Copyright ã 1996 Revised from 1985 by James Michael Howard.
Current Synopsis: It is my hypothesis that schizophrenia is caused by low DHEA in utero. This results in poor brain development. Later in life, cortisol and testosterone act to reduce the effects of already low DHEA and adversely affect brain function as well as maintenance of anatomy. DHEA naturally begins to decline in the early twenties. This is why schizophrenia often occurs in the late teens / early twenties (puberty and loss of DHEA) and is often triggered by a stressful event (cortisol). Therefore, at this time, brain function and maintenance is inhibited and, in the case of cortisol, may be reduced. (Some would call this “disconnection / disconectivity;” I think it is a switch of supported function from one site of DHEA use to another.) I suggest this reduces prefrontal function and increases lower brain function, the seat of hallucinations. It is known that DHEA is low in schizophrenia and that DHEA acts positively in neuron growth and function. (DHEA has also been found to be high in schizophrenia. I suggest low DHEA may account for negative symptoms and high DHEA may account for positive symptoms of schizophrenia.) DHEA in sufficient levels acts to positively affect growth and development of the brain and, following growth and development, to positively affect neuronal activities.
(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 http://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, Fayetteville, Arkansas, U.S.A.)
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.