Treating the negative symptoms of schizophrenia

The negative symptoms of schizophrenia are at least partly due to a shortage of coenzyme A which is used by the E2 unit of the 2-oxoglutarate dehydrogenase complex and the E2 unit of the pyruvate dehydrogenase complex in the citric acid cycle. What is needed is to increase levels of coenzyme A which can be done by supplemental pantothenic acid.

Why are coenzyme A levels low in schizophrenia? L-cysteine is required to synthesize coenzyme A. Due dysregulation of the transsulfuration pathway in schizophrenia, as explained in my paper Treatment-resistant schizophrenia: focus on the transsulfuration pathway, intracellular levels of L-cysteine can be low in schizophrenia which will decrease synthesis of coenzyme A.

Supplementation with L-carnitine from carnitine tartrate is needed as L-carnitine reverses the inhibition of pantothenic kinase by coenzyme A and acetyl-coenzyme A. Pantothenic kinase is the rate-limiting enzyme in coenzyme A synthesis. Supplementation with acetyl-l-carnitine is avoided as palmitonylcarnitine , which is what actually reverses the inhibition of pantothenic kinase, is synthesized from L-carnitine not acetyl-L-carnitine. For reasons I will not go into here the L-carnitine must be L-carnitine from L-carnitine tartrate. L-carnitine fumarate must be avoided.

Supplementation with sulbutiamine will also be helpful in the treatment of the negative symptoms of schizophrenia. Sulbutiamine is a fat-soluble form of thiamine which can greatly increase thiamine diphosphate levels . Thiamine diphoshpate is used by the E1 unit of the 2-oxogularate dehydrogenase complex and the E1 subunit of the pyruvate dehydrogenase complex.

Supplementation with sublingual biotin would be useful. The sodium-dependent multivitamin transporter (SMVT) transports pantothenic acid, biotin and lipoate. Biotinyalition of histones associated with with the sodium-dependent multivitamin transporter silences transcription of the sodium-dependent multivitamin transporter gene. High dosages of pantothenic acid could competitively biotin transport in the gut but this would be avoided with sublingual biotin. Very surprisingly coenzyme Q10 must be taken when biotin is supplemented. Biotin apparently can have a large effect on the TCA cycle. If the TCA cycle hangs up at the succinate dehydrogenase step supplemental biotin is not of assistance.

Acetyl-coenzyme A can be synthesized from fatty acids. EPA + DHA where EPA makes up 65 to 70% of the EPA + DHA combination will be helpful. A EPA + DHA combination has been extensively studied and has good safety profile.

Supplemental coenzyme Q10 is also required. Succinate dehydrogenase which is an iron-sulfur protein in the citric acid cycle, requires coenzyme Q10. Biotin is not useful without coenzyme Q10. If the citric acid cycle gets hung up at the succinate dehydrogenase step biotin is not helpful.

Activities of the E3 subunits of the pyruvate dehydrogenase complex and 2-oxoglutarate dehydrogenase complex, which have NAD+ as substrates, unstimulated by supplements are  completely acceptable as is.

If niacin, niacin derivatives,  riboflavin and/or lipoic acid are supplemented pantothenic acid and thiamine will not work against the negative symptoms of schizophrenia.  A B-50 supplement is a terrible supplement. What not to supplement with is as important as what to supplement with.  Lipoic acid increases l-cysteine levels by reducing cystine to L-cysteine but cystine must be present to enter cells by way of the cystine/glutamate antiporter. Once in cells cystine is rapidly reduced to L-cysteine.  In any case lipoic acid is synthesized on lysine residues of proteins so supplemental lipoic acid would not boost activities of the  E2 subunit of the pyruvate dehydrogenase complex and E2 subunit of the 2-oxoglutarate complex. Do not supplement with pantethine. Pantethine depletes cystine.

The supplements must be taken with food. Taking the supplements with food makes a huge difference.

Can pantothenic acid, sulbutiamine, sublingual biotin, EPA + DHA, coenzyme Q10 and l-carnitine be effective againstĀ  the negative symptoms of schizophrenia when taken alone? I don’t know. Minimally, to be avoided supplements as listed on the Treatment page should be avoided.

Thiamine deficiencies and the citric acid cycle

Thiamine deficiencies result in very pronounced decreases in citric acid cycle enzymes.

Neurochem Int. 2004 Dec;45(7):1021-8.

Tricarboxylic acid cycle enzymes following thiamine deficiency.

Bubber P, Ke ZJ, Gibson GE.

Abstract

Thiamine (Vitamin B1) deficiency (TD) leads to memory deficits and neurological disease in animals and humans. The thiamine-dependent enzymes of the tricarboxylic acid (TCA) cycle are reduced following TD and in the brains of patients that died from multiple neurodegenerative diseases. Whether reductions in thiamine or thiamine-dependent enzymes leads to changes in all TCA cycle enzymes has never been tested. In the current studies, the pyruvate dehydrogenase complex (PDHC) and all of enzymes of the TCA cycle were measured in the brains of TD mice. Non-thiamine-dependent enzymes such as succinate dehydrogenase (SDH), succinate thiokinase (STH) and malate dehydrogenase (MDH) were altered as much or more than thiamine-dependent enzymes such as the alpha-ketoglutarate dehydrogenase complex (KGDHC) (-21.5%) and PDHC (-10.5%). Succinate dehydrogenase (SDH) activity decreased by 27% and succinate thiokinase (STH) decreased by 24%. The reductions in these other enzymes may result from oxidative stress because of TD or because these other enzymes of the TCA cycle are part of a metabolon that respond as a group of enzymes. The results suggest that other TCA cycle enzymes should be measured in brains from patients that died from neurological disease in which thiamine-dependent enzymes are known to be reduced. The diminished activities of multiple TCA cycle enzymes may be important in our understanding of how metabolic lesions alter brain function in neurodegenerative disorders.