Lithium monotherapy is associated with global DNA hypomethylation

Mood Stabilizers and the Influence on Global Leukocyte DNA Methylation in Bipolar Disorder

Lena Backlund,b,d,e,*Ya Bin Wei,b,eLina Martinsson,a,bPhilippe A. Melas,a,eJia Jia Liu,b,e,fNinni Mu,b,eClaes-Göran Östenson,cTomas J. Ekström,a,eMartin Schalling,b,e and Catharina Lavebrattb,e

Abstract

Little is known about the relationship between treatments for bipolar disorder (BD), their therapeutic responses and the DNA methylation status. We investigated whether global DNA methylation levels differ between healthy controls and bipolar patients under different treatments. Global DNA methylation was measured in leukocyte DNA from bipolar patients under lithium monotherapy (n = 29) or combination therapy (n = 32) and from healthy controls (n = 26). Lithium response was assessed using the Alda scale. Lithium in monotherapy was associated with hypomethylation (F = 4.63, p = 0.036). Lithium + valproate showed a hypermethylated pattern compared to lithium alone (F = 7.27, p = 0.011). Lithium response was not associated with DNA methylation levels. These data suggest that the choice of treatment in BD may lead to different levels of global DNA methylation. However, further research is needed to understand its clinical significance.

My take – In bipolar patients not on medications there could be a global DNA hypomethylation. Whether lithium results in global DNA hypomethylation, there is a pre-existing global DNA hypermethylation in bipolar disorder or both is not clear from this research.

Serendipity and drug discovery

Frequently scientists talk about the serendipitous finding that leads to important discoveries. In psychiatry serendipitous drug discoveries, however, may not advance understanding of psychiatric illnesses very much. Dopamine antagonists are useful in the treatment of schizophrenia but there has been no revolution in the understanding of schizophrenia resulting from the discovery that dopamine antagonists can partially treat schizophrenia. Lithium has uses but lithium has not revolutionized the understanding of bipolar disorder.

A lot of research seems directed at finding the hidden fact that will be the key to unraveling a disease. Researchers seem to be in search of serendipity which is not how serendipity works. Psychiatric research would better off if there was more emphasis on basic research with translational research then sticking closely to basic research. Succeeding at translational research may require that all the various factors that complicate a hypothesis be considered. The devil is the details. Possessing a sliver of truth is surer route to scientific discovery than searching for serendipity.

The basic idea that the transsulfuration pathway is dysregulated in schizophrenia is a simple idea but treatment is complicated by the fact that downstream pathways from the transsulfuration pathway have to be addressed. Treatment would be so much simpler if only lowering homocysteine levels worked or only increasing l-cysteine levels worked but neither do. There can be effective treatments for schizophrenia that address the fundamental biology of schizophrenia but there can be no simple effective treatments for schizophrenia that address the fundamental biology of schizophrenia.

Occam’s razor and mood stabilizing drugs for bipolar disorder

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Occam’s razor – the simplest explanation is usually the right one. How do mood stabilizers work to stabilize mood?

Lithium can stabilize sodium-dependent transporters and sodium-dependent G-protein coupled receptors in inactive states. Lithium  reduces activity of various 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).

Occam’s razor applied to mood stabilizers – Mood stabilizers work by affecting sodium-dependent transporters and/or sodium-dependent G-protein coupled receptors.

Huge increase in anti-psychotic usage in bipolar disorder in recent years

In the treatment of bipolar disorder anti-psychotics have increasingly become more commonly prescribed, increasing from 12.4% of outpatient visits for bipolar disorder in the 1997-2000 period to 51.4% in the 2013-2016 period.

The page on bipolar disorder of this site both points to why lithium and anti-convulsants work at all while also pointing to why lithium and anti-convulsants are very inadequate treatments for bipolar disorder. Lithium and anti-convulsants target the SMVT but do so poorly where the dysregulation of the sodium-dependent multivitamin transporter (SMVT) is only one factor that gives rise to bipolar disorder.

Anti-psychotics are terrible drugs but many psychiatrists and patients find them preferable to lithium and anti-convulsants.