|
SOME FACTORS IN STRESS, INSOMNIA AND THE BRAIN SYNDROMES:
Serotonin, an important
mediator of stress, shock, and inflammation, is a vasoconstrictor that
impairs circulation in a great variety of circumstances.
Stress impairs metabolism, and serotonin suppresses mitochondrial energy
production.
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.
Schizophrenia is one outcome of stress, both cumulative and acute. Prenatal
stress commonly predisposes a person to develop schizophrenia at a later
age.
Serotonins restriction of circulation to the uterus is a major factor
in toxemia of pregnancy and related complications of pregnancy.
Hypothyroidism increases serotonin activity in the body, as it increases
estrogen dominance.
Estrogen inhibits the enzyme monoamino oxidase (MAO), and is highly
associated with increased serotonin activity. Progesterone has the opposite
effect on MAO.
The frontal lobes of the brain are hypometabolic in schizophrenia. Serotonin
can cause vasoconstriction in the brain.
Serotonin release causes lipid peroxidation.
Schizophrenics have high levels of lipid peroxidation.
Antioxidants, including uric acid, are deficient in schizophrenics.
Therapies which improve mitochondrial respiration alleviate the symptoms
of schizophrenia.
Energy depletion leads to brain atrophy, but with normal stimulation
and nutrition even adult brains can grow.
Schizophrenics and depressed people have defective sleep.
Increasing the bodys energy level and temperature improves the quality
of sleep.
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 cant 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 dont adapt to societys norms. In a
society that chooses to destroy ecosystems, rather than adapting to
them, the question of sanity should be an everyday political issue.
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 isnt any scientific validity behind the terms. In
their historical senses, crazy (flawed) and insane (unsound) are probaby
more objective terms than the medically-invented terms, dementia praecox
(premature idiocy) or schizophrenia (divided mind).
Odd Speech is one of the dimensions used in the diagnosis of insanity.
I am reminded of William Wordsworths dismissal of William Blake as insane
after failing to understand some of Blakes poems--Wordsworth was conventional
enough to become Englands Poet Laureate, and to his limited perspective,
Blakes clear verses were incomprehensibly odd.
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.
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 its 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.
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.
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 hasnt 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.
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.
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.
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.
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.
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.
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.
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 excess of that prostaglandin
mimics the symptoms of psychosis.
The drug industrys 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 only at the surface of cells, and
not inside the cells.
The consequences of this mistake have been catastrophic. For example,
serotonins 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 industrys 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.
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.
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.
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 doesnt 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.
Oliver Gillie (in his book, Who Do You Think You Are?) 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 wont allow their readers to see criticisms of it.
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.
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:
The defective baby was the cause of a difficult birth. That argument
has recently been discredited (McNeil and Cantor-Graae, 1999).
Schizophrenics are known to have had a higher rate of obstetrical complications,
including oxygen deprivation and Cesarian deliveries, than normal people.
Like people with Alzheimers disease, the circumference of their heads
at birth was small, in proportion to their body weight and gestational
age.
Animal studies show that perinatal brain problems tend to persist, influencing
the brains metabolism and function in adulthood.
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.
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.
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, doesnt decrease
immediately. Nothing detectable happens to the neurotransmitters, synapses,
or membrane structures in this short period; 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.
In this context, I think its 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 patients physiology and history.
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.
The idea that schizophrenia is a disease in itself tends to distract
attention from the things it has in common with Alzheimers 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.
For the present, its 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.
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.
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.
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.
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.
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.
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.
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 isnt like non-REM deep
sleep, and in fact seems to be like wakefulness, in the sense
that a sleep-debt is incurred: 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.
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.
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.
(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 wouldnt be very interesting to pharmacologists
looking for transmitter-specific drugs.)
Torpor is the opposite of restful sleep, and with aging, depression,
hypothyroidism, and a variety of brain syndromes, sleep tends toward
the hypothermic torpor.
An individual cell behaves analogously to the whole person. A babys
high energy resting state is paralleled by the stable condition of a
cell that is abundantly charged with energy; ATP and carbon dioxide
are at high levels in these cells. Progesterones effects on nerve cells
include favoring the high energy resting state, and this is closely
involved in progesterones thermogenic effect, in which it raises the
temperature set-point.
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.
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.
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.
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.
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.
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.
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 sodiums that we can get clues to sodiums actions
by watching what lithium does.
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.
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 lithiums 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).
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.
REFERENCES
Gen Pharmacol 1994 Oct;25(6):1257-1262. Serotonin-induced decrease
in brain ATP, stimulation of brain anaerobic glycolysis and elevation
of plasma hemoglobin; the protective action of calmodulin antagonists.
Koren-Schwartzer N, Chen-Zion M, Ben-Porat H, Beitner R Department of
Life Sciences, Bar-Ilan University, Ramat Gan, Israel. 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 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.. Injection of serotonin
also induced a marked elevation of plasma hemoglobin, reflecting lysed
erythrocytes, which was also prevented by treatment with the CaM
antagonists. 5. 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.
WMJ 1990 Nov-Dec;62(6):93-7. [Effect of inflammatory mediators
on respiration in rat liver mitochondria]. Semenov VL.
Vopr Med Khim 1990 Sep-Oct;36(5):18-21 [Regulation by biogenic amines
of energy functions of mitochondria]. Medvedev A.E. Biogenic amines
(phenylethylamine, tyramine, dopamine, tryptamine, serotonin and
spermine) decreased activities of the rotenone-insensitive NADH-cytochrome
c reductase, the succinate cytochrome c reductase and the succinate
dehydrogenase.
Vopr Med Khim 1991 Sep-Oct;37(5):2-6. [The role of monoamine oxidase
in the regulation of mitochondrial energy functions]. Medvedev AE,
Gorkin VZ.
Lik Sprava 1997 Jan-Feb;(1):61-5. [Microhemodynamics and energy metabolism
in schizophrenia patients]. Kut'ko II, Frolov VM, Rachkauskas GS,
Pavlenko VV, Petrunia AM. An apparent disturbance was revealed in microhaemodynamics
of patients diagnosed as having schizophrenia (n = 210) which was more
pronounced in continuously progredient form of the above medical condition.
An increase in conjunctival indexes, polymorphic character of capillaries,
decrease in numbers of capillary loops were revealed by biomicroscopy
of the bulbar conjunctiva and capillaroscopy respectively. The patients
showed lowering of ATP level and rise in the content of cathodic LDG4-LDG5
fractions, accumulation in blood of lactic and pyruvic acids.
Schizophr Res 1996 Oct 18;22(1):41-7. Are reduced head circumference
at birth and increased obstetric complications associated only with
schizophrenic psychosis? A comparison with schizo-affective and unspecified
functional psychoses. McNeil TF, Cantor-Graae E, Nordstrom LG, Rosenlund
T.
Schizophr Res 1993 Jun;10(1):7-14. Puberty and the onset of psychosis.
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) onset of psychosis in females would be related to menarche.
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.
Int J Psychophysiol 1999 Dec;34(3):237-47. Timing of puberty and
syndromes of schizotypy: a replication. Kaiser J, Gruzelier JH.
Active syndrome findings were confined to the male subsample with late
maturing males showing higher scores on the Cognitive Failures and
Odd Speech 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.
Am J Physiol 1978 Mar;234(3):H300-4. Potentiation of the cerebrovascular
response to intra-arterial 5-hydroxytryptamine. 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. 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. 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).
FASEB J 1989 Apr;3(6):1753-9. Steroid regulation of monoamine oxidase
activity in the adrenal medulla. 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 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,
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.
J Pharmacol Exp Ther 1984 Apr;229(1):244-9 Mechanisms of specific
change by estradiol in sensitivity of rat uterus to serotonin. Ichida
S, Oda Y, Tokunaga H, Hayashi T, Murakami T, Kita T.
Neuroendocrinology 1983;36 (3): 235-41. Gonadal hormone regulation
of MAO and other enzymes in hypothalamic areas. 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. 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.
Administration of the protein synthesis inhibitor anisomycin prior to
progesterone 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.
J Neurochem 1981 Sep;37(3):640-8. Gonadal influences on the sexual
differentiation of monoamine oxidase type A and B activities in the
rat brain. Vaccari A, Caviglia A, Sparatore A, Biassoni R When
masculinization was prevented by neonatal administration of estradiol
(E) 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. The activity of MAO-A was also decreased by high concentrations
of E or TS in vitro. The imprinting for patterns of hypothalamic
MAO-A and MAO-B in the two sexes results, probably, from genetic predetermination.
Gynecol Obstet Invest 2000;49(3):150-5. Transport and metabolism
of serotonin in the human placenta from normal and severely pre-eclamptic
pregnancies. 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 are mainly due to a reduction
in MAO-A activity and not limited by the rate of serotonin uptake
into the cells.
Psychiatry Res 1989 Jun;28(3):279-88. Acetazolamide and thiamine:
an ancillary therapy for chronic mental illness. 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. Overall, 50%
of the patients showed improvement on all assessment scales. 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.
J Neural Transm 1998;105(8-9):975-86. Role of tryptophan in the elevated
serotonin-turnover in hepatic encephalopathy. 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).
J Neurosci Res 1981;6(2):225-36 A difference in the in vivo cerebral
production of [1-14C] lactate from D-[3-14C] glucose in chronic mental
patients. 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.
Ther Umsch 2000 Feb;57(2):76-80. [Antidepressive therapy by modifying
sleep]. Haug HJ, Fahndrich E.
Schizophr Res 1998 Jun 22;32(1):1-8. Reduced status of plasma total
antioxidant capacity in schizophrenia. Yao JK, Reddy R, McElhinny
LG, van Kammen DP.
FASEB J 1998 Dec;12(15):1777-83. Increased F2-isoprostanes in Alzheimer's
disease: evidence for enhanced lipid peroxidation in vivo. Pratico
D, MY Lee V, Trojanowski JQ, Rokach J, Fitzgerald GA.
Dis Nerv Syst 1976 Feb;37(2):98-103. Glucose-insulin metabolism in
chronic schizophrenia. Brambilla F, Guastalla A, Guerrini A, Riggi
F, Rovere C, Zanoboni A, Zanoboni-Muciaccia W.
Psychiatr Clin (Basel) 1975;8(6):304-13. Blood flow and oxidative
metabolism of the brain in patients with schizophrenia. Hoyer S,
Oesterreich K.
Zh Nevropatol Psikhiatr Im S S Korsakova 1977;77(8):1179-86 [Effect
of lithium on the energy metabolism of nervous tissue]. Gulidova
GP, Khzardzhian VG, Mikhailova NM.
"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."
Ateneo Parmense Acta Biomed 1975 Jan-Apr;46(1-2):5-19. [Clinical
significance of changes in tryptophan metabolism]. Ambanelli U,
Manganelli P. "The oxidative pathway is most important of the metabolic
pathway of the amino acid; the degredation of tryptophan is
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)."
Acta Neurol Scand Suppl 1977;64:534-5. Blood flow and oxidative metabolism
of the brain in the course of acute schizophrenia. Hoyer S, Oesterreich
K.
Med Hypotheses 1994 Dec;43(6):420-35 Schizophrenia is a diabetic
brain state: an elucidation of impaired neurometabolism. Holden
RJ, Mooney PA.
Neuropsychobiology 1990-91;24(1):1-7. Frontality, laterality, and
cortical-subcortical gradient of cerebral blood flow in schizophrenia:
relationship to symptoms and neuropsychological functions. Sagawa
K, Kawakatsu S, Komatani A, Totsuka S.
Schizophr Res 1989 Nov-Dec;2(6):439-48. Effect of attention on frontal
distribution of delta activity and cerebral metabolic rate in schizophrenia.
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 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.
Br J Psychiatry 1990 Feb;156:216-27. Glucose metabolic rate in
normals and schizophrenics during the Continuous Performance Test assessed
by positron emission tomography. 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 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.
Psychol Med 1994 Nov;24(4):947-55. Patterns of cortical activity
in schizophrenia. Schroeder J, Buchsbaum MS, Siegel BV, Geider FJ,
Haier RJ, Lohr J, Wu J, Potkin SG. Schizophrenics were significantly
more hypofrontal than the controls, with higher values on the 'parietal
cortex and motor strip' factor and a trend towards higher values in
the temporal cortex. A canonical discriminant analysis confirmed
that the 'hypofrontality' and 'parietal cortex and motor strip' factors
accurately separated the schizophrenic group from the healthy controls.
Schizophr Res 1996 Mar;19(1):41-53. Cerebral metabolic activity
correlates of subsyndromes in chronic schizophrenia. Schroder J,
Buchsbaum MS, Siegel BV, Geider FJ, Lohr J, Tang C, Wu J, Potkin SG.
The delusional cluster showed a significantly reduced hippocampal
activity, while the negative symptoms cluster presented with a prominent
hypofrontality and significantly increased left temporal cortex values.
Psychiatry Res 1997 Oct 31;75(3):131-44. Cerebral glucose metabolism
in childhood onset schizophrenia. 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.
Pharmacol Biochem Behav 1990 Apr; 35(4):955-62. The effects of ondansetron,
a 5-HT3 receptor antagonist, on cognition in rodents and primates.
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 conclude that ondansetron
potently improves basal performance in rodent and primate tests of cognition
and inhibits the impairments in performance caused by cholinergic deficits.
Pharmacol Biochem Behav 1992 May;42(1):75-83. Ondansetron and arecoline
prevent scopolamine-induced cognitive deficits in the marmoset. Carey
GJ, Costall B, Domeney AM, Gerrard PA, Jones DN, Naylor RJ, Tyers MB
School of Pharmacy, University of Bradford, UK. 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.
J Comp Physiol Psychol 1977 Jun;91(3): 642-8. Tryptophan and
tonic immobility in chickens: effects of dietary and systemic manipulations.
Gallup GG Jr, Wallnau LB, Boren JL, Gagliardi GJ, Maser JD, Edson PH.
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. Dietary replacement served to reinstate
the response. The data are discussed in light of evidence showing
serotonergic involvement in tonic immobility.
J Neurosci Res 1995 Feb 15;40(3):407-413. Endotoxin administration
stimulates cerebral catecholamine release in freely moving rats as assessed
by microdialysis. Lavicky J, Dunn AJ.
J Neurosci Res 1998 Feb 15;51(4):517-525. Lipopolysaccharide regulates
both serotonin- and thrombin-induced intracellular calcium mobilization
in rat C6 glioma cells: possible involvement of nitric oxide synthase-mediated
pathway. Tawara Y, Kagaya A, Uchitomi Y, Horiguchi J, Yamawaki S.
Life Sci 1997;61(18):1819-1827. Serotonin 5HT2A receptor activation
inhibits inducible nitric oxide synthase activity in C6 glioma cells.
Miller KJ, Mariano CL, Cruz WR.
Harefuah 2000 May 15;138(10):809-12, 910. [Jet lag causing or exacerbating
psychiatric disorders]. 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.
Life Sci 1987 May 18;40(20):2031-9. Dysfunction in a prefrontal substrate
of sustained attention in schizophrenia. 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 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.
Acta Psychiatr Scand 1987 Dec;76(6):628-41. Regional brain glucose
metabolism in drug free schizophrenic patients and clinical correlates.
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.
Chung Hua Shen Ching Ching Shen Ko Tsa Chih 1991 Oct;24(5):268-71, 316-7.
[Developments observation of serum thyrohormone level in schizophrenics.
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.
Biol Psychiatry 1991 Mar
1;29(5):457-66. Multidimensional hormonal discrimination of paranoid
schizophrenic from bipolar manic patients. Mason JW, Kosten TR,
Giller EL.
Zh Nevropatol Psikhiatr Im S S Korsakova 1991;91(1):122-3 [Status
of the thyroid gland in patients with schizophrenia]. 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.
Can J Psychiatry 1990 May;35(4):342-3. Increased detection of elevated
TSH using immunoradiometric assay. 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.
Metabolism 1990 May;39(5):538-43. Serum thyrotropin in hospitalized
psychiatric patients: evidence for hyperthyrotropinemia as measured
by an ultrasensitive thyrotropin assay. Chopra IJ, Solomon DH, Huang
TS.
J Nerv Ment Dis 1989 Jun;177(6):351-8. Serum thyroxine levels in
schizophrenic and affective disorder diagnostic subgroups. Mason
JW, Kennedy JL, Kosten TR, Giller EL Jr.. 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.
Biol Psychiatry 1989 Jan;25(1):67-74. Serum thyroxine change
and clinical recovery in psychiatric inpatients. 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.
J Clin Psychiatry 1980
Sep;41(9):316-8. Myxedema psychosis--insanity defense in homicide.
Easson WM.
Int J Psychiatry Med 1988;18(3):263-70. The diagnostic dilemma of
myxedema and madness, axis I and axis II: a longitudinal case report.
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.
P R Health Sci J 1993 Jun;12(2):85-7.
[Alzheimer's disease: the untold story]. 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.
Psychiatry Res 1998 Jul 27;80(1):29-39. Reduced level of plasma antioxidant
uric acid in schizophrenia. Yao JK, Reddy R, van Kammen DP. There
is evidence of dysregulation of the antioxidant defense system in schizophrenia.
The purpose of the present study was to examine whether uric acid, a
potent antioxidant, is reduced in the plasma of patients with schizophrenia.
Male schizophrenic patients with either a haloperidol treatment (n=47)
or a drug-free condition (n=35) had significantly lower levels of plasma
uric acid than the age- and sex-matched normal control subjects (n=34).
In addition, the plasma levels of uric acid in patient groups were significantly
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 selective antioxidant provides
additional support to the hypothesis that oxidative stress in schizophrenia
may be due to a defect in the antioxidant defense system.
Zh Nevropatol Psikhiatr
Im S S Korsakova 1989; 89(5):108-10. [Lipid peroxidation processes
in patients with schizophrenia]. Kovaleva ES, Orlov ON, Tsutsu'lkovskaia
MIa, Vladimirova TV, Beliaev BS.
Zh Nevropatol Psikhiatr Im S S Korsakova 1991;91(7):121-4. [Significance
of disorders of the processes of lipid peroxidation in patients with
persistent paranoid schizophrenia resistant to the treatment]. Govorin
NV, Govorin AV, Skazhutin SA.
Patol Fiziol Eksp Ter 1999
Jul-Sep;(3):19-22. [The biogenic amine content of rat tissues in
the postresuscitation period following hemorrhagic shock and the effect
of the preparation semax]. 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.
Prostaglandins Leukot Essent
Fatty Acids 1996 Aug;55(1-2):33-43. Free radical pathology in schizophrenia:
a review. Reddy RD, Yao JK.
Schizophr Res 1996 Mar;19(1):19-26. Impaired antioxidant defense
at the onset of psychosis. Mukerjee S, Mahadik SP, Scheffer R, Correnti
EE, Kelkar H.
Biol Psychiatry 1998 May 1;43(9):674-9. Elevated plasma lipid peroxides
at the onset of nonaffective psychosis. Mahadik SP, Mukherjee S,
Scheffer R, Correnti EE, Mahadik JS.
Brain Res 1999 Aug 21;839(1):74-84.
Psychological stress-induced enhancement of brain lipid peroxidation
via nitric oxide systems and its modulation by anxiolytic and anxiogenic
drugs in mice. 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.
Anesteziol Reanimatol 1998 Nov-Dec; (6):20-5. [Role of hyperbaric
oxygenation in the treatment of posthypoxic encephalopathy of toxic
etiology]. 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, decreased endotoxicosis, reduced psychopathological
and neurological disorders, and promoted social adaptation.
J Neurochem 2000 Jan; 74(1): 114-24. Metabolic impairment elicits
brain cell type-selective changes in oxidative stress and cell death
in culture. 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.
Psychol Med 1976 Aug;6(3):359-69. Possible association of schizophrenia
with a disturbance in prostaglandin metabolism: a physiological hypothesis.
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,
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.
Zh Nevropatol Psikhiatr
Im S S Korsakova 1966;66(6):912-7. [Treatment of acute schizophrenia
with antibiotics, gamma-globulin and vitamins]. Neikoya M.
Prostaglandins Med 1979 Jan;2(1):77-80. Penicillin and essential
fatty acid supplementation in schizophrenia. Vaddadi KS.
Psychiatr Dev 1989 Spring;7(1):19-47. Positron emission tomography
in psychiatry. 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.
Arch Gen Psychiatry 1976
Nov;33(11):1377-81. Platelet monamine oxidase in chronic schizophrenia.
Some enzyme characteristics relevant to reduced activity. 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.
Exp Neurol 1997 May;145(1):118-29. Long-term reciprocal changes in
dopamine levels in prefrontal cortex versus nucleus accumbens in rats
born by Caesarean section compared to vaginal birth. 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 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 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
in the central nervous system of the rat.
Rehabilitation (Stuttg) 1983 May;22(2):81-5 [Physical capacity of
schizophrenic patients]. Deimel H, Lohmann S.
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 in
respect of the aerobic-anaerobic threshold.
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.
Folia Psychiatr Neurol Jpn 1984;38(4):425-36 Antipsychotic and prophylactic
effects of acetazolamide (Diamox) on atypical psychosis. 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, 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. The high therapeutic
effects of acetazolamide were shown in the cases whose symptoms were
aggravated at the interval of the menstrual cycle. 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. Since side effects due to acetazolamide
were rarely observed, the present drug was considered to have a high
safety margin.
Am J Psychiatry 1999 Apr;156(4):617-23 Minor physical anomalies,
dermatoglyphic asymmetries, and cortisol levels in adolescents with
schizotypal personality disorder. 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.
Am J Psychiatry 1992 Jan;149(1):57-61 Congenital malformations and
structural developmental anomalies in groups at high risk for psychosis.
McNeil TF, Blennow G, Lundberg L. The inferred genetic risk for
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.
Schizophr Bull 1984;10(2):204-32. Psychophysiological dysfunctions
in the developmental course of schizophrenic disorders. Dawson ME,
Nuechterlein KH. Two electrodermal anomalies are identified in different
subgroups of symptomatic patients: (1) an abnormally high sympathetic
arousal and (2) an abnormal absence of skin conductance orienting responses
to innocuous environmental stimuli.
Behav Brain Res 2000 Jan;107(1-2):71-83. Changes in adult brain and
behavior caused by neonatal limbic damage: implications for the etiology
of schizophrenia. 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.
Neurochem Res 1996 Sep; 21(9):995-1004. Mitochondrial involvement
in schizophrenia and other functional psychoses. 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.
Eur J Pharmacol 1994 Aug
11;261(1-2):25-32. The effect of alpha 2-adrenoceptor antagonists
in isolated globally ischemic rat hearts. Sargent CA, Dzwonczyk
S, Grover GJ. The alpha 2-adrenoceptor antagonist, yohimbine, has been
reported to protect hypoxic myocardium. Yohimbine has several other
activities, including 5-HT receptor antagonism, at the concentrations
at which protection was found. The 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.
J Cardiovasc Pharmacol 1993 Oct;22(4):664-672. Protective effect
of serotonin (5-HT2) receptor antagonists in ischemic rat hearts.
Grover GJ, Sargent CA, Dzwonczyk S, Normandin DE, Antonaccio MJ.
J Appl Physiol 1994 Jul;77(1):277-284. Aerobic muscle contraction
impaired by serotonin-mediated vasoconstriction. Dora KA, Rattigan
S, Colquhoun EQ, Clark MG.
J Cereb Blood Flow Metab 1995 Jul;15(4):706-13. Enhanced cerebrovascular
responsiveness to hypercapnia following depletion of central serotonergic
terminals. Kelly PA, Ritchie IM, McBean DE, Sharkey J, Olverman
HJ.
Arch Gen Psychiatry 1984 Mar;41(3): 293-300. Regional brain glucose
metabolism in chronic schizophrenia. A positron emission transaxial
tomographic study. Farkas T, Wolf AP, Jaeger J, Brodie JD, Christman
DR, Fowler JS. . . . schizophrenics had significantly lower activity
in the frontal lobes, relative to posterior regions.
Semin Nucl Med 1986
Jan;16(1):2-34. Positron emission tomography imaging of regional
cerebral glucose metabolism. 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.
Schizophr Bull 1988; 14(2): 169-76. From syndrome to illness: delineating
the pathophysiology of schizophrenia with PET. 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
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.
Biol Psychiatry 1989 Apr
1;25(7):835-51. Increased temporal lobe glucose use in chronic schizophrenic
patients. 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 metabolic activity in the left than the right anterior temporal
lobe, and the extent of this lateralization was in proportion to the
severity of psychopathology.
Am J Obstet Gynecol 1999 Dec;181(6):1479-84. Stimulated nitric oxide
release and nitric oxide sensitivity in forearm arterial vasculature
during normotensive and preeclamptic pregnancy. 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.
J Hypertens 1999 Mar;17(3):389-96. U46619-mediated vasoconstriction
of the fetal placental vasculature in vitro in normal and hypertensive
pregnancies. Read MA, Leitch IM, Giles WB, Bisits AM, Boura AL,
Walters WA.
Am J Obstet Gynecol 1999 Feb;180(2 Pt 1):371-7. Ketanserin versus
dihydralazine in the management of severe early-onset preeclampsia:
maternal outcome. 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.
Am J Obstet Gynecol 1996
Dec;175(6):1543-50. Novel appearance of placental nuclear monoamine
oxidase: biochemical and histochemical evidence for hyperserotonomic
state in preeclampsia-eclampsia. 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.
Chung Hua Fu Chan Ko Tsa Chih 1996 Nov;31(11):670-2 [Changes of plasma
levels of monoamines in normal pregnancy and pregnancy-induced hypertension
women and their significance]. 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.
Lancet 1997 Nov 1;350(9087):1267-71. Randomised controlled trial
of ketanserin and aspirin in prevention of pre-eclampsia. Steyn
DW, Odendaal HJ. Pre-eclampsia is associated with extensive endothelial-cell
damage and platelet activation, resulting in lower production of vasodilator
prostaglandins and increased release of the vasoconstrictors thromboxane
A2 and serotonin. We investigated the role of ketanserin, a selective
serotonin-2-receptor antagonist, in lowering the rate of pre-eclampsia
among pregnant women with mild to moderate hypertension. There were
significantly fewer cases of pre-eclampsia (two vs 13; relative risk
0.15 [95% CI 0.04-0.66], p = 0.006) and severe hypertension (six vs
17; p = 0.02) in the ketanserin than in the placebo group. There was
also a trend towards less perinatal mortality (one vs six deaths) but
this was not significant (p = 0.28). Rates of abruptio placentae and
pre-eclampsia before 34 weeks' gestation were lower in the ketanserin
group, and mean birthweight was significantly higher.
Osaka City Med J 1989 Jun;35(1):1-11. Serotonin and tryptamine metabolism
in the acute hepatic failure model: changes in tryptophan and its metabolites
in the liver, brain and kidney. Kodama C, Mizoguchi Y, Kawada N,
Sakagami Y, Seki S, Kobayashi K, Morisawa S.
Br J Pharmacol 1984 Apr;81(4):645-650. Induction of hypoglycaemia
and accumulation of 5-hydroxytryptamine in the liver after the injection
of mitogenic substances into mice.
Endo Y.
Eur J Pharmacol 1983 Aug 5;91(4):493-499. A lipopolysaccharide
and concanavalin A induce variations of serotonin levels in mouse tissues.
Endo Y.
Brain Res 1986 Jul 16;378(1):164-8
5-Hydroxytryptamine-2 antagonist increases human slow wave sleep.
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.
Med Hypotheses 2000 Apr;54(4):645-7 Role of the pineal gland in hibernators:
a concept proposed to clarify why hibernators have to leave torpor and
sleep. Kocsard-Varo G.
Chronobiol Int 2000 Mar;17(2):103-28. The temporal organization of
daily torpor and hibernation: circadian and circannual rhythms.
Kortner G, Geiser F.
Neuroreport 2000 Mar 20;11(4):881-5 Slow waves in the sleep electroencephalogram
after daily torpor are homeostatically regulated. Deboer T, Tobler
I.
Neuroendocrinology 1982
Jun; 34(6): 438-443. Sleep organization in hypo- and hyperthyroid
rats. 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. 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. A corollary finding is that daily sleep quotas
are independent of whole body metabolic rates.