Bipolar Depression

Mania must be closely monitored for.

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

Thomas Berry

Abstract

Research points to bipolar depression being associated with dysregulation of the sodium-dependent multivitamin transporter (SMVT). The SMVT transports biotin, pantothenate, lipoate and iodide.  Swings in biotin, pantothenate and iodide availability could lead to swings in mood and energy seen in bipolar disorder. Dysregulation of the SMVT is consistent with lithium, valproic acid and carbamazepine being effective in bipolar disorder in the treatment of mania but not effective in bipolar depression.  Lithium blocks the SMVT and anticonvulsants block transport of biotin and decrease biotin levels. In this article, we discuss how lithium and anticonvulsants could be stabilizing the SMVT but at low activity levels of the SMVT which can treat mania but leave bipolar depressions untreated.  Given further research shows that there are pre-existing deficiencies of biotin, pantothenic acid, and protein-bound iodine in patients with bipolar depressions, who are not on mood stabilizers, then prescription of mood stabilizers in bipolar depression has to be re-thought. If there are pre-existing biotin, pantothenic acid, coenzyme A and protein bound iodide deficiencies in bipolar depression there could be a new treatment for bipolar depression.

Key words: bipolar disorder; bipolar depression; biotin; pantothenic acid; sodium-dependent multivitamin transporter (SMVT). 

Introduction 

                Bipolar disorder affects more than 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. Bipolar disorder involves symptoms such as mania (or hypomania) and depression. In 2015, the total costs of treating bipolar I disorder in the United States were $202.1 billion while the excess costs of treating individuals with bipolar disorder I 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).  In many instances bipolar disorder is treatment resistant  (Hui Poon et al., 2015).  Bipolar depression is particularly difficult to treat (Post, 2005). New pharmacological treatments are needed for bipolar disorder especially for bipolar depression. This paper provides a review of the sodium-dependent multivitamin transporter (SMVT) in connection with bipolar disorder and presents a possible new treatment for bipolar depression. 

               The mechanism by which drugs currently used to treat bipolar disorder treat bipolar disorder 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-like cells lithium, carbamazepine and valproic acid inhibit the sodium-myo-inositol co-transporter and reduce mRNA concentrations of the sodium-myo-inositol co-transporter (Lubrich and van Calker, 1999). In patients with bipolar disorder, mRNA for the sodium-myo-inositol co-transporter was downregulated in neutrophils with lithium or valproic acid treatment (Wilmroth et al., 2007). The effectiveness of lithium, valproic acid, and carbamazepine and lamotrigine in treating  bipolar disorder can be explained by their effects on transport by the SMVT.

               In this paper, we will discuss the effects of lithium and anticonvulsants on transport by the SMVT.  Effects of lithium and anticonvulsants on sodium (Na+) homeostasis and how alterations in Na+ homeostasis could affect transport by the SMVT are also discussed.  How Na+ homeostasis could be upset in bipolar disorder is next addressed. Na+ dysregulation in bipolar disorder is viewed as due to dysregulation of the transsulfuration pathway which dysregulates taurine metabolism upsetting Na+ homeostasis.  Finally, a possible treatment for bipolar depression is presented which would be an add-on treatment to patients with bipolar depression who are only taking antipsychotics.

Sodium-dependent multivitamin transporter (SMVT)

                The SMVT transports pantothenate biotin and lipoate (Prasad et al., 1998). The SMVT also transports iodide (de Carvalho et al., 2011). As lipoate is synthesized on residues lipoate is not addressed in this article. Lithium blocks the SMVT (Zehnpfennig et al., 2015).  Transport of pantothenate is blocked by lithium (Fenstermacher et al., 1986).  Lithium can displace Na+ on sodium-dependent transporters stabilizing sodium-dependent transporters in inactive states (Dudev et al., 2018). Lithium by displacing Na+ on the SMVT and stabilizing the SMVT in an inactive state could decrease transport of biotin, pantothenate and iodide by the SMVT. Lithium  reduces activity of other 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).  Figure 1. points to how dysregulation of the SMVT could affect biotin-dependent enzymes, enzymes that require coenzyme A and thyroid hormones.

F

               Research points to anticonvulsants decreasing transport by the SMVT.  Biotin transport is inhibited by anticonvulsant drugs in a concentration-dependent manner in brush border membrane vesicles of human intestines (Said et al., 1989). Plasma biotin levels are reduced in individuals who take anticonvulsants (Krause et al.,  1985). Over 80% of individuals who take anticonvulsants have reduced levels of biotin in plasma (Krause et al., 1970).  Carbamazepine decreases activity of liver pyruvate carboxylase, which has biotin as co-factor (Rathman et al., 2003).  The abundance of enzymes, which have biotin as a co-factor, are reduced by carbamazepine (Rathman et al., 2002). Valproic acid decreases coenzyme A (CoA) levels (Thurston et al.,1985; Deutsch et al. 2003). CoA is synthesized from pantothenate.       

               Blocking Na+ 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 Na+ channel blocker (Kennebäck et al., 1995). Valproic acid blocks Na+ channels (Zanatta et al., 2019). Lamotrigine also blocks Na+ channels Kuo, 1998). The Na+ channel blocking actions of carbamazepine, valproic acid and lamotrigine could affect the ability of the SMVT, which is sodium-dependent, to transport biotin, pantothenate. and iodide. Carbamazepine, valproic acid and lamotrigine could be stabilizing the SMVT via affecting Na+ levels but the stabilization would be at a low, far from optimal level.  Carbamazepine and valproic acid can stabilize mood but are not effective in treating the depression of bipolar disorder. Carbamazepine, valproic acid and lamotrigine can all cause hyponatremia with the Odds Ratio for hyponatremia leading to hospitalization compared to controls 9.63 for carbamazepine, 4.96 for valproate and 1.67 for lamotrigine (Falhammar et al., 2018). The differing profiles of carbamazepine, valproic acid and lamotrigine in the treatment in bipolar disorder could be due to stronger or less strong effects on Na+ levels. Lamotrigine has been used to treat bipolar depression (Geddes et al., 2009; Calabrese et al., 1999). The modest effectiveness of lamotrigine in bipolar depression could be due to the lessened probability of lamotrigine causing hyponatremia.

The SMVT and bipolar disorder

               Biotin is of intrinsic biological importance whose dysregulation would affect many biological processes. Biotin in a cofactor for pyruvate carboxylase, which is involved in glucogenesis and supplies substrates for the tricarboxylic acid (TCA) cycle, is required for acetyl-CoA carboxylase, which is the rate limiting step is fatty acid biosynthesis, for propionyl-CoA carboxylase and 3-methylcrotonyl-CoA carboxylase which are involved in branched-chain amino acid metabolism (Tong, 2013).  Biotin deficiencies dysregulate polyunsaturated fatty acid metabolism (Kramer et al., 1984). Biotin deficiencies can have many causes, for example, rare inborn errors of metabolism and through use of antibiotics which upset gut microbiota (Saleem and Soos, 2020).

               Pantothenic acid is a precursor of CoA (Tahiliani and Beinlich, 1991). CoA 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 in the TCA cycle (Sheu et al., 1999). Reduction in the activity of the 2-oxoglutarate dehydrogenase complex can result in a decrease in ATP production by the TCA cycle and by oxidative phosphorylation (Berndt et al., 2012). Biotin is a co-factor for pyruvate carboxylase which supplies oxaloacetate for the TCA cycle (McClure et al., 1971; Scrutton et al., 1965).  Bipolar disorder is associated with swings in mood and energy (Grande et al., 2016). Switches in pyruvate metabolism and activity of the TCA cycle with concomitant swings in ATP synthesis could result in swings in mood and energy seen in bipolar disorder. In bipolar disorder, there is downregulation in the expression of mitochondrial genes involved in oxidative phosphorylation (Konradi et al., 2004) which could be due to dysregulation of the TCA cycle.

                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 fatigue, apathy and malaise (Hodges et al., 1958; Tahiliani and Beinlich, 1991) which could if severe be a depression equivalent to a bipolar depression. No pantothenic acid deficiencies in diets 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 CoA from pantothenic acid. Synthesis of CoA requires pantothenic acid (Leonardi and Jackowski, 2007).  Valproic acid decreases CoA levels (Thurston et al.,1985; Deutsch et al. 2003) which could be due to decreases in pantothenate transport.

               The SMVT transports iodide (de Carvalho et al., 2011). Iodine is required for thyroid function (Laurberget et al. 2006). Thyroid difficulties arising from lithium usage would be expected if lithium blocked the SMVT. Hypothyroidism is associated with  the use of lithium (Kleiner et al., 1999; Johnston and Eagles, 1999;  Kirov et al.,  2005) Thyroid difficulties arising from usage of anticonvulsants would also be expected if anticonvulsants blocked the SMVT. Hypothyroidism is associated with usage of anticonvulsants (Isojärvi  et al., 1992; Vainionpää et al., 2004; Hamed, 2015). Symptoms of hypothyroidism can mimic symptoms of depression (Feldman et al., 2013).

Range of symptoms seen in bipolar disorder

                Individuals with bipolar disorder can have a variety of symptoms. Some individuals with bipolar disorder never experience mania but rather only have short hypomanic episodes. Other individuals with bipolar disorder rapidly cycle. Most individuals diagnosed with bipolar disorder have an additional psychiatric disorder.  Many but not all individuals with bipolar disorder have had substance abuse problems. Bipolar disorder can be associated with enhanced creativity and ability to work while other individuals with bipolar disorder are disabled by their illness and unable to work. Age of onset of illness differs between bipolar patients.

               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.  TCA cycle intermediates regulate DNA methylation and histone methylation (Xiao et al., 2015; Tran et al., 2017).   Ten-eleven translocation (TET) proteins are alpha-ketoglutarate 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).  Dysregulation of the TCA cycle could dysregulate epigenetic mechanisms whereby there would be decreased demethylation of DNA and decreased histone demethylation resulting in different symptoms in different individuals with bipolar disorder. 

               The nuclear pyruvate dehydrogenase complex synthesizes acetyl-CoA that is used for histone acetylation (Sutendra et al., 2014). The E2 component of the pyruvate dehydrogenase complex requires CoA (Patel et al., 2014). With a shortage of CoA, synthesis of acetyl-CoA will decrease resulting in decreased histone acetylation. Valproic acid is a histone deacetylase inhibitor (Krämer et al., 2003; Göttlicher, 2004). Re-regulating the PDHC thereby increasing levels of acetyl-CoA could have much the same effect on histone acetylation as histone deacetylase inhibitors, such as valproic acid, where both approaches would increase histone acetylation.

Sodium, L-cysteine and taurine                

               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 levels and diminished glutathione levels indicate the transsulfuration pathway is dysregulated (Vitvitsky et al, 2006). In bipolar disorder there were 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). L-cysteine is the rate-limiting amino acid in the synthesis of glutathione (Lu, 2009).  There were decreased glutathione levels in plasma of bipolar patients (Rosa et al., 2014; Nucifora et al., 2017; Raffa et al.,2012). In post-mortem brains of individuals who had bipolar disorder there were decreased levels of glutathione (Gawryluk et al., 2011).

               Dysregulation of Na+ levels in bipolar disorder could be due to low levels of taurine due to low levels of L-cysteine. Taurine is synthesized from L-cysteine (Beetsch and Olson, 1998). The taurine transporter is a cotransporter which transports both taurine and Na+ (Chesney et al., 1990; Zelikovic et al., 1989;  Bryson et al., 2001). Taurine is an osmolyte and Na+/taurine cotransporters can work in reverse (Baliou et al., 2020; Lambert, 2004). The Na+/taurine symporter results in an efflux of Na+ and taurine from cells when either rise above their physiological level in cells (Suleiman et al.,  1992). Taurine given long term decreases intracellular Na+ levels (Bkaily et al., 2020) which would increase extracellular Na+ enhancing transport by the SMVT, which is sodium-dependent. Dysregulation of the transsulfuration pathway could dysregulate taurine synthesis which would lead to dysregulation of Na+ homeostasis and dysregulation of the SMVT.

Proposals for further research

               There could be pre-existing dysregulations of the SMVT prior to patients with bipolar disorder being treated with mood stabilizers leading to bipolar depressions. Lithium and anticonvulsants would only be stabilizing the SMVT at low activity levels whereby lithium and anticonvulsants can act as mood stabilizers but are ineffective against depression. 

                Biotin, pantothenic acid levels, CoA levels and protein-bound iodide levels should be investigated in patients with bipolar depressions who are not on lithium or anticonvulsants (Eng et al., 2013). Biotin-deficient and biotin-sufficient individuals can only be distinguished by levels of biotinylated 3-methylcrotonyl-CoA carboxylase (holo-MCC) and propionyl-CoA carboxylase (holo-PCC) (Eng et al., 2013).     Given patients with bipolar depressions, who are not on lithium or anticonvulsants, are found to have pre-existing deficiencies of biotin, pantothenic acid, CoA and/or protein bound iodide levels prescription of lithium and anticonvulsants to treat bipolar depression has to be re-thought.

               A necessary first step in clinical trials of the suggested supplements is testing first to see if there are pre-existing deficiencies in biotin, pantothenic acid, CoA and protein-bound iodine in patients who have bipolar depression who are not mood stabilizers. Only upon finding that there are pre-existing deficiencies would clinical trials commence. The supplements would be synergistic. 

Treatment

Bipolar depression is due to dysregulation of the sodium-dependent multivitamin transporter. Biotin and pantothenic acid, which supposedly no one has deficiencies of unless one spends a couple of years in a concentration camp, can become deficient given the SMVT is dysregulated.

Biotin, pantothenic acid, MCT oil, sodium bicarbonate, taurine and brancheded-chain amino acids are taken three times a day. Iodide from potassium iodide is taken once a day. Sodium bicarbonate contains sodium so blood pressure must be watched. Individuals with high blood pressure may not be able to take sodium bicarbonate..

Biotin is required for fatty acid synthesis. Even with biotin supplemented non-essential fatty acids are not being synthesized. MCT oil contains medium chain fatty acids that are synthesized right after the biotin-dependent acetyl-CoA carboxylase step. MCT oil is a useful supplement. MCT oil which is a mixture of caprylic acid and and capric acid works much better than MCT oil that is only .composed of caprylic acid.

1000 mg. of taurine would be taken three times a day. A benefit of taurine is that taurine can reduce cholesterol levels (Yokogoshi et al. 1999; Militanti and Lombardini 2004).

Biotin-containing enzymes require bicarbonate. Sodium bicarbonate is helpful.

Branched-chain amino acids are supplemented. Biotin-dependent enzymes methylcrotonyl CoA carboxylase and propionyl-CoA carboxylase are involved in the metabolism of branched-chain amino acids.

The SMVT transports iodide. Iodine from potassium iodine must by supplemented. With the SMVT dysregulated iodine must be transported by SLC5A5 which is strongly expressed in the stomach but not in the rest of the gut Iodine from kelp would not be available in the stomach. Thyroid tests can be normal and still iodine from potassium iodine must still be supplemented.

Pantothenic kinase is the rate limiting step in the synthesis of coenzyme A. Pantothenic acid regulates pantothenic kinase.

Clearly the proposed treatment is a lot and would not be started unless biotin, pantothenic acid and/or coenzyme A levels are found to be low in individuals with bipolar depressions who are not taking lithium and/or anticonvulsants. As the treatment could interfere with the actions of lithium and/or anticonvulsants the proposed treatment would not be tried by individuals who are on lithium and/or anticonvulsants, however, biotin, pantothenic acid and coenzyme A levels should be checked in individuals who are are on lithium and/or anticonvulsants.

The importance of obtaining basic tests, metabolic panels, thyroid panels CBC’s etc regularly cannot be overstressed.

The proposed treatment especially with the addition of iodide from potassium iodide could result in mania. Elsewhere on this blog I have argued that 600 mg of carbonyl iron taken at bedtime can treat psychosis.

Discussion

                Drugs used to treat bipolar disorder could be acting by blocking the SMVT. Research shows that lithium blocks the SMVT and anticonvulsants block the transport of biotin and decreases biotin levels.  Lithium and anticonvulsants can act by affecting Na+ levels at the SMVT. Mood stabilizers by acting on Na+ could be stabilizing the SMVT but at low, far from optimal levels. Why exactly the SMVT is dysregulated in bipolar disorder is unclear. There could be a dysregulation of Na+ homeostasis in bipolar disorder arising from dysregulation of taurine metabolism due to dysregulation of the transsulfuration pathway.

               Biotin dependent enzymes are involved in fatty acid synthesis, beta-oxidation, branched-chain amino acid degradation, pyruvate metabolism, the tricarboxylic acid cycle and in gluconeogenesis. CoA is required for fatty acid synthesis, metabolism of pyruvate, the tricarboxylic cycle and in numerous other biological processes. Swings in biotin, pantothenate and iodide  could result in mood swing which could tend to stabilize in depressive phases of bipolar disorder.  

               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 epigenetic dysregulations giving rise to the wide variety of symptoms seen in bipolar disorder. Low levels of acetyl-CoA due to dysregulation of the PDC could also adversely affect histone acetylation.

               Future research should investigate biotin levels, pantothenate levels, CoA levels and protein bound iodide levels in patients with bipolar depression not on mood stabilizers. Individuals with bipolar disorder in depressive phases of their illness could have decreased levels of biotin, pantothenate, protein bound iodide and/or CoA even though not on mood stabilizers. Biotin levels in bipolar disorder have not been investigated. A search of PubMed using “biotin AND bipolar disorder” returned no relevant papers.  A search of PubMed using “pantothenic acid AND bipolar disorder” returned one tangentially relevant paper. Lithium lowers levels of protein-bound iodide (Rifkin et al., 1974). Patients tested would have to be in depressive phases of their illnesses.  Mood stabilizers would lower levels of biotin, pantothenic acid levels, protein bound iodide and/or CoA.             

               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.

               In this review, bipolar disorder and the SMVT have been discussed.  Given further research shows that there are low levels of biotin, pantothenic acid, protein bound iodide and/or CoA in patients with bipolar depression who are not being treated with mood stabilizers then a new treatment could be possible for bipolar depression. Bipolar depression is the aspect of bipolar disorder most difficult to treat.  New treatments for bipolar depression are very much needed. The SMVT could be a new target in the battle against bipolar depression. 


References:

Andrini O, Meinild AK, Ghezzi C, Murer H, Forster IC. Lithium interactions with Na+-coupled inorganic phosphate cotransporters: insights into the mechanism of sequential cation binding. Am J Physiol Cell Physiol. 2012;302(3):C539-C554. doi:10.1152/ajpcell.00364.2011

Baker DH. Comparative species utilization and toxicity of sulfur amino acids. J Nutr. 2006;136(6 Suppl):1670S‐1675S. doi:10.1093/jn/136.6.1670S

Beetsch JW, Olson JE. Taurine synthesis and cysteine metabolism in cultured rat astrocytes: effects of hyperosmotic exposure. Am J Physiol. 1998;274(4):C866-C874. doi:10.1152/ajpcell.1998.274.4.C866

Berndt N, Bulik S, Holzhütter HG. Kinetic Modeling of the Mitochondrial Energy Metabolism of Neuronal Cells: The Impact of Reduced α-Ketoglutarate Dehydrogenase Activities on ATP Production and Generation of Reactive Oxygen Species. Int J Cell Biol. 2012;2012:757594. doi: 10.1155/2012/757594. Epub 2012 Jun 10. Erratum in: Int J Cell Biol. 2018 Sep 9;2018:6139262. PMID: 22719765; PMCID: PMC3376505.

Beurel E, Grieco SF, Jope RS. Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther. 2015;148:114‐131. doi:10.1016/j.pharmthera.2014.11.016

Bkaily G, Jazzar A, Normand A, Simon Y, Al-Khoury J, Jacques D. Taurine and cardiac disease: state of the art and perspectives. Can J Physiol Pharmacol. 2020 Feb;98(2):67-73. doi: 10.1139/cjpp-2019-0313. PMID: 31560859.

Bowden CL, Karren NU. Anticonvulsants in bipolar disorder. Aust N Z J Psychiatry. 2006;40(5):386-393. doi:10.1080/j.1440-1614.2006.01815.x

Bridges RJ, Natale NR, Patel SA. System xc⁻ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol. 2012;165(1):20‐34. doi:10.1111/j.1476-5381.2011.01480.x

Brodie MJ. Sodium Channel Blockers in the Treatment of Epilepsy. CNS Drugs. 2017;31(7):527-534. doi:10.1007/s40263-017-0441-0

Brown GM. The metabolism of pantothenic acid. J Biol Chem. 1959;234(2):370‐378.

Bryson JM, Jackson SC, Wang H, Hurley WL. Cellular uptake of taurine by lactating porcine mammary tissue. Comp Biochem Physiol B Biochem Mol Biol. 2001 Apr;128(4):667-73. doi: 10.1016/s1096-4959(00)00361-4. PMID: 11290448.

Burgess, S., Geddes, J., Hawton, K., Townsend, E, Jamison, K., and Goodwin G. (2001). Lithium for Maintenance Treatment of Mood Disorders. Cochrane Database Syst Rev. (2):CD003013. 10.1002/14651858.CD003013.

Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry. 1999;60(2):79-88. doi:10.4088/jcp.v60n0203

Chen W, Guo JX, Chang P. The effect of taurine on cholesterol metabolism. Mol Nutr Food Res. 2012 May;56(5):681-90. doi: 10.1002/mnfr.201100799. PMID: 22648615.Chesney RW, Zelikovic I, Jones DP, Budreau A, Jolly K. The renal transport of taurine and the regulation of renal sodium-chloride-dependent transporter activity. Pediatr Nephrol. 1990;4(4):399-407. doi:10.1007/BF00862526

Cloutier, M., Greene, M., Guerin, A., Touya, M., Wu, E. (2018). The Economic Burden of Bipolar I Disorder in the United States in 2015. J Affect Disord 226, 45-51.

Crisp SE, Griffin JB, White BR, et al. Biotin supply affects rates of cell proliferation, biotinylation of carboxylases and histones, and expression of the gene encoding the sodium-dependent multivitamin transporter in JAr choriocarcinoma cells. Eur J Nutr. 2004;43(1):23‐31. doi:10.1007/s00394-004-0435-9

Cronan JE Jr, Waldrop GL. Multi-subunit acetyl-CoA carboxylases. Prog Lipid Res. 2002;41(5):407-435. doi:10.1016/s0163-7827(02)00007-3

de Carvalho FD, Quick M. Surprising substrate versatility in SLC5A6: Na+-coupled I- transport by the human Na+/multivitamin transporter (hSMVT). J Biol Chem. 2011;286(1):131-137. doi:10.1074/jbc.M110.167197

Deutsch J, Rapoport SI, Rosenberger TA. Valproyl-CoA and esterified valproic acid are not found in brains of rats treated with valproic acid, but the brain concentrations of CoA and acetyl-CoA are altered. Neurochem Res. 2003;28(6):861‐866. doi:10.1023/a:1023267224819

Di Ciaula A, Garruti G, Lunardi Baccetto R, et al. Bile Acid Physiology. Ann Hepatol. 2017;16(Suppl. 1: s3-105.):s4-s14. doi:10.5604/01.3001.0010.5493

Dilsaver SC. (2011). An estimate of the minimum economic burden of bipolar I and II disorders in the United States: 2009. J Affect Disord. 129, 79-83.

Dudev T, Mazmanian K, Lim C. Competition between Li+ and Na+ in sodium transporters and receptors: Which Na+-Binding sites are “therapeutic” Li+ targets?. Chem Sci. 2018;9(17):4093-4103. Published 2018 Apr 2. doi:10.1039/c7sc05284g

Ezzaher A, Mouhamed DH, Mechri A, et al. Hyperhomocysteinemia in Tunisian bipolar I patients. Psychiatry Clin Neurosci. 2011;65(7):664‐671. doi:10.1111/j.1440-1819.2011.02284.x

Falhammar H, Lindh JD, Calissendorff J, et al. Differences in associations of antiepileptic drugs and hospitalization due to hyponatremia: A population-based case-control study. Seizure. 2018;59:28-33. doi:10.1016/j.seizure.2018.04.025

Falhammar H, Lindh JD, Calissendorff J, Skov J, Nathanson D, Mannheimer B. Antipsychotics and severe hyponatremia: A Swedish population-based case-control study. Eur J Intern Med. 2019;60:71-77. doi:10.1016/j.ejim.2018.11.011

Fallingborg J. Intraluminal pH of the human gastrointestinal tract. Dan Med Bull. 1999;46(3):183-196.

Feldman AZ, Shrestha RT, Hennessey JV. Neuropsychiatric manifestations of thyroid disease. Endocrinol Metab Clin North Am. 2013;42(3):453-476. doi:10.1016/j.ecl.2013.05.005https://pubmed.ncbi.nlm.nih.gov/24011880/

Fenstermacher DK, Rose RC. Absorption of pantothenic acid in rat and chick intestine. Am J Physiol. 1986;250(2 Pt 1):G155‐G160. doi:10.1152/ajpgi.1986.250.2.G155

Fung J, Mok H, Yatham LN. (2004) Lamotrigine for bipolar disorder: translating research into clinical practice. Expert Rev Neurother. 4, 363‐370.

Gandhi S, Shariff SZ, Al-Jaishi A, et al. Second-Generation Antidepressants and Hyponatremia Risk: A Population-Based Cohort Study of Older Adults. Am J Kidney Dis. 2017;69(1):87-96. doi:10.1053/j.ajkd.2016.08.020

Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT. Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol. 2011;14(1):123‐130. doi:10.1017/S1461145710000805

Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194(1):4-9. doi:10.1192/bjp.bp.107.048504

Göttlicher M. Valproic acid: an old drug newly discovered as inhibitor of histone deacetylases. Ann Hematol. 2004;83 Suppl 1:S91‐S92. doi:10.1007/s00277-004-0850-2

Grande, I., Berk, M., Birmaher, B., and Vieta E. (2016). Bipolar Disorder. Lancet 387, 1561-1572.

Hamed SA. The effect of antiepileptic drugs on thyroid hormonal function: causes and implications. Expert Rev Clin Pharmacol. 2015;8(6):741-750. doi:10.1586/17512433.2015.1091302

Han D, Handelman G, Marcocci L, Sen CK, Roy S, Kobuchi H, Tritschler HJ, Flohé L, Packer L. Lipoic acid increases de https://pubmed.ncbi.nlm.nih.gov/9288403/novo synthesis of cellular glutathione by improving cystine utilization. Biofactors. 1997;6(3):321-38. doi: 10.1002/biof.5520060303.

Hodges RE, Ohlson MA, Bean WB. Pantothenic acid deficiency in man. J Clin Invest. 1958;37(11):1642‐1657. doi:10.1172/JCI103756

Hui Poon S, Sim K, Baldessarini RJ. Pharmacological Approaches for Treatment-resistant Bipolar Disorder. Curr Neuropharmacol. 2015;13(5):592‐604. doi:10.2174/1570159×13666150630171954

Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington (DC): National Academies Press (US); 1998.

Institute of Medicine (US) Panel on Micronutrients. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington (DC): National Academies Press (US); 2001.

Isojärvi JI, Pakarinen AJ, Myllylä VV. Thyroid function with antiepileptic drugs. Epilepsia. 1992;33(1):142-148. doi:10.1111/j.1528-1157.1992.tb02297.x

Johnston AM, Eagles JM. Lithium-associated clinical hypothyroidism. Prevalence and risk factors. Br J Psychiatry. 1999;175:336-339. doi:10.1192/bjp.175.4.336Keck, P.E. Jr. and McElroy S.L. (2002). Carbamazepine and valproate in the maintenance treatment of bipolar disorder. J Clin Psychiatry. 63 Suppl 10:13-7.

Kennebäck G, Bergfeldt L, Tomson T. Electrophysiological evaluation of the sodium-channel blocker carbamazepine in healthy human subjects. Cardiovasc Drugs Ther. 1995;9(5):709-714. doi:10.1007/BF00878554

Kirov G, Tredget J, John R, Owen MJ, Lazarus JH. A cross-sectional and a prospective study of thyroid disorders in lithium-treated patients. J Affect Disord. 2005;87(2-3):313-317. doi:10.1016/j.jad.2005.03.010

Kleiner J, Altshuler L, Hendrick V, Hershman JM. Lithium-induced subclinical hypothyroidism: review of the literature and guidelines for treatment. J Clin Psychiatry. 1999;60(4):249-255.

Klose RJ, Kallin EM, Zhang Y. JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet. 2006;7(9):715‐727. doi:10.1038/nrg1945

Konradi C, Eaton M, MacDonald ML, Walsh J, Benes FM, Heckers S. Molecular evidence for mitochondrial dysfunction in bipolar disorder [published correction appears in Arch Gen Psychiatry. 2004 Jun;61(6):538]. Arch Gen Psychiatry. 2004;61(3):300‐308. doi:10.1001/archpsyc.61.3.300

Krämer, O.H., Zhu, P., Ostendorff, H,P. et al. (2003). The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J. 22, 3411‐3420.

Krause KH, Berlit P, Bonjour JP. Erniedrigung des Biotins als möglicher Faktor im Wirkmechanismus von Atiepileptika [Reduction of biotin level as a possible factor in the mode of action of anticonvulsants (author’s transl)]. Arch Psychiatr Nervenkr (1970). 1982;231(2):141‐148. doi:10.1007/BF00343835

Krause KH, Bonjour JP, Berlit P, Kochen W. Biotin status of epileptics. Ann N Y Acad Sci. 1985;447:297‐313. doi:10.1111/j.1749-6632.1985.tb18447.x

Kumaran S, Patel MS, Jordan F. Nuclear magnetic resonance approaches in the study of 2-oxo acid dehydrogenase multienzyme complexes–a literature review. Molecules. 2013;18(10):11873‐11903. Published 2013 Sep 26. doi:10.3390/molecules181011873

Kürzinger K, Hamprecht B. Na+-dependent uptake and release of taurine by neuroblastoma x glioma hybrid cells. J Neurochem. 1981 Oct;37(4):956-67. doi: 10.1111/j.1471-4159.1981.tb04483.x. PMID: 7320733.

Kuo CC. A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. Mol Pharmacol. 1998;54(4):712-721.

Laurberg P, Jørgensen T, Perrild H, et al. The Danish investigation on iodine intake and thyroid disease, DanThyr: status and perspectives [published correction appears in Eur J Endocrinol. 2006 Oct;155(4):643]. Eur J Endocrinol. 2006;155(2):219-228. doi:10.1530/eje.1.02210

Lee CK, Cheong HK, Ryu KS, et al. Biotinoyl domain of human acetyl-CoA carboxylase: Structural insights into the carboxyl transfer mechanism. Proteins. 2008;72(2):613-624. doi:10.1002/prot.21952

Leonardi R, Jackowski S. Biosynthesis of Pantothenic Acid and Coenzyme A. EcoSal Plus. 2007;2(2):10.1128/ecosalplus.3.6.3.4. doi:10.1128/ecosalplus.3.6.3.4

Leth-Møller KB, Hansen AH, Torstensson M, et al. Antidepressants and the risk of hyponatremia: a Danish register-based population study. BMJ Open. 2016;6(5):e011200. Published 2016 May 18. doi:10.1136/bmjopen-2016-011200

Lewerenz J, Hewett SJ, Huang Y, et al. The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxid Redox Signal. 2013;18(5):522‐555. doi:10.1089/ars.2011.4391

Lu SC. Regulation of glutathione synthesis. Mol Aspects Med. 2009;30(1-2):42‐59. doi:10.1016/j.mam.2008.05.005

Lubrich B, van Calker D. Inhibition of the high affinity myo-inositol transport system: a common mechanism of action of antibipolar drugs? Neuropsychopharmacology. 1999;21(4):519‐529.

Luo S, Kansara VS, Zhu X, Mandava NK, Pal D, Mitra AK. Functional characterization of sodium-dependent multivitamin transporter in MDCK-MDR1 cells and its utilization as a target for drug delivery. Mol Pharm. 2006;3(3):329-339. doi:10.1021/mp0500768

McClure WR, Lardy HA, Kneifel HP. Rat liver pyruvate carboxylase. I. Preparation, properties, and cation specificity. J Biol Chhttps://pubmed.ncbi.nlm.nih.gov/5578910/em. 1971;246(11):3569‐3578.

McGarry JD, Leatherman GF, Foster DW. Carnitine palmitoyltransferase I. The site of inhibition of hepatic fatty acid oxidation by malonyl-CoA. J Biol Chem. 1978 Jun 25;253(12):4128-36. PMID: 659409.

McGarry JD, Mannaerts GP, Foster DW. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest. 1977 Jul;60(1):265-70. doi: 10.1172/JCI108764. PMID: 874089; PMCID: PMC372365.

Nucifora LG, Tanaka T, Hayes LN, et al. Reduction of plasma glutathione in psychosis associated with schizophrenia and bipolar disorder in translational psychiatry. Transl Psychiatry. 2017;7(8):e1215. Published 2017 Aug 22. doi:10.1038/tp.2017.178

Ovesen L, Bendtsen F, Tage-Jensen U, Pedersen NT, Gram BR, Rune SJ. Intraluminal pH in the stomach, duodenum, and proximal jejunum in normal subjects and patients with exocrine pancreatic insufficiency. Gastroenterology. 1986;90(4):958-962. doi:10.1016/0016-5085(86)90873-5

Patel MS, Nemeria NS, Furey W, Jordan F. The pyruvate dehydrogenase complexes: structure-based function and regulation. J Biol Chem. 2014;289(24):16615‐16623. doi:10.1074/jbc.R114.563148

Pérez-Siles G, Morreale A, Leo-Macías A, et al. Molecular basis of the differential interaction with lithium of glycine transporters GLYT1 and GLYT2. J Neurochem. 2011;118(2):195-204. doi:10.1111/j.1471-4159.2011.07309.x

Permoda-Osip A, Dorszewska J, Skibinska M, Chlopocka-Wozniak M, Rybakowski JK. Hyperhomocysteinemia in bipolar depression: clinical and biochemical correlates. Neuropsychobiology. 2013;68(4):193‐196. doi:10.1159/000355292

Prasad PD, Wang H, Kekuda R, et al. Cloning and functional expression of a cDNA encoding a mammalian sodium-dependent vitamin transporter mediating the uptake of pantothenate, biotin, and lipoate. J Biol Chem. 1998;273(13):7501‐7506. doi:10.1074/jbc.273.13.7501

Raffa M, Barhoumi S, Atig F, Fendri C, Kerkeni A, Mechri A. Reduced antioxidant defense systems in schizophrenia and bipolar I disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39(2):371‐375. doi:10.1016/j.pnpbp.2012.07.013

Rathman SC, Blanchard RK, Badinga L, Gregory JF 3rd, Eisenschenk S, McMahon RJ. Dietary carbamazepine administration decreases liver pyruvate carboxylase activity and biotinylation by decreasing protein and mRNA expression in rats. J Nutr. 2003;133(7):2119‐2124. doi:10.1093/jn/133.7.2119

Rathman SC, Eisenschenk S, McMahon RJ. The abundance and function of biotin-dependent enzymes are reduced in rats chronically administered carbamazepine. J Nutr. 2002;132(11):3405‐3410. doi:10.1093/jn/132.11.3405

Rhee TG, Olfson M, Nierenberg AA, Wilkinson ST. 20-Year Trends in the Pharmacologic Treatment of Bipolar Disorder by Psychiatrists in Outpatient Care Settings. Am J Psychiatry. 2020;177(8):706-715. doi:10.1176/appi.ajp.2020.19091000

Rifkin A, Quitkin F, Blumberg AG, Klein DF. The effect of lithium on thyroid functioning: a controlled study. J Psychiatr Res. 1974;10(2):115-120. doi:10.1016/0022-3956(74)90031-4

Robishaw JD, Neely JR. Coenzyme A metabolism. Am J Physiol. 1985 Jan;248(1 Pt 1):E1-9. doi: 10.1152/ajpendo.1985.248.1.E1. PMID: 2981478.

Rosa AR, Singh N, Whitaker E, et al. Altered plasma glutathione levels in bipolar disorder indicates higher oxidative stress; a possible risk factor for illness onset despite normal brain-derived neurotrophic factor (BDNF) levels. Psychol Med. 2014;44(11):2409‐2418. doi:10.1017/S0033291714000014Said HM. Cellular uptake of biotin: mechanisms and regulation. J Nutr. 1999;129(2S Suppl):490S‐493S. doi:10.1093/jn/129.2.490S

Said HM, Redha R, Nylander W. Biotin transport in the human intestine: inhibition by anticonvulsant drugs. Am J Clin Nutr. 1989;49(1):127-131. doi:10.1093/ajcn/49.1.127https://pubmed.ncbi.nlm.nih.gov/2911998/

Salagre E, Vizuete AF, Leite M, et al. Homocysteine as a peripheral biomarker in bipolar disorder: A meta-analysis. Eur Psychiatry. 2017;43:81‐91. doi:10.1016/j.eurpsy.2017.02.482

Scourzic L, Mouly E, Bernard OA. TET proteins and the control of cytosine demethylation in cancer. Genome Med. 2015;7(1):9. Published 2015 Jan 29. doi:10.1186/s13073-015-0134-6

SCRUTTON MC, UTTER MF. PYRUVATE CARBOXYLASE. 3. SOME PHYSICAL AND CHEMICAL PROPERTIES OF THE HIGHLY PURIFIED ENZYME. J Biol Chem. 1965;240:1‐9.

Shao A, Hathcock JN. Risk assessment for the amino acids taurine, L-glutamine and L-arginine. Regul Toxicol Pharmacol. 2008;50(3):376-399. doi:10.1016/j.yrtph.2008.01.004

Sheu KF, Blass JP. The alpha-ketoglutarate dehydrogenase complex. Ann N Y Acad Sci. 1999;893:61‐78. doi:10.1111/j.1749-6632.1999.tb07818.x

Stahl EA, Breen G, Forstner AJ, et al. Genome-wide association study identifies 30 loci associated with bipolar disorder. Nat Genet. 2019;51(5):793‐803. doi:10.1038/s41588-019-0397-8

Stambolic V, Ruel L, Woodgett JR. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells [published correction appears in Curr Biol 1997 Mar 1;7(3):196]. Curr Biol. 1996;6(12):1664‐1668. doi:10.1016/s0960-9822(02)70790-2

Suleiman MS. New concepts in the cardioprotective action of magnesium and taurine during the calcium paradox and ischaemia of the heart. Magnes Res. 1994;7(3-4):295-312.

Suleiman MS, Rodrigo GC, Chapman RA. Interdependence of intracellular taurine and sodium in guinea pig heart. Cardiovasc Res. 1992;26(9):897-905. doi:10.1093/cvr/26.9.897

Sutendra G, Kinnaird A, Dromparis P, et al. A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation. Cell. 2014;158(1):84‐97. doi:10.1016/j.cell.2014.04.046

Tahiliani AG, Beinlich CJ. Pantothenic acid in health and disease. Vitam Horm. 1991;46:165‐228. doi:10.1016/s0083-6729(08)60684-6

Tong L. Structure and function of biotin-dependent carboxylases. Cell Mol Life Sci. 2013;70(5):863-891. doi:10.1007/s00018-012-1096-0

Tresguerres M, Buck J, Levin LR. Physiological carbon dioxide, bicarbonate, and pH sensing. Pflugers Arch. 2010;460(6):953-964. doi:10.1007/s00424-010-0865-6

Thurston JH, Carroll JE, Hauhart RE, Schiro JA. A single therapeutic dose of valproate affects liver carbohydrate, fat, adenylate, amino acid, coenzyme A, and carnitine metabolism in infant mice: possible clinical significance. Life Sci. 1985;36(17):1643‐1651. doi:10.1016/0024-3205(85)90367-4

Tran TQ, Lowman XH, Kong M. Molecular Pathways: Metabolic Control of Histone Methylation and Gene Expression in Cancer. Clin Cancer Res. 2017;23(15):4004‐4009. doi:10.1158/1078-0432.CCR-16-2506

Uhlén M, Fagerberg L, Hallström BM, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. doi:10.1126/science.1260419 https://www.proteinatlas.org/ENSG00000138074-SLC5A6/tissue

Vainionpää LK, Mikkonen K, Rättyä J, et al. Thyroid function in girls with epilepsy with carbamazepine, oxcarbazepine, or valproate monotherapy and after withdrawal of medication. Epilepsia. 2004;45(3):197-203. doi:10.1111/j.0013-9580.2004.26003.x

Vitvitsky V, Thomas M, Ghorpade A, Gendelman HE, Banerjee R. A functional transsulfuration pathway in the brain links to glutathione homeostasis. J Biol Chem. 2006;281(47):35785‐35793. doi:10.1074/jbc.M602799200

Whillier S, Raftos JE, Chapman B, Kuchel PW. Role of N-acetylcysteine and cystine in glutathione synthesis in human erythrocytes. Redox Rep. 2009;14(3):115‐124. doi:10.1179/135100009X392539

Willmroth, F., Drieling, T., Lamla. U., Marcushen. M, Wark HJ, van Calker D. Sodium-myo-inositol co-transporter (SMIT-1) mRNA is increased in neutrophils of patients with bipolar 1 disorder and down-regulated under treatment with mood stabilizers. Int J Neuropsychopharmacol. 2007;10(1):63‐71. doi:10.1017/S1461145705006371

Wolfson M, Bersudsky Y, Zinger E, Simkin M, Belmaker RH, Hertz L. Chronic treatment of human astrocytoma cells with lithium, carbamazepine or valproic acid decreases inositol uptake at high inositol concentrations but increases it at low inositol concentrations. Brain Res. 2000;855(1):158‐161. doi:10.1016/s0006-8993(99)02371-9

Xiao M, Yang H, Xu W, et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors [published correction appears in Genes Dev. 2015 Apr 15;29(8):887]. Genes Dev. 2012;26(12):1326‐1338. doi:10.1101/gad.191056.112

Xu YJ, Arneja AS, Tappia PS, Dhalla NS. The potential health benefits of taurine in cardiovascular disease. Exp Clin Cardiol. 2008 Summer;13(2):57-65. PMID: 19343117; PMCID: PMC2586397.

Zanatta G, Sula A, Miles AJ, et al. Valproic acid interactions with the NavMs voltage-gated sodium channel [published online ahead of print, 2019 Dec 10]. Proc Natl Acad Sci U S A. 2019;116(52):26549-26554. doi:10.1073/pnas.1909696116

Zehnpfennig B, Wiriyasermkul P, Carlson DA, Quick M. Interaction of α-Lipoic Acid with the Human Na+/Multivitamin Transporter (hSMVT). J Biol Chem. 2015;290(26):16372‐16382. doi:10.1074/jbc.M114.622555

Zelikovic I, Stejskal-Lorenz E, Lohstroh P, Budreau A, Chesney RW. Anion dependence of taurine transport by rat renal brush-border membrane vesicles. Am J Physiol. 1989;256(4 Pt 2):F646-F655. doi:10.1152/ajprenal.1989.256.4.F646

Zhou SJ, Zhang LG, Chen HM, et al. Prevalence and clinical-demographic correlates of hyperhomocysteinemia in inpatients with bipolar disorder in a Han Chinese population. Psychiatry Res. 2018;259:364‐369. doi:10.1016/j.psychres.2017.08.063

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