Molecular biology of lithium treatment for bipolar affective disorder

Bipolar is often treated with lithium...

If the bipolar lifestyle is a rollercoaster ride, then lithium is one of the more established seatbelts available. Lithium is considered the gold standard treatment for bipolar. While it is not as effective in treatment of acute depression, it is very effective for acute mania as well as for maintaining stability

Technically lithium is just another element; number three on the periodic table. But let it lose an electron and start sharing with other molecules, and it becomes a salt with special qualities. Credit for viability and proof of this salt - Li2CO3 - belongs to the Australian scientist John Cade who experimented with lithium after observations he made as a POW at the Japanese Changi Prison.

Despite therapeutic lithium's age - Cade's rediscovery was in 1949 - there remains a lot to learn about it's mechanism of action as a mood stabilizer, and what is known about shows it to be very different to other mood modifying drugs. What follows are a few outlines of molecular pathways indicated in lithium treatment, especially those that support what's known as the inositol-depletion hypothesis. This hypothesis holds lithium's therapeutic mechanism as being due to indirectly decreasing inositol levels.

...lithium depletes inositol levels...

The inositol-depletion hypothesis implies that a reduction in a sugar called inositol is vital. This reduction results in a complex sequence of molecular interactions that have the net effect of altering neuronal behaviour in such a way as to endorse emotional stability. It follows, as a corrollary, a counter-hypothesis: deviations in inositol-involved pathways predispose individuals to bouts of emotional extremities (see below).

The actual depletion of the inositol by lithium occurs via a number of pathways (see Appendix), but most significantly by lithium's inhibiting the enzyme (IMPase) that produces inositol. The significance of inositol in bipolar, and thereby its effect on by lithium, is supported by the fact that other traditional bipolar treatments also affect inositol. That said, the inositol-depletion hypothesis remains just that, and clinical data has yet to convincingly prove inositol's role in either pathology or treatment.

...inositol affects protein activity, level, and location...

Even if inositol regulation is responsible for its therapeutic effect, that effect could be due to any number of downstream changes.

One pathway could be the inositol production of membrane lipids that are positively involved in the release of calcium (Ca2+). Lithium attenuates this pathway, and consequentially reduce calcium's modulation of neurotransmitter release. Another pathway is that of protein kinase C (PKC) whose level, activity and prerequisite translocation to the cell membrane are inhibited by lithium. 

The above two factors could by direct signal transduction be responsible for lithium's beneficial effect, but given the timeframe involved - on the order of weeks - it is no surprise to expect longer acting and more pervasive alterations. This could be due to changes in gene expression, which is easy to say but at this point in history impossible to assign to any particular pathology or prognosis. In parallel and/or downstream of changes to expression is the likelihood of changes to cells' cytoskeleton. One pertinent way cytoskeletal changes could be evoked is following lithium alteration to membrane phosphatidylinositols (see Appendix) which can signal the production of the infrastructure that underlies growth cones. Growth cones are the tips of neurons' neurites, hence their place for sending messages to one another, and thus a change that would be expected to some degree in bipolar treatment.

...yet still so difficult to diagnose the lithium-inositol link.

At the present time the best evidence for bipolar treatment comes from lithium-inositol studies, that being of course only a single medication and single molecular target amongst a host of others. And yet even here clinical evidence remains poor.

It is possible that research is yet to achieve the spatial or temporal finesse to identify changes to inositol (and related metabolites) in the brain. Changes might only be apparent in particular areas, or under particular circumstances. Additionally it is not clear which inositol phosphate (if at all) should be measured, nor is it safe to assume that just because a molecule is a therapeutic target that it (or its variants or signal transducers, etc) can also serve as a biomarker for bipolar.


Appendix: Signal Transduction

Lithium inhibits inositol recycling:

  • Lithium inhibits IMPase which is an enzyme that converts InsP1 to myo-inositol (this has been confirmed in mammalian brain slices)
  • Lithium inhibits IPP which is an enzyme that converts Ins(1,4)P2 to InsP1
  • Lithium inhibits the transporter SMIT that transports myo-inositol

Downstream effects following from myo-inositol inhibition:

  • Reduced conversion of myo-inositol to PtdIns
  • Reduced phosphorylation of PtdIns varieties
  • Reduced production of DAG which promotes PKC membrane translocation
  • Reduced release of intracellular Ca2+ which promotes PKC membrane translocation
  • Increased axonal growth cones
  • Changes to osmotic-regulation

Appendix: Alternative Targets

Lithium blocks:

  • PAP (3'phosphoadenosine 5'phosphate)
  • PGM (phosphoglucomutase) - involved in glycolysis/energy production
  • GSK-3 (glycogen synthase kinase-3) - as a target, this is the major alternative to the inositol depletion hypothesis. GSK-3 inhibition alters neuronal number and morphology, and can induce changes to behaviour similar to some antidepressants
  • Gene expression via PKC or CamkII

  • Atak J.R. et al Inositol monophosphatase - a putative target for Li+ in the treatment of bipolar disorder (1995) TINS
  • Fountoulakis K.N. An update of evidence based treatment of bipolar depression (2010) Curr Op Psy
  • Harwood A.J. Lithium and bipolar mood disorder: the inositol-depletionhypothesis revisited (2005) Mol Psych
  • Nivoli A.M.A. Lithium: Still a cornerstone in the long-term treatment in bipolar disorder? (2010) Neuropsychol - This paper is a meta-study that evaluating the efficacy of lithium (and comparable medications and placebos) for the treatment of bipolar
  • Sheard M.H. The biological effects of lithium (1980) TINS