A new way of looking at schizophrenia and other neurolgical illnesses that addresses the fundamental biology of the illnesses
Bipolar Depression
Individuals who are depressed will not benefit from supplemental biotin in much more than RDA amounts due to supplemental biotin biotinylating histones. Pantothenic acid taken alone does not help much. The SMVT is dysregulated, in bipolar disorder, however, a lot of sodium-dependent transporters are dysregulated in neurological illnesses, for example in bipolar disorder. Individuals on mood stabilizers could have biotin and/or pantothenic acid deficiencies but biotin and/or pantothenic acid supplementation in much more than RDA amounts won’t likely help.
Bipolardepression 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.
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, There are no straigtforward treatments that follow from this paper. More research is called for.
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.
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
