If the\u00a0bipolar lifestyle<\/a>\u00a0is a rollercoaster ride, then lithium is one of the more established seatbelts available.\u00a0Lithium is considered the\u00a0gold standard<\/a>\u00a0treatment for bipolar. While it is not as effective in the treatment of acute\u00a0depression<\/a>, it is very effective for acute\u00a0mania<\/a>\u00a0as well as for maintaining\u00a0stability<\/a>.<\/p>\n Technically\u00a0lithium<\/a>\u00a0is just another element; number three on the\u00a0periodic table<\/a>. But let it lose an\u00a0electron<\/a>\u00a0and start\u00a0sharing<\/a>\u00a0with other molecules, and it becomes a\u00a0salt<\/a>\u00a0with special qualities. Credit for viability and proof of this salt –\u00a0Li2<\/sub>CO3<\/sub><\/a>\u00a0– belongs to the Australian scientist\u00a0John Cade<\/a>\u00a0who experimented with lithium after observations he made as a\u00a0POW<\/a>\u00a0at the\u00a0Japanese<\/a>\u00a0Changi Prison<\/a>.<\/p>\n Despite therapeutic lithium’s\u00a0age<\/a>\u00a0– Cade’s rediscovery was in 1949 – there remains a lot to\u00a0learn<\/a>\u00a0about its mechanism of action as a mood\u00a0stabilizer<\/a>, and what\u00a0is<\/em>\u00a0known about shows it to be very different to\u00a0other<\/a>\u00a0mood modifying drugs<\/a>. What follows are a few outlines of molecular pathways indicated in lithium treatment, especially those that support what’s known as the\u00a0inositol-depletion\u00a0hypothesis<\/a>.\u00a0<\/em>This hypothesis holds lithium’s therapeutic mechanism as being due to indirectly decreasing inositol levels.<\/p>\n The inositol-depletion hypothesis implies that a reduction in a sugar called\u00a0inositol<\/a>\u00a0is vital. This reduction results in a complex sequence of molecular interactions that have the net effect of altering\u00a0neuronal<\/a> behaviour in such a way as to endorse emotional stability. It follows, as a corollary, a\u00a0counter<\/a>-hypothesis: deviations in inositol-involved pathways predispose individuals to bouts of emotional extremities (see below).<\/p>\n 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<\/a>) that produces inositol. The significance of inositol in bipolar, and thereby its effect on by lithium, is supported by the fact that\u00a0ot<\/a>her<\/a>\u00a0traditional bipolar treatments also affect inositol. That said, the inositol-depletion\u00a0hypothesis<\/em>\u00a0remains just that, and clinical data has yet to convincingly\u00a0prove<\/a>\u00a0inositol’s role in either pathology or treatment.<\/p>\n Even if inositol regulation is responsible for its therapeutic effect, that effect could be due to any number of downstream changes.<\/p>\n One pathway could be the inositol production of\u00a0membrane lipids<\/a>\u00a0that are positively involved in the release of\u00a0calcium<\/a>\u00a0(Ca2+<\/sup><\/a>). Lithium attenuates this pathway, and consequentially reduce calcium’s modulation of\u00a0neurotransmitter<\/a>\u00a0release.\u00a0Another pathway is that of\u00a0protein kinase C<\/a>\u00a0(PKC<\/a>) whose level, activity and prerequisite translocation to the cell membrane are inhibited by lithium.<\/p>\n 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\u00a0gene expression<\/a>, 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’\u00a0cytoskeleton<\/a>. 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.\u00a0Growth cones<\/a>\u00a0are the tips of neurons’ neurites,\u00a0hence<\/a>\u00a0their place for sending messages to one another, and thus a change that would be expected to some degree in bipolar treatment.<\/p>\n 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.<\/p>\n 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\u00a0signal transducers<\/a>, etc) can also serve as a\u00a0biomarker<\/a>\u00a0for bipolar.<\/p>\n Lithium inhibits inositol recycling:<\/p>\n Downstream effects following from Myo-inositol inhibition:<\/p>\n…lithium depletes inositol levels…<\/h3>\n
…inositol affects protein activity, level, and location…<\/h3>\n
…yet still so difficult to diagnose the lithium-inositol link.<\/h3>\n
\nAppendix I: Signal Transduction<\/h5>\n
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