Lithium: Wonder Drug? Part II

Posted by kkiritah on October 16, 2014 in Drugs, Mental Illness, Neurodegenerative disorders, Neuroscience, Pharmacology | Leave a comment

Note from the author: This post is dedicated to my biology nerds out there.  If you follow my Gene-of-the-Week posts (and you should because they’re the weirdest), you know that I often get lost in the cellular and molecular details of life, and it’s totally overwhelming.  I wrote this post specifically to discuss the mechanisms of action of lithium, so it is by far the most overwhelming and technical NeuWriteSD post I’ve ever written (and I have written several).  The main idea is that lithium can do a lot of crazy (good) things in our bodies.  If you haven’t taken a bio course in a while, you might want to just skim, but if you’re up for it, I think it’s worth suffering through the details!  Think of this post as that textbook chapter you read to procrastinate reading that other, required textbook chapter when you were in college.  Because you definitely used to do that, too, right??  Anyway, moving on… 

A couple of weeks ago, Melissa introduced us to the history and potential wonders of lithium.  She examined Dr. Anna Fels’ claim that trace amounts of lithium in drinking water may have positive effects against suicide and dementia.  In her New York Times op-ed, Dr. Fels suggested the possibility of adding a micro-dose of lithium to our soft drinks, vitamins, and maybe even the water supply!  After reading Melissa’s article and surveying some relevant literature (e.g.: Marmol, 2008; Mauer et al., 2014; Vita et al., 2014), I was mostly in favor of adding a little extra lithium to my diet here and there, but there was still too much left to wonder about this “wonder drug.”  I still needed to know…how does it work?!

During my quest to answer this question, I found out that lithium works in far too many ways to discuss adequately in a single post.  Nevertheless, I will do my best to give a broad yet satisfying and not-too-boring overview of all the things that lithium can do to protect against mania, depression, suicide, and neurodegeneration.  Additional, boring-to-some details can be found in boxed paragraphs.  And for those of you left craving yet more detail at the end of this post, I’ll direct you to reviews by Chiu & Chuang (2010) and Oruch et al. (2014) and wish you luck.

Li⁺ the Ion

Lithium, weighing in at just 6.941amu, is the lightest, least dense metal.  Although we haven’t yet found a vital function for the element, it is widely abundant and is considered, by some, an “essential” element (Schrauzer, 2002).  In nature, lithium easily gives up its outer electron, forming a stable cation, Li⁺.  Once in our bodies, the cation Li⁺ competes with other, more abundant cations, such as sodium (Na⁺), potassium (K⁺), calcium (Ca²⁺), and magnesium (Mg²⁺).  Competition with these cations is, in fact, one of lithium’s many proposed mechanisms of action.

All of our cells maintain an electrochemical gradient.  The movement of ions in and out of cells is adjusted, in part, to balance charges and concentrations across the cell membrane.  In 1945, Klein et al. studied the metabolic activity of a bipolar patient, “H. L—” (nope, the line isn’t a typo!), and found that the amount of Na⁺ and Cl^– in his urine were significantly higher when he was manic than when he was not.  This suggested that his cells, including his neurons, were irregularly balanced during mania.  Later, Shaw (1966) and others (Dubovsky et al., 1989) reported that additional bipolar patients had elevated intracellular Na⁺ and Ca²⁺ concentrations that were normalized upon lithium treatment.  In neurons, these high intracellular cation concentrations mean lower membrane resting potential (i.e., increased excitability due to Na⁺ buildup) and higher probability of neurotransmitter release (which is dependent on Ca²⁺).  It seems that when Li⁺ enters these excitable cells, it displaces Na⁺ and (as Na⁺ is actively pumped out by the sodium-potassium pump) stays there, slowing Na⁺ transport and regulating neuronal excitability.  It is unclear if Li⁺ influences Ca²⁺ activity in a similarly seemingly-simple manner or if it decreases Ca²⁺ concentration via more convoluted means.  In any case, the ionic mechanism of lithium is just one of its many modes of action which may or may not contribute to its anti-suicidal and anti-neurodegenerative effects.

Lithium and Neurotransmission

First, let’s talk about the anti-suicidal effects of lithium.  Suicide is complicated, and its biological roots are difficult to determine (for a well-researched review, I recommend the book  Night Falls Fast by Kay Redfield Jamison).  Even so, it is believed that increased impulsivity and aggression contribute to suicidal tendencies.  Both impulsivity and aggression may be a result of low serotonin availability.  For example, depletion of tryptophan (a serotonin precursor) increases impulsivity (Hughes, 2003) and a subgroup of bipolar patients with high aggression, impulsivity, and suicidality were found to have significantly low plasma levels of 5-hydroxyindoleacetic acid (5-HIAA, the main serotonin metabolite; Coccaro and Siever, 1989).  Lithium has been found to decrease levels of aggression and impulsivity (Cipriani et al., 2013), likely by increasing serotonin release (Baumann et al., 1996).

Compared to the ionic theory of action, the idea of lithium-induced serotonergic modulation is more in line with our general notion of psychiatric medications acting on neurotransmitter systems.  Lithium may also reduce presynaptic dopaminergic activity, as well as prevent dopamine receptor upregulation and supersensitivity (Lenox and Frazer, 2002; although the primary sources for this claim are elusive…).  Finally, there is evidence that the noradrenergic system is also involved in suicide and depression and lithium’s treatment of both (Valdizán et al., 2003; Bunney and Bunney, 2013).  Though the details are still unraveling, it is likely that the effects of lithium on multiple neurotransmitter systems are important for its beneficial psychological effects in patients.

Lithium the Neuroprotector  

Okay, so the ionic and neurotransmitter mechanisms seem to be the main hypotheses for lithium’s action in bipolar disorder and suicide prevention.  But there’s also been a lot of talk about the benefit of lithium treatment for neurodegenerative diseases.  In fact, the bulk of recent research on lithium seems to be dedicated to its (many) neuroprotective and neurotrophic effects.  Despite its relative novelty in the public realm, lithium is now accepted by science as a bona fide neuroprotector.  This means that it can prevent or slow neuronal atrophy or apoptosis (programmed cell death).  It can protect against the following types of neuronal injury in the following ways (Chiu and Chuang, 2010):

• glutamate-induced excitotoxicity: implicated in stroke, Huntington’s disease, ALS, brain trauma, spinal cord injury, Alzheimer’s disease, Parkinson’s disease
  • lithium fights this via inhibition of NMDA receptor-mediated calcium influx—interestingly, this effect is not found with other monovalent cations or antidepressants (Hashimoto et al., 2002)
  • also: glutamate inactivates but lithium activates the PI3K/Akt pathway, which activates CREB and deactivates “Bcl-2 associated death promoter” (aka BAD, lol)
• endoplasmic reticulum (ER) stress: the ER regulates calcium activity; ER dysfunction is related to impaired synaptic plasticity in bipolar disorder, Alzheimer’s disease, and cerebral eschemia
  • Lithium treatment protects against ER stress via activation of activator protein 1 (AP-1) and anti-apoptotic protein Bcl-2 (Hiroi et al., 2005)
• growth factor withdrawal, β-amyloid, high potassium deprivation, and anticonvulsive treatment:
  • Lithium may somehow tackle all of the above via the MEK/ERK pathway, which activates CREB and inhibits GSK-3β.  I’ll talk about GSK-3 in a minute, but CREB also does a lot, like regulating glutamate synapses and promoting expression of cell-protective proteins like BDNF (discussed below) and Bcl-2!
• Lithium also downregulates expression of pro-apoptotic molecules, such as p53 and Bax (Marmol, 2008)

Lithium and GSK-3 Inhibition

In addition to the above, one of lithium’s major neuroprotective roles is as an inhibior of GSK-3.  GSK-3 (which comes in two flavors, α and β) is a serine/threonine kinase that mediates various signaling pathways.  In general, it is pro-apoptotic and a major regulator of inflammation.  GSK-3 dysfunction has been implicated in mood disorders, schizophrenia, diabetes, cancers, and autoimmune diseases (Marmol, 2008).  Li⁺, as it sometimes does, directly competes with Mg²⁺ to inhibit the ATP-magnesium-dependent catalytic activity of GSK-3.  Lithium also enhances phosphorylation of GSK-3 at various points to indirectly inhibit its activity.

In the context of bipolar disorder, GSK-3 inhibitors reduce hyperactivity and produce anti-depressive effects in mice, similar to the effects of lithium (Marmol, 2008).  Lithium may also help restore circadian function, which is disrupted in patients with bipolar disorder.  Lithium inhibits and reduces transcription of GSK-3β.  In doing so, it may cause the degradation of specific proteins (e.g., Rev-erbα) to restore oscillatory gene expression necessary for circadian activities, such as sleep and metabolism (Yin et al., 2006).  Finally, GSK-3 may be an important pathway through which aberrant serotonergic signaling induces abnormal behavior, so drugs that target serotonin levels, such as selective serotonin reuptake inhibitors (SSRIs) may also act through the GSK-3 pathway (Beaulieu et al., 2008).

Lithium the Neurotrophic Factor

In addition to being a neuroprotector, lithium is a neurotrophic factor.  Neurotrophic factors increase proliferation, differentiation, growth, and regeneration of cells.  For example, lithium induces expression of brain-derived neurotrophic factor (BDNF), a major neurotrophin that is essential for cortical development, synaptic plasticity, and cell survival.  Lithium’s GSK-3β inhibition increases vascular endothelial growth factor (VEGF), which promotes cell proliferation, differentiation, and migration of neuronal progenitor cells, as well as astrocytes, and increases neurovascular remodeling after stroke (Oruch et al., 2014).  Through the GSK-3 and ERK pathways, lithium has been shown to enhance neurogenesis in the hippocampus of normal mice (Chen et al., 2002) and restore neurogenesis in an animal model of Down’s syndrome (Bianchi et al., 2010).

Lithium treatment of other diseases:

All of the effects of lithium described above should make its potential in treating other diseases obvious, but here are some specific examples to take home:

• Many forms of stroke are induced by excessive increases in extracellular glutamate following ischemia.  See above for the benefits of lithium against glutamate-induced excitotoxicity.  So far, studies in rats have found that long-term pre-treatment and also immediate post-ischemia treatment with lithium can decrease damage and neurological deficits that follow stroke (Ren and Senatorov, 2003).
• Hyperactivation/sensitivity of NMDA receptors may contribute to the pathophysiology of Huntington’s disease, so the effect of lithium against glutamate-induced excitotoxicity should be similarly effective in patients with HD.  In fact, in the 1970s, lithium was found to reduce chorea and improve voluntary movements and motor function in patients with HD  (Mattsson, 1973).
• Abnormal increases in GSK-3 levels and activity are associated with Alzheimer’s disease. In addition to inhibiting GSK-3, chronic lithium has been found to block Aβ production and reduce tau phosphorylation (Sun et al., 2002; Pérez et al., 2003).
• Lithium has been shown to improve motor function and slow of disease progression in a mouse model of ALS.  This may be due to its pro-autophagy activity, as well as VEGF induction and GSK-3 inhibition.
• Lithium can also be used to help treat prion diseases!  Prion diseases are caused by aggregates of an abnormal isoform of prion protein (PrP).  PrP-induced cell death is mediated through GSK-3 and therefore blocked by lithium.  Induction of autophagy may also increase clearance of PrP (Heiseke et al., 2009). Nice!

Therapeutic lithium v. Li⁺ on tap

As I wrap up this post, I want to remind you that the trace amounts of lithium that may be present in our drinking water, and eventually in our dietary supplements, are several orders of magnitude lower than therapeutic amounts.  The effects of such small doses may be completely different from those described above, which are based on therapeutic amounts.  The exact mechanisms underlying the anti-suicide and anti-neurodegenerative effects of trace amounts of lithium, as well as the long-term effects of such consumption, remain and ought to be explored.

I think Melissa and I have made a fairly strong case for trace lithium, but maybe you’re still a little leery of lithium on tap.  If so, just know that lithium has a half-life of 12 hours, and although it can accumulate in the body (particularly in the elderly), it probably won’t reach very high levels.  If it does, it has not been found to be carcinogenic nor mutagenic, so that’s a relief!  The addition of such small amounts should not affect patients taking therapeutic doses either, and regular monitoring is always necessary, so any dangerous fluctuations due to dietary exposure will probably be caught (Chiu and Chuang, 2010; Oruch et al., 2014)… so I don’t know about you, but I’m willing to give it a try!

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