Bipolar Depression

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As I have stated on this blog I think there is a key connection between iron and psychosis. The treatment suggested for bipolar depression would likely not be a treatment for psychosis. Supplements on the ‘supplements too be avoided’ list on the Treatment page would have to be avoided. Coffee, sodas and tea should be avoided. A couple of 100 mg caffeine capsules a day should be OK. Supplements that supply cysteine would have to be avoided. Supplementation with cysteine, cystine, n-acetyl-cysteine, l-methionine and/or s-adenosyl-l-methione would all have to be avoided. Lipoic acid must not be supplemented.

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

Thomas Berry1, Ahmed A. Moustafa1,2

1School of Psychology & Marcs Institute for Brain and Behaviour, Western Sydney University, Sydney, New South Wales, Australia.

1,2 Department of Human Anatomy and Physiology, the Faculty of Health Sciences, University of Johannesburg, South Africa  

Abstract

Bipolar depressions could be 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 and as mood stabilizers, but not effective in 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 would stabilize mood but leave bipolar depressions untreated. Bipolar disorder depressions are now extremely difficult to treat.We propose that prescribing supplements, which address dysregulation of the SMVT, to patients with low levels of biotin, pantothenate, protein bound iodide and/or CoA, who are not taking mood stabilizers but who are on antipsychotics, would treat bipolar depression.

Key words: bipolar disorder; biipolar depression; sodium-dependent multivitamin transporter (SMVT);  treatment.

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). Unlike[AM4]  mania, bipolar depression is particularly difficult to treat (Hui Poon et al., 2015). New pharmacological treatments are needed for bipolar disorder especially for bipolar depression[AM5] . This paper provides a review of the 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[TB6] . 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). The effectiveness of lithium, valproic acid, and carbamazepine and lamotrigine in treating  bipolar disorder can be explained by their effects on transport by the sodium-dependent multivitamin transporter (SMVT[AM7] ).

  In this paper, we will will discuss the effects of lithium and anticonvulsants on transport by the SMVT.  Effects of lithium and anticonvulsants on sodium homeostasis and how alterations in sodium homeostasis could affect transport by the SMVT are also discussed.  Next the paper discusses how dysregulation of the SMVT could lead to various symptoms of bipolar disorder. Then how dysregulation of the tricarboxylic acid cycle attendant on dysregulation of the SMVT can lead to the variety of symptoms seen is bipolar disorder is discussed. Next how dysregulation of the SMVT could lead to thyroid abnormalities is discussed.  How sodium homeostasis could be upset in bipolar disorder is next addressed where sodium dysregulation is seen as due to dysregulation of the transsulfuration pathway which dysregulates taurine metabolism upsetting sodium 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 sodium-dependent multivitamin transporter (SMVT) transports pantothenate[AM8] [TB9]  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 paper. Transport of pantothenate is blocked by lithium (Fenstermacher et al., 1986, Subsequently lithium  was found to block the SMVT(Zehnpfennig et al., 2015[AM10] [TB11] ) which explains why lithium blocks transport of pantothenate.  Lithium can displace sodium on sodium-dependent transporters (Dudev et al., 2018). Lithium by displacing sodium on the SMVT could be decreasing transport of biotin, pantothenate and iodide by the SMVT. Lithium can reduce 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).

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

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 CoA levels (Thurston et al.,1985; Deutsch et al. 2003). CoA is synthesized from pantothenate.

The SMVT and bipolar disorder  

 Acetyl-CoA carboxylase is a biotin-dependent enzyme that synthesizes malonyl-CoA which is required for the first step in the synthesis of fatty acids (Lee et al.  2008). Acetyl-CoA carboxylase requires bicarbonate to produce malonyl-CoA (Tong, 2013). Malonyl-CoA inhibits beta-oxidation (McGarry et al., 1978; McGarry et al., 1977). With low levels of malonyl-CoA due to low activity of acetyl-CoA carboxylase, there will be an increased beta-oxidation while at the same time fatty acid synthesis is impaired.  Malonyl CoA is metabolized to acetyl-CoA and carbon dioxide by malonyl-CoA decarboxylase (Buckner et al., 1976).  Carbon dioxide exists in equilibrium with bicarbonate where  bicarbonate in conjunction with carbon dioxide and protons acts as a buffer for pH (Tresguerres et al., 2010).    With actions of acetyl-CoA carboxylase closely tied to levels of bicarbonate and carbon dioxide appropriate activity of acetyl-CoA carboxylase is required for appropriate pH buffering.  The SMVT is dependent on pH with increases in transport of substrates occurring with increases in acidity (Luo et al., 2006). pH of the human gastrointestinal tract is acidic and can change rapidly (Fallingborg, 1999, Ovesen et al., 1986). A pH buffer in the gastrointestinal tract, where biotin, pantothenate  and iodideare absorbed, could be particularly important.  Dysregulation of acetyl-CoA carboxylase due to biotin deficiencies would dysregulate gastrointestinal pH, further dysregulating the SMVT.    

 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 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). Bicarbonate is the CO2 donor for biotin-dependent carboxylases ((Tong, 2013).

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 tricarboxylic acid (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). Bipolar disorder is associated with swings in mood and energy (Grande et al., 2016). Plausibly switches in 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 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.

 Individuals with bipolar disorder can have a variety of symptoms[AM12] . 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.

 TCA cycle intermediates regulate DNA methylation and histone methylation (Xiao et al., 2015; 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-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).  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.               

 Valproic acid is a histone deacetylase inhibitor (Krämer et al., 2003; Göttlicher, 2004). The pyruvate dehydrogenase complex synthesizes acetyl-CoA which can be 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. Reregulating 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.

Hypothyroidism due to lithium and anticonvulsants

 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). There could be pre-existing dysregulations of the SMVT prior to patients with bipolar disorder being treated with mood stabilizers which could lead 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 as antidepressants.

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). 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). In post-mortem brains of individuals who had bipolar disorder there are decreased levels of glutathione (Gawryluk et al., 2011).

 Dysregulation of sodium 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 sodium (Chesney et al., 1990). (Zelikovic et al., 1989;  Bryson et al., 2001) Na/taurine cotransporters can work in reverse (Tamai et al., 1995)  The Na/taurine symporter results in an efflux of sodium and taurine from cells when either rise above their physiological level in cells (Suleiman et al.,  1992). Taurine given long term decreases intracellular sodium levels (Bkaily et al., 2020) which would increase extracellular sodium enhancing transport by the SMVT, which is sodium-dependent. Dysregulation of the transsulfuration pathway could dysregulate taurine synthesis which would lead to dysregulation of sodium homeostasis and dysregulation of the SMVT.

A possible add-on treatment for bipolar depression

Given tests shows levels of biotin, pantothenate , protein bound iodide and/or CoA levels  are low in patients with bipolar depression who are not being treated with mood stabilizers a supplement trial in bipolar depression to address dysregulation of the SMVT would be warranted. The suggested supplements would only be prescribed for patients with bipolar disorder who are not on mood stabilizers. Antipsychotics are currently more commonly prescribed than mood stabilizers for bipolar disorder (Rhee et al., 2020). Antipsychotics can be associated with hyponatremia (Falhammar et al., 2019), however, the action of antipsychotics are held to be due effects the effects of antipsychotics on dopaminergic neurotransmission.  Aripiprazole, which is frequently used in bipolar disorder, is not associated with hyponatremia (Falhammar et al., 2019).  Antidepressants are associated with hyponatremia (Gandhi et al., 2017; Leth-Møller et al., 2016).  At first the suggested supplements would only be an add-on to patients being treated with only antipsychotics who also have low biotin levels, low pantothenate levels, low protein bound iodide levels and/or low CoA levels. 

Supplements listed in Table 1. could be useful for the treatment of bipolar depression.

Table 1.

SupplementReasonResearch as to Safety
high dosages of biotin taken away from pantothenic acidincrease biotin levelsInstitute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline, 1998
pantothenic acid take taken away from biotinIncreases pantothenic acid levels by passive diffusionInstitute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline, 1998
iodine taken away from pantothenic acidthe SMVT transports iodide Supplementation with iodine will prevent competitive inhibition of iodide absorptionInstitute 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. 2001.
butter or gheesupports increased beta-oxidation and supplies non-essential fatty acidsKhaw et al., 2018
taurineregulates Na+ levelsShao and Hathcock, 2008;  Chen et al., 2012; Xu YJ e al., 2008
and assists with fat absorption

sodium bicarbonate supports biotin containing enzymes Abramowitz et al. 2013

 The Institute of Medicine (US) was unable to set a Tolerable Upper Intake Level (UL) for pantothenic acid or biotin 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 or biotin (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; Crisp et al.,  2004 ) which would reduce pantothenic uptake.  Pantothenic acid deficiencies are associated with apathy, fatigue, and malaise (Hodges et al., 1958).  Patients presenting with malaise are difficult to diagnose as apathy, fatigue and malaise can have many causes.  Supplementing with both pantothenic acid and biotin would be safer than supplementing with only pantothenic acid or biotin. The Tolerable Upper Level Limit for iodine is 1100 micrograms a day Institute of Medicine, 2001). With acetyl-CoA carboxylase dysregulated various saturated non-essential fatty acids are not synthesized.  Butter or ghee will supply various non-essential saturated fatty acids that are not being synthesized due to dysregulation of acetyl-CoA carboxylase.  Butter can raise cholesterol levels (Khaw et al., 2018). Taurine will assist with the absorption of the fatty acids.  Taurine conjugated with bile acids aids fat absorption (Di Ciaula  et al., 2017).  Taurine reduces cholesterol levels (Chen et al., 2012). The Observed Safe Level for taurine is 3000 milligrams a day (Shao and Hathcock, 2008). Research indicates that taurine can decrease cardiovascular disease (Xu YJ e al., 2008).

L-cysteine would not be supplemented. L-cysteine can be highly toxic when supplemented (Baker, 2006). 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, must 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). Lipoic acid could also competitively inhibit transport of biotin, pantothenic and/or iodide by the SMVT.

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 could be acting 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 swings while difficulties fatty acid synthesis could bring on long lasting depressions.  

 Hypermethylation of DNA and/lor histones at the SMVT locus could result in low levels of biotin, pantothenate  and/or CoA and upset iodine homeostasis.   With decreased transport of pantothenate 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.  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 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 invesnigate biotin levels, pantothenate levels, protein bound iodide levels and CoA 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 SMVT is highly expressed in the proximal digestive tract (Uhlén et al., 2015).  Genes for the SMVT and histones at the SMVT loci in the gastrointestinal tract could be hypermethylated. Research or the methylation status of genes for the SMVT and histones at the SMVT loci in the gastrointestinal tract in bipolar disorder would be very helpful.  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. Supplemental biotin, pantothenic acid, iodide, butter or ghee and taurine could alleviate depressions in patients in depressive phases of bipolar disorder who are only taking antipsychotics,  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.         

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