Copyright ă 1996 Revised from
1985 by James Michael Howard.
(Note: I am in the process of
reconsidering my interpretation of "hyperprolactenemia" for this
treatise. At this moment, I refer you to my article "Hypothetical
Explanation of Panic Disorder" at www.anthropogeny.com/physiology.html for my current understanding of DHEAS and
hyperprolactinemia. This does not affect my explanation of schizophrenia.)
Added April 9, 2004: As
part of my explanation of schizophrenia, I have suspected that the
"hyperprolactinemia" induced by many antipsychotics meant that this
probably increased DHEA. Since prolactin
stimulates DHEA, I thought this meant that the increased prolactin probably
increased the DHEA. Since I produced my
explanation of "panic disorder," I have changed this view. I think hyperprolactemia occurs when DHEA is
reduced. That is, DHEA in proper amounts
feeds back to shut down prolactin production.
So, the antipsychotics produce their effect by reducing DHEA. This helps because it decreases DHEA
activation of the over active structures in schizophrenics. This fits with the FDA report about
"clozapine" causing diabetes and hyperglycemia of today's date. DHEA is useful against diabetes and
hyperglycemia so clozapine also works by reducing DHEA. Therefore, I have to change my explanation of
how antipsychotic drugs help with schizophrenics with that of this post of April
9, 2004. (Copyright 2004, James Michael Howard,
I suggest schizophrenia is caused by low
availability of the adrenal hormone, DHEA, and the pineal hormone, melatonin,
during critical times of brain development. Reduced DHEA reduces growth and
development of the cerebral hemispheres. Later in life, events occur that
decrease the availability of DHEA, in addition to already low DHEA; this
reduces function in under-developed areas of the brain and produces
schizophrenia. This pattern has been noticed in the past, but this explanation
is an entirely new theory.
"The
data are more consistent with a neurodevelopmental model in which a fixed
‘lesion’ from early in life interacts with normal brain maturational events
that occur much later." (Archives of General Psychiatry 1987, 44:
660)
DHEA naturally begins to decline around age
twenty to twenty-five, and this probably occurs earlier in schizophrenics. In
addition to this decline, interference with the availability of DHEA may occur
because of another adrenal hormone, cortisol, and, beginning at puberty, the
hormone, testosterone. DHEA exerts a very positive effect on growth of the
basic unit of the brain, the neuron: "DHEA greatly increases neuronal
survival and differentiation" (J. Neuroscience Research 1987, 17:
225). The cerebral cortex of the brain is mainly "gray matter," which
is mainly neurons. Schizophrenics exhibit significantly low DHEA (Biological
Psychiatry 1973, 6: 23), which I think is the cause of their
significantly reduced cerebral cortices (Archives of General Psychiatry
1992, 49: 195). That is, low DHEA during brain development may result in
impaired cerebral development, and reduced DHEA later in life produces a
dysfunction that is called schizophrenia. Schizophrenia is a term applied to
numerous types of brain dysfunction. The connection of low DHEA to all of these
is that different parts of the brain are affected differently by lack of proper
development. The results of low DHEA during brain development will be different
in different individuals. Therefore, low DHEA can be directly involved in
reduced cerebral development that results in a varying neuropathy. However,
similarities exist that unite this group of symptoms under the term
"schizophrenia." There are other similarities not often mentioned
that I think also result from low DHEA; let me give you some examples. DHEA is
low in schizophrenia, AIDS, and Alzheimer’s disease (Biological Psychiatry
1991, 30: 688); diseases which I think result from low DHEA. Olfactory
deficits occur in all three; schizophrenia (Biological Psychiatry 1988, 23:
123), Alzheimer’s disease (Biological Psychiatry 1986, 21: 116)
and in HIV (AIDS virus) infection (American J. Psychiatry 1991, 148:
248). Schizophrenics exhibit decreased activity in the prefrontal areas and
increased activity in the basal ganglia (American J. Psychiatry 1985, 142:
564). This brain pattern is identical in advanced AIDS (Science 1988, 239:
587). These similarities are due to low DHEA. A cytokine (immune cell
activator) known simply as IL-2 is also low in schizophrenia and AIDS, both of
which I attribute to low DHEA.
In my articles on evolution and sleep at this
website, I connect the pineal hormone, melatonin, with DHEA. I suggest
melatonin may be involved in producing receptors, chemical doorways, for DHEA.
For DHEA to produce its growth promoting activities on neurons, it must have a
pathway into the neuron. Melatonin stimulates these receptor at night. I think
this pathway is reduced in schizophrenics, because nighttime melatonin is
reduced in schizophrenia (Biological Psychiatry 1989, 25: 500).
Proper amounts of melatonin are necessary for slow wave sleep to occur; the
deepest stage of slow wave sleep is stage 4. Lack of stage 4 sleep is
documented in schizophrenia. The second quotation below shows that others think
reduced melatonin may be involved in some forms of schizophrenia, however, the
investigators do not mention DHEA.
"In
1965, Lairy and co-workers noted a relative dearth of stage 4 (S4) in the sleep
of delusional schizophrenic patients. In a more systematic study, Caldwell and
Domino demonstrated a 50% reduction of mean S4 sleep in 25 unmedicated
schizophrenic patients as compared with ten medical student controls. This
finding has since bee repeatedly confirmed in both acute and chronic
schizophrenics and with precise control for age and some control for
hospitalization." (Archives of General Psychiatry 1985, 42:
797)
"It
has long been suggested that abnormal functions of the pineal gland may be
implicated in the pathophysiology of schizophrenia. We present evidence
proposing that diminished melatonin secretion may be associated with the
pathophysiology of a subgroup of schizophrenic patients characterized by
cerebral atrophy and ventricular enlargement, negative symptoms, impaired
cognitive and psychosexual development, onset at pubescence, poor response to
neuroleptic medication, and possible increased risk of extrapyramidal symptoms.
This view holds that a subnormal plasma melatonin level may be a marker of a
subgroup of schizophrenia and may also denote a specific genetic
susceptibility." (Schizophrenia Bulletin 1990, 16: 653)
In the following quotation, a reason for
reduced melatonin in schizophrenics is reported. The pineal gland produces
melatonin, and this gland normally begins to "calcify" as production
of melatonin decreases. Abnormalities occur in the pineal gland of
schizophrenics. The frontal lobes of the brains of schizophrenics show reduced
function, reduced development, and frontal atrophy. The following quotation
demonstrates that pineal calcification (PC) is connected with frontal lobe
atrophy in schizophrenics.
"Results
of the first study revealed that the presence of PC was significantly
associated with measurements of prefrontal cortical atrophy (p less than .01),
while there was no association with measurements of parieto-occipital atrophy,
sulcal prominence, or ventricular brain ratio (VBR). These findings support the
notion that the various structural brain abnormalities in schizophrenia may
reflect different pathological processes and that abnormal pineal melatonin
functions may be associated with the pathophysiology of prefrontal cortical
atrophy. In addition, since some clinical facets of schizophrenia covary with
frontal lobe dysfunction, our findings highlight the significance of abnormal
pineal functions for the pathophysiology of schizophrenia. In the second study
we found a significantly higher prevalence of pathologically enlarged PC (i.e.,
greater than 1 cm in diameter) in schizophrenia as compared to controls of
similar age. In addition, we found a significant association between CT scan
measurements of cortical atrophy and pathologically enlarged PC size (p less
than .05). By contrast, PC size was unrelated to VBR. These findings
demonstrate a specific association between pathologically enlarged PC and
cortical atrophy in schizophrenia. The implications of these findings to the
pathophysiology of schizophrenia and, specifically, to the morphological
abnormalities that accompany the disease are discussed." (International
J. Neuroscience 1991, 57: 179)
My sleep mechanism connects melatonin, DHEA,
and a hormone released by the pituitary gland, prolactin . Basically, sleep
occurs as our supply of DHEA is used up at the end of the day. This reduction
in DHEA allows melatonin to be released. Melatonin release momentarily reduces
prolactin release; prolactin is a stimulator of DHEA production. This reduction
in prolactin release reduces the level of DHEA further, and deep sleep (slow
wave sleep) occurs. Melatonin and prolactin alternate so that DHEA does not
fall too low; a small production of DHEA is necessary to maintain brainstem
activity (heart and breathing) during sleep. As melatonin is used up during
sleep, the level of DHEA increases periodically upon stimulation by prolactin.
Sometimes the DHEA reaches a high enough level to activate the brain without
causing consciousness; these are times of REM (rapid eye movement) or dream
sleep. As melatonin is used up, awakening occurs because of higher levels of
DHEA and, again, melatonin release is inhibited. This is the circadian rhythm
of sleep and consciousness.
Melatonin is low in schizophrenics. I suggest
this causes the abnormalities in prolactin release reported in the following
quotation. That is, prolactin release at night is very elevated, because of
lack of melatonin repression of prolactin release. The "rebound" of
prolactin in this case is exaggerated. To properly interpret the rest of this
quotation, you should know that DHEA and cortisol, another adrenal hormone, are
frequently released together. Prolactin is specific for stimulating DHEA, but
another pituitary hormone that is usually released with prolactin, called ACTH,
will stimulate both DHEA and cortisol. The investigators found that cortisol
levels and timing were normal. I interpret this to mean that the reduced DHEA
of sleep is not being produced in normal amounts. My sleep mechanism states that
slightly elevated DHEA during sleep is the cause of rapid eye movement sleep,
and melatonin is necessary for slow wave sleep. The latency to sleep, according
to my mechanism, is determined by the amount of melatonin. A person with low
melatonin will have a "prolonged sleep latency." (They will have
trouble going to sleep.) It is reported below that "The major sleep
abnormalities [of schizophrenics] were a prolonged sleep latency and a
reduction in total rapid eye movement stage sleep." These are due to lack
of melatonin and DHEA.
"The
major abnormality of neuroendocrine release that was observed in the
schizophrenic patients was an almost threefold enhancement of the sleep-related
increase in the prolactin level, associated with an intensified frequency of
nocturnal prolactin pulses. This increased stimulatory effect of sleep on
prolactin secretion was evident immediately after sleep onset. The normal
inhibition of cortisol secretion during early sleep was absent in schizophrenic
patients. The major sleep abnormalities were a prolonged sleep latency and a
reduction in total rapid eye movement stage sleep. During wakefulness,
prolactin and cortisol levels were normal. ...Both the amplitude and the timing
of the cortisol rhythm were normal." (Archives of General Psychiatry
1991, 48: 348)
Schizophrenia occurs when DHEA availability
is reduced in late teens or early twenties. Since reduced melatonin is
producing few receptors for DHEA, anything that will reduce the limited
supplies of DHEA of schizophrenics will dramatically reduce its positive
effects on the brain. DHEA stimulates metabolism, especially in the brain .
This is most pronounced in the frontal areas of schizophrenics, who are known
to exhibit reduced frontal metabolism.
The stress hormone, cortisol, and
testosterone both reduce the availability of DHEA. Schizophrenia is often
started by, but not caused, by stress. Cortisol evolved as the direct
physiological modulator of DHEA; it is produced to inhibit the actions of DHEA.
The ratio of DHEA to cortisol is the basis of the "fight or flight"
mechanism. That is, DHEA activates the brain, while cortisol does the opposite.
If the ratio is high in DHEA, the person will confront the source of stress;
the person will retreat if the ratio of cortisol is too high. This mechanism
evolved to give a second chance to lower DHEA animals. Under stress, cortisol
is produced in increased amounts at the expense of DHEA production. This
disrupts the effects of DHEA on the central nervous system. Therefore, in a
person of very low DHEA, stress will dramatically affect DHEA levels. In a
normal person, cortisol is a nerve toxin if exposure is prolonged. The toxic
effects would be increased in a person of low DHEA. Therefore, stress may not
cause schizophrenia, but it may trigger the onset by harming an already reduced
number of cortical neurons.
Testosterone directs the gene stimulating
effects of DHEA toward "testosterone target genes." DHEA is used for
transcription of all genes, including testosterone’s targets. This is why men
are bigger than women. The onset of puberty and increased testosterone
production will reduce the availability of DHEA to even lower levels. This will
also increase the ratio of available cortisol in the blood. Given sufficient
time and sufficient testosterone, this will expose the underlying mechanism of
schizophrenia. If stress occurs, which is almost inevitable in adolescence, the
mechanism of increased cortisol to DHEA will intensity the negative effects of
testosterone. I suggest this is why schizophrenia often occurs in late teens or
early twenties. Schizophrenia is two to three times more common in males than
females (American J. Psychiatry 1992, 149: 1070).
The drugs used to control schizophrenia, I
suggest, actually exert their effects by stimulating DHEA production. That is,
"...antipsychotic potencies of most neuroleptic drugs closely correspond
to their prolactin-releasing potencies at low doses..." (Biological
Psychiatry 1990, 27: 1204). Therefore, it may actually be DHEA that
ameliorates schizophrenia upon antipsychotic drug administration. Schizophrenia
is thought to result from dopaminergic over-activity; essentially all
antipsychotic drugs block postsynaptic dopamine receptors. This increases
prolactin release. The dopaminergic agonist, bromocriptine, often used as an
anti-prolactin agent, produces hallucinations, delusions, and confused thinking
when used in excess.
It would make sense that individuals of low
DHEA would seek drugs that increase DHEA. Schizophrenics would be more prone to
this sort of behavior because of their significantly low DHEA. It is known that
nicotine significantly increases the reserve form of DHEA, DHEA sulfate (New
England J. Medicine 1988, 318: 1705). DHEA is made from DHEAS. This
should be pronounced in schizophrenics. You can clearly see this in terms of
low DHEA and testosterone in males and females in the following quotation. (My
work suggests many mental illnesses probably result from low DHEA; note the
high percentage of patients who are smokers in this study.) This could also
account for increased smoking at the onset of adolescence; people of low DHEA,
or people of moderate DHEA and high testosterone, would be attracted to the
positive effects of nicotine, starting around puberty. In my explanation of
sleep at this website, I point out that SIDS is probably due to low DHEA.
Often, the mothers of SIDS victims are smokers; investigators often attribute
the subsequent SIDS deaths to smoking by the mother. It very well may be that
these mothers are low DHEA and smoke to increase DHEA. My theory suggests the
mother produces DHEA for herself and her fetus during gestation; this would
increase the attraction of nicotine in women of low DHEA. Low DHEA mothers have
babies who are low DHEA, which increases the probability of SIDS. Likewise, in
the second quotation below, I do not think smoking hastened the onset of
schizophrenia; schizophrenics seek DHEA through smoking.
"Cigarette
smoking was measured in all patients hospitalized at a state hospital (N = 360)
and compared in relation to gender and diagnosis (schizophrenic versus
nonschizophrenic). RESULTS: The overall frequency of smoking was 79% (N = 284).
Male schizophrenic patients had the highest frequency of smoking, followed by
male nonschizophrenic patients, female schizophrenic patients, and female
nonschizophrenic patients, respectively. CONCLUSIONS: After correction for
other variables, schizophrenia appears to increase the risk of being both a smoker
and a heavy smoker." (American J. Psychiatry 1995, 152: 453)
"We
found that [schizophrenic] patients who smoked had a significantly earlier age
at onset of psychiatric illness as compared to the nonsmokers." (Internal
J. Neurosciene 1991, 57: 259)
Schizophrenia results from lack of cerebral
hemisphere growth as a result of severe reductions in DHEA and melatonin during
brain growth and development. It is triggered by events later in life that
reduce DHEA availability and increase the negative effects of cortisol. I
suggest treating schizophrenics with melatonin at night and DHEA during the day
may help in some circumstances, depending on the level of damage done by
prolonged cortisol exposure.