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.

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.

Occam’s razor and mood stabilizing drugs for bipolar disorder

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Occam’s razor – the simplest explanation is usually the right one. How do mood stabilizers work to stabilize mood?

Lithium can stabilize sodium-dependent transporters and sodium-dependent G-protein coupled receptors in inactive states. Lithium  reduces activity of various sodium-dependent transporters, for example, Na(+)-coupled inorganic phosphate cotransporters (Andrini et al., 2012), Na+/Cl)/glycine cotransport (Pérez-Siles et al., 2011) and the sodium-myo-inositol co-transporter (Willmroth et al., 2007).

Blocking sodium channels is one of the key mechanisms by which anticonvulsants work (Brodie,  2017). Carbamazepine, valproic acid and lamotrigine are anticonvulsants used to treat bipolar disorder (Bowden and Karren, 2006.). Carbamazepine is a sodium channel blocker (Kennebäck et al., 1995). Valproic acid blocks sodium channels (Zanatta et al., 2019). Lamotrigine also blocks sodium channels (Kuo, 1998).

Occam’s razor applied to mood stabilizers – Mood stabilizers work by affecting sodium-dependent transporters and/or sodium-dependent G-protein coupled receptors.

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.

Bipolar disorder and bone mineral density

There are decreases in bone mineral density in drug naive individuals with bipolar disorder compared to age- and gender-matched healthy controls. Individuals with bipolar I disorder have have high homocysteine levels. High homocysteine levels in individuals with bipolar disorder point to the transsulfuration pathway being dysregulated. Via the transsulfuration pathway L-cysteine is synthesized from homocysteine. L-taurine is synthesized from L-cysteine.

Taurine is required for calcium homeostasis. Taurine, also, is conjugated to various bile acids. Bile acids are are required for absorption of fat-soluble vitamins. Vitamin D and vitamin K are fat-soluble vitamins. Individuals with bipolar disorder are 4.7 times more likely to be vitamin D deficient than individuals amongst the general population of the Netherlands, however, deficient levels of vitamin D are not specific to bipolar disorder but are also present in individuals with schizophrenia. The taurine transporter is present in osteoblasts. Osteoblasts synthesize bone.

With taurine metabolism dysregulated calcium homeostasis is dysregulated and absorption of vitamin D and vitamin K is decreased. Decreases in bone mineral density in bipolar disorder could be due to dysregulation of the transsulfuration pathway which dysregulates calcium homeostasis and vitamin D and vitamin K absorption resulting in low bone mineral density.

Bipolar disorder and inflammation

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Bipolar disorder is associated with inflammation. See also this paper.

Inflammation is increased by ecosanoids derived from arachidonic acid, however, inflammation can be reduced by the sythesis of eicosanoids derived from eicosapentaenoic acid (EPA) and dihomo-γ-linolenic acid (DGLA). DGLA is synthesized from gamma-linolenic acid (GLA), which is in evening primlrose oil, while EPA is in fish oils. Cyclooxygenases and lipoxygenases can act on DGLA, EPA and/or arachidonic acid. DGLA and EPA competitively inhibit synthesis of inflammatory eicosanoids from arachidonic acid,

To stop inflammation in bipolar disorder supplmentation with GLA and EPA could be of assistance. GLA and and EPA are synthesized from linolenic acid and alpha-linoleic acid respectively. Linoleic acid is an omega-6 fatty acid while alpha-linolenic acid is an omega-3 fatty acid both of which are essential fatty acids. Eicosanoid homeostasis is upset when GLA and EPA are not available more or less second by second. Both GLA and EPA must be supplemented as the difficulty in eicosanoid homeostasis arises from difficulties in absorbing essential fatty acids due to defiencies in taurine.

Deficiencies in vitamin D in schizophrenia, bipolar disorder, Alzheimer’s disease and Parkinson’s disease

Low levels of vitamin D are associated with schizophrenia, bipolar disorder Alzheimer’s disease and Parkinson’s disease. Vitamin D is a fat soluble vitamin. Bile acids are required for fat absorption. Taurocholic acid is a bile acid that is a conjugate of cholic acid with taurine. Taurochenodeoxycholic acid is a bile acid formed in the liver by conjugation of chenodeoxycholic acid with taurine. Taurine increases absorption of vitamin D.

There are low levels of vitamin D in schizophrenia, bipolar disorder, Alzheimer’s disease and Parkinson’s disease due to dysregulation of taurine synthesis in these illnesses attendant on dysregulation of the transsulfuration pathway which synthesizes L-cysteine from which taurine is synthesized.

Supplementation with vitamin D in these illnesses heretofore has not helped much as difficulties in fat absorption have not been addressed. Taurine, which regulates calcium homeostasis besides aiding in fat absorption, taurine would be taken with vitamin D, vitamin K and calcium carbonate to address low levels of vitamin D where there are chronic illnesses. Vitamin K is also a fat soluble vitamin whose abosoprtion could be impaired by low levels of taurine.