span>
</p>
<p>
<span style="font-weight: normal">Med Hypotheses 2000 Apr;54(4):645-7</span>
<span style="font-weight: bold">
Role of the pineal gland in hibernators: a concept proposed to clarify why hibernators have to leave
torpor and sleep.</span>
<span style="font-weight: normal"> Kocsard-Varo G</span>
<span style="font-weight: bold">.</span>
<span style="font-weight: normal"> </span>
</p>
<p>
<span style="font-weight: normal">Chronobiol Int 2000 Mar;17(2):103-28.</span>
<span style="font-weight: bold">
The temporal organization of daily torpor and hibernation: circadian and circannual rhythms.</span>
<span style="font-weight: normal"> Kortner G, Geiser F.</span>
</p>
<p>
<span style="font-weight: normal">Neuroreport 2000 Mar 20;11(4):881-5 </span>
<span style="font-weight: bold"
>Slow waves in the sleep electroencephalogram after daily torpor are homeostatically regulated.</span>
<span style="font-weight: normal"> Deboer T, Tobler I.</span>
</p>
<p>
<span style="font-size: 10pt">Neuroendocrinology 1982 Jun; 34(6): 438-443.<span style="font-weight: bold">
Sleep organization in hypo- and hyperthyroid rats.
</span><span style="font-weight: normal">Carpenter AC, Timiras PS. "The results show an increased number
of awakenings during slow wave sleep (SWS) in hypothyroid animals, whereas total sleep time, levels
of SWS, paradoxical sleep, and diurnal organization were unaffected by thyroid status.
</span><span style="font-weight: bold"
>Our findings indicate that adequate levels of thyroid hormone are necessary to sustain extended periods
of SWS in the adult rat while hyperthyroid animals show no disruption of sleep organization.</span
><span style="font-weight: normal">
A corollary finding is that daily sleep quotas are independent of whole body metabolic rates."</span
></span>
</p>
© Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
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