Serendipity and drug discovery

Frequently scientists talk about the serendipitous finding that leads to important discoveries. In psychiatry serendipitous drug discoveries, however, may not advance understanding of psychiatric illnesses very much. Dopamine antagonists are useful in the treatment of schizophrenia but there has been no revolution in the understanding of schizophrenia resulting from the discovery that dopamine antagonists can partially treat schizophrenia. Lithium has uses but lithium has not revolutionized the understanding of bipolar disorder.

A lot of research seems directed at finding the hidden fact that will be the key to unraveling a disease. Researchers seem to be in search of serendipity which is not how serendipity works. Psychiatric research would better off if there was more emphasis on basic research with translational research then sticking closely to basic research. Succeeding at translational research may require that all the various factors that complicate a hypothesis be considered. The devil is the details. Possessing a sliver of truth is surer route to scientific discovery than searching for serendipity.

The basic idea that the transsulfuration pathway is dysregulated in schizophrenia is a simple idea but treatment is complicated by the fact that downstream pathways from the transsulfuration pathway have to be addressed. Treatment would be so much simpler if only lowering homocysteine levels worked or only increasing l-cysteine levels worked but neither do. There can be effective treatments for schizophrenia that address the fundamental biology of schizophrenia but there can be no simple effective treatments for schizophrenia that address the fundamental biology of schizophrenia.

Muscarinic agonists and schizophrenia

chewing betel nut

Muscarinic agonists are being studied in terms of the treatment of schizophrenia. There is some indication that muscarinic agonists can successfully treat schizophrenia. So far so good.

Nicotine is one of the most addictive substances on Earth. Nicotine agonizes nicotinic acetylcholine receptors which are a different kind of acetylcholine receptor than muscarinic acetylcholine receptors. Muscarinic agonists may have no addictive potential and may in fact be drugs that can treat addictions. However, betel nut which activates muscarinic receptors is very addictive . Before mucarinic agonists are generally prescribed any addiction potential of muscarninic agonists has to be thoroughly addressed.

Phrenology and schizophrenia

All books that address the history of scientific research on the brain have sections on phrenology. The upshot of book sections on phrenology is that phrenology was the dark ages of brain research. A lot of phrenology was nonsense. But is there a kernel of truth to phrenology? I have been claiming that the negative symptoms of schizophrenia are due to brains being compressed due to hidden osteomalacia arising from dysregulation of calcium homeostasis due to deficiencies in taurine.

Wolfgang Pauli once said ‘the idea is so bad it is neither right or wrong‘. My idea could be wrong. I am not quite certain what imagining techniques are used to detect osteomalacia but the evidence may right now be stored in data banks. Currently skulls are stripped from MRI images. A search of PubMed using the search terms “osteomalacia” and “schizophrenia” turned up three articles which were irrelevant. There is apparently a reduction in brain volumes in schizophrenia which could be due to skulls being compressed due to hidden osteomalacias.

So far brain imaging has only discovered that individuals with brain structures that are all in the normal range of sizes can have schizophrenia. Still brain imaging or at least skull imaging could could be a key to treatment of the negative symptoms of schizophrenia which can be devastating.

Cytomegalovirus and schizophrenia

In individuals with schizophrenia 68% of the patients had an increased CSF/serum antibody ratio for cytomegalovirus (CMV) antibody, Cytomegalovirus is associated with anemia. Like toxoplasma gondii the association of cytomegalovirus to schizophrenia could be due to the effect of cytomegalovirus on iron status.

Lots of viruses are associated with anemia. Given that the effect of parasites, bacteria and viruses on incidences of schizophrenia is due to the effect of parasites, bacteria and viruses on iron status then treatments that directly address parasites, bacteria and viruses would not be useful treatments for schizophrenia as individuals can be hit from many different directions while antiparasitics, anti-virals and and antibacterial agents etc would address only a single route. To treat schizophrenia iron status would have to be directly addressed.

Schizophrenia, toxoplasma gondii and iron-responsive protein 1

toxoplasma gondii

The Odd Ratio for schizophrenia for indivduals with IgG antibodies for toxoplasma gondii were 1.81, With toxoplasma gondii infection.there is increased activity of iron-responsive protein 1 (IRP1). Aconitase 1 is a dual fuction protein, When iron levels are low aconitase 1 looses and iron sulfur cluster and becomes IRP1 but when iron levels are increased IRP1 gains an iron-sulfur cluster and becomes aconitase 1. Aconitase 1 is an enzyme in the tricarboxylic acid (TCA) cycle. Increased levels of IRP1 would indicate that the TCA cycle is dysregulated which could set the set the stage for schizophrenia. See my paper Treatment-resistant schizophrenia: focus on the transsulfuration pathway. on how dysregulation of IRP1, aconitase 1 and the TCA cyle could play a part in the development of schizophrenia.

CACNA1C (Cav1.2) and psychiatric disease

The calcium channel, voltage-dependent, L type, alpha 1C subunit is a protein that is encoded by the CACNA1C gene. Via calcium channels calcium influxes into cells. Mutations in CACNA1C are associated with bipolar disorder, depression, schizophrenia and autism. Gain of function mutations in CACNA1C are associated with disease, for example, autism.

Taurine regulates intracellular calcium levels by preventing influxes of calcium into cells but not effluxes of calcium out of cells. Via regulating influxes of calcium into cells taurine has a role in the treatment of psychiatric disorders that are in part due to gain of function mutations in CACNA1C.

Morning coffee

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Many studies report coffee as having beneficial effects and a couple of cups of coffee drink only in the morning could have beneficial effects. A meta-analysis indicates that there is at inverse relationship between coffee/caffeine and risk of Parkinson’s disease. A weakness of the forgoing meta-analysis is that the meta-anaylsis focuses on caffeine. Studied indivduals, however, were drinking coffee with is much different than taking caffeine pills. A meta-analysis indicates that moderate coffee intakes is associated with decreased cardiovascular risks. There are, however, increased risks for schizophrenia where there is heavy use of coffee. Where there is heavy use of coffee, coffee most likely is not drunk only in mornings.

Difficulties with coffee can arise given coffee is drunk throughout the day. Coffee inhibits iron absorption in a concentration-dependent fashion. Polyphenols in coffee inhibit iron absorption. A couple of cups of coffee drunk only in the morning would have minimal effects on iron metabolism. Coffee drunk throughout the day could have very adverse effects on iron metabolism.

Bone mineral density and negative symptoms of schizophrenia

A meta-analysis points to bone mineral density being significantly decreased in individuals with schizophrenia compared to healthy controls. Bone mineral density in schizophrenia could be decreased in individuals with schizophrenia due to dysregulation of the transsulfuration pathway. Taurine is synthesized from L-cysteine which is synthesized via the transsulfuration pathway.

Taurine is required for intracellular calcium homeostasis. Bile acids are required for absorption of fat soluble vitamins. Vitamin D and vitamin K are fat soluble vitamins involved in bone formation. Various bile acids are synthesized from taurine. With deficiencies of taurine calcium homeostasis can be upset and there can also be deficiencies of vitamin D and vitamin K which could lead to low bone mineral density in schizophrenia.

Low bone mineral density in schizophrenia point to there being hidden osteomalicias in schizophrenia. With taurine deficiencies intracellular calcium homeostasis can be upset, though extracellular calcium levels could be normal, leading to a hidden osteomalicias.

Dysregulation of the transsulfuration pathway can result in epigenetic changes whereby there could be localized osteomalacias. Given osteomalacias due to taurine deficiencies develop in the back of the head negative symptoms of schizophrenia could develop due to compressions of cerebellums. There are a wide range of symptoms in schizophrenia so individuals with schizophrenia do not present as only having back of the head pains which makes correct diagnoses difficult though x-ray studies of backs of skulls in individuals with symptoms of schizophrenia could go a long ways in making correct diagnoses straightforward.

Negative symptoms of schizophrenia could be treated by supplementation with taurine, Vitamin K2 MK-7, which a kind of vitamin K that is highly absorbed, and vitamin D3. As negative symptoms of schizophrenia are due to hidden osteomalicias taurine, vitamin K2 MK-7 could take a long while to be completely effective. To treat the range of symptoms seen is schizophrenia due to dysregulations of the transsulfuration pathway supplements, beyond supplements that treat hidden osteomalicias, are required.

Iron, aconitase 1, glutamate and schizophrenia

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Diminished glutamatergic neurotransmission is present in schizophrenia. N-methyl-D-aspartate receptor antagonists such as ketamine, can induce symptoms of acute schizophreniaIron.

Iron increases glutamate secretion by increasing cytosolic aconitase activity. The synthesis of isocitrate by cytosolic aconitase is the the first step in a three step synthesis of glutamate. Glutamate, arising from increases in cytosolic aconitase due to increases in iron, is secreted via the cystine/glutamate antiporter where at the same time cystine is imported into cells increasing glutathione levels in cells.

With iron supplementation in schizophrenia via iron carbonyl taken three times a day there could be increased glutamatergic neurotransmission via increases is secreted glutamate where at the same time there would be increases in cystine in cells and thereby increases in glutathione levels in cells. Supplementation with iron from iron carbonyl could be part the treatment of schizophrenia.