Bipolar Disorder

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As I have said elsewhere on the site I think iron plays a huge role in mental illnesses. Tea and sodas should be avoided and the supplements ‘to be avoided’ listed on the Treatment page should also be avoided. Coffee should be limited to two cups oy coffee in the morning an hour before supplements are taken with food.

Bipolar disorder and the sodium-dependent multivitamin transporter (SMVT)

Thomas Berry

Bipolar disorder is associated with swings in mood state and energy. The sodium-dependent multivitamin transporter (SMVT) transports pantothenate, biotin and lipoate. Coenzyme A is synthesized from pantothenic acid. Coenzyme A is required for the pyruvate dehydrogenase complex (PDC) and alpha-ketoglutarate complex (OGDC). Swings in activites of the PDC and OGDC could result in swings in ATP production which could result in swings in mood state and energy seen in bipolar disorder.Coenzyme A and biotin are required for fatty acid synthesis.With fatty acid acid metabolism dysregulated depressions of bipolar disorder could develop. Dysregulation of the SMVT and/or decreased levels of biotin are consistent with lithium, valproic acid and carbamazepine being effective in the treatment of bipolar disorder. Lithium blocks the SMVT which would explain the anti-mania actions of lithium. Anticonvulsants reduce biotin levels and reduce levels of biotinidase which recyles biotin. Transcription of the SMVT gene is regulated by biotinylation of histones at the SMVT locus. Biotinylation decreases transcription of the gene for the SMVT. With the SMVT dysregulated there could be switches between mania and depression. Re-regulating the PDC. the OGDC and fatty acid metabolism and which require coenzyme A and biotin, by supplementation with pantothenic acid, biotin, sulbutiamine, coenzyme Q10, L-carnitine, L-taurine and animal fats could be a treatment for bipolar disorder.     

Introduction  

Bipolar disorder affects 1% of the world’s population (Grande et al., 2016). Lithium (Burgess et al., 2001 carbamazepine, valproate (Keck and McElroy, 2002) and lamotrigine (Fung et al.,2004)   are mainline treatments for bipolar disorder.  In 2015 total costs in the United States of treating bipolar I disorder were $202.1 billion while the excess costs of treating individuals with bipolar disorder compared to individuals in the general population were $119.8 billion (Cloutier et al.,  2018). The estimated total economic burden for bipolar I and bipolar II in 2009 in the United States was $151.0 billion (Dilsaver, 2011). Bipolar depression is particularly difficult to treat (Hui Poon et al., 2015). New pharmacological treatments are needed for bipolar disorder especially for bipolar depression.

  The mechanism by which drugs now used to treat bipolar disorder work is not clear. Lithium inhibits glycogen synthase kinase-3 beta (GSK3B) (Stambolic and Woodgett, 1996). Valproic acid is a histone deacetylase inhibitor (Krämer et al., 2003). In astrocytes lithium, carbamazepine and valproic acid reduce activity of the sodium myo-inositol co-transporter  and reduce mRNA concentrations of the sodium-myo-inositol co-transporter (Lubrich and van Calker, 1999; Wolfson et. al., 2000). In patients with bipolar disorder mRNA for the sodium-myo-inositol co-transporter is downregulated in neutrophils with lithium or valproic acid treatment (Wilmroth et al., 2007).

Drugs to treat bipolar disorder have a variety of actions. Efficacy of the drugs to treat bipolar disorder can be explained by effects of the drugs on transport by the sodium-dependent multivitamin transporter (SMVT) and on biotin levels

Sodium-dependent multivitamin transporter (SMVT) and drugs used to treat bipolar disorder

Figure 1. Drugs used to treat bipolar disorder, mechanisms of actions, and effects on bipolar disorder

DrugsBiological ActionsEffects on Mood
LithiumBlocks the SMVTAnti-manic
Anti-convulsantsReduce biotin levelsStabilize Mood

The SMVT transports pantothenate, biotin and lipoate (Prasad et al., 1998). Transport of pantothenate is blocked by lithium (Fenstermacher et al., 1986) by lithium blocking the SMVT (Zehnpfennig et al., 2015).

Biotin levels are reduced in individuals who take anti-convulsants  (Krause et al.,  1985). Biotin transport is inhibited by anticonvulsant drugs in a concentration-dependent manner in brush border membrane vesicles of human intestines (Said et al., 1989). Carbamazepine decreases activity of liver pyruvate carboxylase, which has biotin as co-factor (Rathman et al.,  2003).  Abundance of enzymes, which have biotin as a co-factor, are reduced by carbamazepine (Rathman et al., 2002). Over 80% of individuals who take anticonvulsants have reduced levels of biotin (Krause et al., 1970).  Anti-convulsants with carbamide groups such as carbamazepine,  compete with biotin for binding to biotinidase  (Chauhan and Dakshinamurti, 1988). Low  serum levels of biotinidase are present in children who take valproic acid (Schulpis  et al., 2001).  Biotinidase assists with the recycling of biotin by cleaving biocytin and biotinyl-peptides, freeing biotin for reutilization (Hymes and Wolf, 1996). Biotinidase has biotinyl-transferase activity resulting in transfer of biotin to histones (Hymes and Wolf, 1996). As lipoate is snthesized on residues lipoate is not addressed in this paper.

Biotin levels are negatively correlated with expression of the SMVT but biotin levels correlate positively with activities of biotin-dependent propionyl-CoA carboxylase, levels of  biotinylated carboxylases, and with biotinylation of histones (Crisp et al., 2004). Transcription of the gene for the SMVT is blocked by biotinylation of histones at the SMVT locus (Gralla et al., 2008; Zempleni et al., 2009;  Mall et al., 2010).  With low biotin levels there could be increased expression of the SMVT and increased transport of pantothenate but decreased activity of biotin dependent carboxylases.   Actions of lithium and anticonvulsants used to treat bipolar disorder can be explained by such drugs acting on the SMVT and/or on biotin levels and biotinidase levels.

The gene for the SMVT is located at 2p23.3. A Genome Wide Association Study on bipolar disorder did not pick up any significant loci at the loci of the SMVT (Stahl et al., 2019). No mutation in the gene for SMVT is being postulated rather the gene is held to be hypermethylated and/or histones at the SMVT locus are hypermethylated. At times histones at the SMVT could be silenced by biotinylation.

Coenzyme A levels in bipolar disorder

 Pantothenic acid deficiencies are held to be rare in humans as pantothenic acid is ubiquitous in food (Hodges et al., 1958).  Pantothenic acid deficiencies result in a malaise (Tahiliani and Beinlich, et al.,  1991) which could if severe be a depression equivalent to a bipolar depression. No pantothenic acid deficiencies in diet are being postulated in bipolar disorder rather what is being postulated is difficulties in the transport of pantothenic acid by the SMVT and difficulties in the synthesis of coenzyme A from pantothenic acid.

 Synthesis of CoA requires l-cysteine (Brown, 1959). Research suggests that L-cysteine is decreased in bipolar disorder. L-cysteine is synthesized from homocysteine  via the transsulfuration pathway where elevated homocysteine and diminished glutathione levels suggest difficulties in the transsulfuration pathway  (Vitvitsky et al, 2006). L-cysteine is the rate-limiting amino acid in the synthesis of glutathione (Lu,  2009).  In bipolar disorder there are elevated homocysteine levels in serum (Permoda-Osip et al., 2013) and  in plasma  (Ezzaher et al., 2011; Zhou et al., 2018;  Salagre et al., 2017). There are also decreased glutathione levels in plasma of bipolar patients (Rosa et al., 2014; Nucifora et al., 2017; Raffa et al.,2012) where also in post-mortem brains of individuals who had bipolar disorder there are decreased levels of glutathione (Gawryluk et al., 2011).

 Pantothenate kinase is the rate-limiting enzyme in the synthesis of CoA (Robishaw et al., 1982; Jackowski and Rock, 1981; Leonardi et al., 2005; Rock et al., 2000). Pantothenate kinase is inhibited by acetyl-coenzyme A, however,  this inhibition is reversed by palmitoylcarnitine (Leonardi et al.,2007). Palmitoylcarnitine can be synthesized from carnitine by carnitine palmitoyltransferase I (Thampy et al.. 1990).  Carnitine reverses the inhibition of pantothenic kinase by CoA and acetyl-CoA (Fisher et al., 1985). The pathway for the synthesis L-carnitine has two 2-oxoglutarate dependent enzymes, trimethyllysine dioxygenase (Hulse et al., 1978) and gamma-butyrobetaine dioxygenase (Lindstedt and Lindstedt, 1970). With the TCA cycle dysregulated, which would dysregulate synthesis of 2-oxoglutarate, deficiencies in L-carnitine could develop.

At high levels of pantothenate, absorption of pantothenate is by passive diffusion (Shibata et al., 1983). At lower levels of pantothenate uptake of pantothenate is by the SMVT which is an active transport of pantothenate (Prasad et al., 1998).  Both pantothenate and biotin are transported by the SMVT (Prasad et al., 1998) with pantothenate being  a competitive inhibitor of biotin uptake (Said, 1999).   Biotin would be supplemented when pantothenate is supplemented.

Plausibility of the SMVT being associated with bipolar disorder

 Pantothenic acid is a precursor of coenzyme A (Tahiliani et al., 1991). Coenzyme A is required for the E2 subunit of pyruvate dehydrogenase complex (Patel et al., 2014) and the E2 subunit of 2-oxoglutarate dehydrogenase complex (Kumaran et al., 2013). The 2-oxoglutarate dehydrogenase complex is a critical step critical in the tricarboxylic acid (TCA) cycle (Sheu et al., 1999). Reductions in the activity of the 2-oxoglutarate dehydrogenase complex can result in decreases in ATP production by the TCA cycle and by oxidative phosphorylation (Berndt et al., 2012). Bipolar disorder is associated with swings in mood and energy (Grande et al., 2016).  Very plausibly switches pyruvate metabolism and the TCA cycle with concomitant swings in ATP synthesis could result in swings in mood and energy seen in bipolar disorder. Biotin is a co-factor for pyruvate carboxylase which supplies oxaloacetate for the TCA cycle (McClure et al., 1971; Scrutton et al., 1965). In bipolar order there is down regulation in the expression of mitochondrial genes involved in oxidative phosphorylation (Konradi et al., 2004) which could be due to dysregulation of the TCA cycle.

 Individuals with bipolar disorder can have a variety of symptoms.  TCA cycle intermediates regulate DNA methylation and histone methylation (Xiao et al., 2012; Tran et al., 2017).   Dysregulation of the TCA cycle could dysregulate epigenetic mechanisms whereby there would be decreased demethylation of DNA and decreased histone demethylation.  Ten-eleven translocation (TET) proteins are alpha-ketogutarate dependent enzymes that demethylate DNA (Scourzic et al., 2015). JumonjiC domain-containing proteins are α-ketoglutarate-dependent dioxygenases that demethylate histones (Klose et al., 2006).  Depending on how DNA and histones are hypermethylated due to dysregulation of the TCA cycle in bipolar disorder there could be a wide variety of symptoms.

 Accumulation of succinate inhibits α-ketoglutarate-dependent dioxygenases, such as JumonjiC domain-containing proteins and TET enzymes (Xiao et al., 2015). Coenzyme Q10 is a cofactor for succinate dehydrogenase which metabolizes succinate in the TCA cycle (Hederstedt and Rutberg, 1981) and  in the oxidative phosphorylation pathway (Rutter et al., 2010). When re-regulating the TCA cycle supplementation with coenzyme Q10 would be of assistance so there is not a buildup of succinate.

Valproic acid is a histone deacetylase inhibitor (Krämer et al., 2003; Göttlicher, 2004). The pyruvate dehydrogenase complex synthesizes acetyl-coenzyme A which can be used for histone acetylation (Sutendra et al., 2014). The E2 component of the pyruvate dehydrogenase complex requires coenzyme A (CoA) (Patel et al., 2014). With a shortage of CoA, synthesis of acetyl-coenzyme A will be decreased resulting in decreased histone acetylation. Reregulating the PDHC thereby increasing levels of acetyl-coenzyme A could have much the same effect on histone acetylation as histone deacetylase inhibitors, such as valproic acid, where both approaches would increase histone acetylation. Valproic acid decreases coenzyme A levels (Thurston et al.,1985; Deutsch et al. 2003) which could work against the effectiveness of valproic acid in bipolar disorder.

The SMVT and fatty acid metabolism

 Dysregulation of the SMVT could dysregulate fatty acid absorption, beta-oxidation of fatty acids and fatty acid synthesis. Taurine is synthesized from L-cysteine (Yin et al., 2016). Taurine is required for the synthesis of taurocholate, which is a bile acid (Bile acids, 2017).  Bile acids are required for absorption of fats (Bile acids, 2017). With shortages of bile acids in bipolar disorder fats would not be absorbed appropriately.  Beta-oxidation of fatty acids requires CoA. Carnitine palmitoyltransferase 1 (CPT1), a control point in beta-oxidation, transfers an acyl group from acyl-CoA to carnitine forming acyl-carnitine which carries an acyl group across the mitochondrial membrane where carnitine palmitoyltransferase 2 (CPT2) reforms acyl-CoA (Schreurs et al., 2010). Acyl-CoA’s then undergoe beta-oxidation.  CoA and biotin are crucial to in fatty acid synthesis. Acetyl-CoA carboxylase is a rate-limiting step in fatty acid biosynthesis (Hunkeler et al., 2018). Acetyl-CoA is a substrate of acetyl-CoA carboxylase, which is a biotin dependent enzyme (Trumble et al.,1995).  There could be significant difficulties in fatty acid absorption, beta-oxidation and fatty acid synthesis in bipolar disorder. Research shows decreases in EPA in bipolar disorder but research findings as of yet do not show widespread dysregulations of fatty acids in bipolar disorder.  What could be occurring is that decreases in beta-oxidation, which would increase fatty acid levels, balance decreases in absorption of fatty acids and decreases in fatty acid synthesis.  Fatty acid metabolism could be only apparently normal in bipolar disorder.  

Treatment

The supplements listed in Figure 1 could be used to treat bipolar disorder.

Figure 1.

SupplementReasonResearch as to Safety
High dosages of pantothenic acidIncrease pantothenate levels by passive diffusion Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline, 1998
biotinIncreases biotin levels. Assists with fatty acid sythesisInstitute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline, 1998
sulbutiaminecofactor for pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase Sevim et al., 2017
coenzyme Q10prevents build-up of succinate which can inhibit TET enzymes and JumonjiC domain-containing proteinsHidaka et al., 2008
L-carnitine from L-carnitine tartrateReverses the inhibition of pantothenic kinase by CoAHatchcock and Shao, 2006
L-taurine taken with beef tallow or a fat based
ketogenic diet
Assists with fatty acid absorption and supplies fatty acidsShao and Hathocok, 2008

 

The Institute of Medicine (US) was unable to set a Tolerable Upper Intake Level (UL) for pantothenic acid, biotin or thiamine as there was not sufficient scientific evidence on which to base a Tolerable Upper Intake Levels (Institute of Medicine, 1998). There have been no reports of toxicity from pantothenate, biotin or thiamine (Institute of Medicine,1998). That the Institute of Medicine was unable to set an UL for pantothenic acid or biotin does not mean that high levels of pantothenate or biotin are necessarily safe. There could be adverse effects from supplementation with pantothenic acid or biotin when taken as single supplements as pantothenate competitively inhibits biotin transport (Said, 1999) while high dosages of biotin via biotinylation of histones at the SMVT locus can silence transcription of the gene for the SMVT (Zempleni et al., 2009) which would reduce pantothenic uptake.  Pantothenic acid deficiencies are associated with malaise (Tahiliani and Beinlich, et al.,  1991)  Patients presenting with malaise are difficult to diagnose as malaise can have many causes.  Supplementing with both pantothenic acid and biotin would be safer than supplementing with only pantothenic acid or biotin. Pantothenic acid and biotin would not be supplemented an the same time to prevent competive inibition of absorption of biotin.

 To address the E2 components of the PDHC and OGDC first the E1 components must be addressed.   Sulbutiamine is a highly lipophilic form of thiamine (Van Reeth, 1999). Formation of the complex between pyruvate and thiamine diphosphate in the E1 component of PDHC is rate-limiting for the PHDC (Patel et al., 2014). Injections of sulbutiamine more than doubles the amount of thiamine diphosphate found in serum compared to injections with thiamine (Bettendorff et al., 1990). 400 mg. of sulbutiamine daily was well tolerated in multiple sclerosis patients (Sevim et al., 2017).

The Observed Safe Level for L-carnitine is 2000 mg/day (Hathcock et al.,  2006). With dysregulation of the TCA cycle there could be deficiencies in L-carnitine.  Acetyl-L-carnitine is not supplemented as palmitoylcarnitine, which reverses the inhibition of pantothenic kinase by CoA and acetyl-coenzyme A, is synthesized from L-carnitine. Carnitine from carnitine tartrate is supplemented rather than carnitine from carnitine fumarate. Fumarate is a TCA intermediate that can inhibit TET enzymes (Laukka et al., 2016).

 The observed safety level (OSL) for CoQ10  based on clinical trials is 1200 mg/day/person (Hidaka et al., 2008).Dry coenzyme Q10 is supplemented rather than softgel coenzyme Q10 as coenzyme Q10 has to be bioavailable in the gut. Ubiquinol is not supplemented as ubiquinol could increase succinate levels. Succinate inhibits TET enzymes (Laukka et al., 2016). 

Taurine is synthesized from L-cysteine. Taurocholic acid is a bile acid which aids in fat absorption. With L-cysteine not synthesized appropriately sufficient L-taurine will not to be synthesized whereby sufficient taurocholic acid will not be synthesized. With dysregulations in pantothenate and biotin transport there are diffiiculties in the synthesis of non-essential fatty acids. Beef tallow is composed of non-essential fatty acids acids from C:14 to C:18 from which various longer non-essential fatty acids can be synthesized. Beef tallow must be taken with L-taurine otherwise taurocholic acid will not be formed and the fatty acids will not be absorbed. Beef tallow will also support beta-oxidation. An animal fat keto diet could substitute for beef tallow. Fats from plant oils are not helpful.

The Observed Safe Level for supplementation with L-taurine is 3 grams a day (Shao and Hathcock, 2008). Supplemental taurine upregulates cystathionine beta-synthase and cystathionine gamma-lyase which are the two enzymes in the transsulfuraiton pathway (Sun et al., 2016). Supplemental taurine also reduces homocysteine levels (Ahn, 2009) likely due to the upregulation of the transsulfuration pathway by taurine. Taurine reduces cholesterol levels (Guo et al., 2017; Chen et al., 2012). Taurine and beef tallow would be taken daily in three or four divided doses with food. Fatty acids synthesized from essetential fatty acids would not need to be supplemented as essential fatty acids are supplied supplied by the diet. Dysregulation of the SMVT is less adverse to fatty acids synthesized from essential fatty acids.

L-cysteine is not supplemented. Supplmental L-cysteine can be very toxic (Baker,  2006). Lipoic acid is not supplemented. N-acetyl-L-cysteine and lipoic acid are not supplemented. N-acetyl-L-cysteine (Whillier et al., 2009) and lipoic acid (Han et al., 1997) increase L-cysteine levels by reducing cystine. Cystine, however, has to be available to be transported into cells by the cystine/glutamate antiporter where glutamate is transported out of cells. Both the transport of cystine into cells, where cystine is then reduced to cysteine, and the transport of glutamate out of cells are important functions of the cystine/glutamate antiporter  (Bridges et al., 2012).  The cystine/glutamate antiporter is closely tied to glutathione levels in cells (Lewerenz et al., 2012).  

Supplements are taken with food.

Discussion

 Drugs used to treat bipolar disorder could be acting by blocking the SMVT and/or by decreasing biotin and biotinidase levels. Lithium blocks the SMVT. Anticonvulsants used to treat bipolar disorder reduce biotin and biotinidase levels.  Anticonvulsants could upregulate the SMVT as with decreased levels of biotin biotinylation of histones at the SMVT locus is reduced resulting in increased transcription of the SMVT. With increased transcription of the SMVT there could be increased transport of pantothenate by the SMVT which could stabilize mood. 

 The TCA cycle could be dysregulated by hypermethylation of DNA or histones at the SMVT locus and/or by biotinylation of histones at  the SMVT locus and by decreased synthesis of coenzyme A due to decreased synthesis of L-cysteine..With decreased transport by the SMVT and decreased synthesis of L-cysteine there will be decreased synthesis of CoA which will dysregulate the PDHC and ODHC dysregulating the TCA cycle leading to swings in energy and mood.

TCA intermediates can inhibit TET enzymes, which demethylate DNA and JumonjiC domain-containing proteins, which demethylate histones. With TET enzymes and JumonjiC domain-containing proteins dysregulated there can be further dysregulations of the TCA cycle and additional supplements have to be given beyond pantothenic acid and biotin.

Fatty acid absorption, beta oxidation of fatty acids and fatty acid synthesis can be dysregulated in bipolar disorder. Due to decreases in L-cysteine synthesis sufficient taurine is not synthesized which reduces taurocholate. Taurocholate is needed for fat absorbtion. Dysregulation of the SMVT dysregulates transport of pantothenate and biotin which decreases synthesis of coenzyme A and decreases biotin levels which decreases beta-oxidation and fatty acid synthesis. Dysregulation of fatty acid metabolism could result in depressions seen in bipolar disorder.

 Pantothenic acid, biotin, sulbutiamine, coenzyme Q10, L-carnitine from L-carnitine tartrate and a fatty acid supplement with L-taurine are a possible treatment for bipolar disorder. The SMVT could be new targets in the battle against bipolar disorder.        

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