Lithium’s Mechanism of Action – A Synopsis and Visual Guide
Lithium is a unique agent that has been used for over half a century for the treatment of bipolar affective disorder. Lithium has compelling evidence in the treatment of mania, acute bipolar depression and prophylaxis in bipolar affective disorder. 
It is also one of the two agents that have anti-suicidal properties in psychiatry, the other being clozapine.  Despite the significant evidence which is in favour of lithium for both prophylaxis of bipolar affective disorder and as an anti-suicidal agent, its use is declining since the beginning of the 21st century.
It thus becomes crucial for clinicians to consider lithium as an important part of the management of bipolar affective disorder. Despite its first discovery 1949 and its subsequent use, the exact mechanisms of action in lithium are unclear.
In this article, we summarise lithium’s multitude of mechanisms of action.
We have previously covered lithium’s mechanism of action with a focus on neuroprotection along with another article on lithium with prescribing and monitoring in clinical practice.
In this article, we focus on two key aspects
- Lithium’s action on neurotransmitters and second messenger systems
- Intracellular mechanisms of action which converge towards neuroprotection.
The main reference for this article is : Potential Mechanisms of Action of Lithium in Bipolar Disorder by Malhi et al., 2013. 
DOPAMINE PATHWAYS - NEUROTRANSMISSION
- Dopamine is an excitatory neurotransmitter that plays an important role in the pathogenesis of bipolar affective disorder. Dopamine transmission is known to be elevated during mania and decreased in clinical depression.
- Postsynaptic dopamine activity is mediated by postsynaptic G proteins which stimulate second messenger systems such as adenyl cyclase (AC) and cyclic adenosine monophosphate (cAMP). Lithium decreases presynaptic dopamine activity and inactivates postsynaptic G protein which reduces excitatory neurotransmission in the brain.
- The subunits of the dopamine associated G protein have been reported to be higher in bipolar disorder patients and may contribute to the pathophysiology of bipolar affective disorder. Lithium administration alters the functionality of these subunits especially the equilibrium between active and inactive subunits thus likely correcting the dopamine dysregulation.
GLUTAMATE PATHWAYS - NEUROTRANSMISSION
- Glutamate is an excitatory neurotransmitter and can lead to excitotoxicity in increased levels.
- Lithium enhances inhibitory neurotransmission by downregulating the NMDA receptor and inhibiting the myoinositol second messenger system directly.
- The Myoinositol (MI) pathway (see later) is responsible for maintaining signal efficiency by the production of two postsynaptic second messenger system pathways on Inositol triphosphate (IP3) and Diaglycerol (DAG), both of which ultimately modulate neurotransmission and regulate gene transcription.
- Lithium modulates the cycle and thus produces long-term changes in neurotransmission and alters gene transcription.
- Lithium also reduces glutamate activity indirectly by decreasing dopamine activity.
- GABA is an inhibitory transmitter that also plays a role in modulating glutamate and dopamine.
- Patients with bipolar affective disorder have diminished GABA neurotransmission. Thus, low GABA levels can result in excitatory toxicity.
- Lithium increases the levels of GABA which in turn reduces glutamate and downregulates the NMDA receptor.
- Lithium also directly activates the GABA receptor.
cAMP SECOND MESSENGER SYSTEM - INTRACELLULAR MECHANISMS
Second messengers are a system that comprises of enzymes and molecules that translate signals that are received by the receptors of the cell surface and by process of signal transduction, translate the signal to a cellular response.
Lithium is known to affect several second messenger systems.
- The AC system is a second messenger system that is activated by monoaminergic transmission. AC is coupled to membrane-bound G-proteins that can stimulate (Gs) or inhibit (Gi) production of cAMP.
- cAMP activates the enzyme Protein kinase A (PKA) which in turn regulates cAMP response element binding protein (CREB) which is directly stimulated by Lithium facilitating the production of neuroprotective factors B-cell lymphoma-2 (Bcl-2) and Brain-derived neurotrophic factor (BDNF).
- Acute administration of lithium increases basal levels of AC and cAMP by inhibiting the G inhibitory protein.
- Once cells are stimulated, Lithium transfers stability to the signalling system by reducing Gs activity.
- Thus, lithium modulates cAMP and AC activity to avoid large fluctuations
THE PHOSPHOINOSITIDE (PI) CYCLE AND THE MYO-INOSITOL DEPLETION HYPOTHESIS
- PI’s are precursors for many molecules important in mediating CNS neurotransmission.
- Activation of a PI cycle-associated membrane receptor stimulates phospholipase C (PLC)-mediated hydrolysis of phosphoinositol-4-5-bisphosphate (PIP2) into inositol triphosphate (IP3) and Diaglycerol (DAG).
- IP3 is then successively phosphorylated via the enzymes inositol phosphate 1-phosphatase (IPPase) and inositol monophosphate 1-phosphatase (ImPase) to replenish myoinositol (mI), which is then used to synthesize PIs.
- mI levels are found to be increased during mania and depression and reduced in the presence of lithium treatment. mI levels are unaffected by lithium in euthymic patients. Thus, it seems that lithium only inhibits myo-inositol when in excess.
- Lithium-induced inhibition of ImPase and IPPase depletes cellular mI, and this compromises the production of PI.
- Extracellular inositol can also enter the cell via a high-affinity sodium mI transport (SMIT) system, which also regulates mI levels.
- Lithium inhibits the expression and activity of the SMIT system, thus limiting the entry of inositol into the cell and produces further depletion.
- The effects of lithium on SMIT take approximately 8 days,
which is similar to the onset of Lithium’s clinical onset of action.
PROTEIN KINASE C AND MYRISTOYLATED ALANINE RICH C KINASE (MARCKS) SUBSTRATE
- During mania increased PKC activity has been found.
- Acute treatment with lithium has shown to activate PKC levels, and over longer periods lithium down regulates PKC and subsequently substrate MARCKS in the hippocampus. This is likely responsible for its neuroprotective effect.
Calcium is a highly diverse cation that plays multiple roles in the cellular functioning from neurotransmission, cellular integrity, metabolism and gene transcription.
Bipolar disorder has significant dysregulation of intracellular calcium.
The most consistent finding of elevation of intracellular calcium levels may be a marker of illness state level and marker.
- Production of IP3 and DAG via the MI pathway initiates PKC activation and the release of intracellular calcium respectively.
- Lithium inhibits the PI cycle which reduces intracellular calcium which in turn reduces excitatory toxicity.
- Lithium also blocks the uptake of calcium into cells, and attenuates the calcium activation of the NMDA receptor.
NEUROPROGRESSION IN BIPOLAR DISORDER
In bipolar disorder, there are several hypotheses that are postulated to lead to neuroprogression
1. Neurosensitisation model: Manic and depressed episodes cause changes in gene progression which alter neuronal activity. This makes the individual more susceptible to relapse and less likely to respond to medication.
2. Allostatic load hypothesis: The wear and tear caused by episodes of mania thus proposes wear and tear of mania and depression, alters the function in key brain circuits which leads to cognitive decline, thus increasing the likelihood of further illness and treatment resistance
3. Neurodevelopmental model: This postulates the decrease in cell density in the bipolar brain due to abnormal neural development.
4. Neuroprogression model: This postulates the disorder follows a progressive course mediated by neuroinflammation, mitochondrial dysfunction and apoptosis.
Lithium enhances neuroprotective effects by preventing apoptosis and promoting cellular longevity.
When cells have excessive glutamate excitatory toxicity, excessive glutamate increases the levels of proapoptotic protein such as p53 and BAX and at the same time reducing BDNF and Bcl-2.
Lithium is known to modulate these apoptotic pathways.
The mitochondria are the energy powerhouses i.e. they produce energy in the form of ATP which the cell can use for its functioning. This process is called oxidative phosphorylation.
The heart and brain are two organs that require large amounts of energy which makes them susceptible to damage if this energy producing function is affected.
ROS are produced as a result of normal production of energy by the mitochondrion and are part of the natural defence system of the microglia to kill invading microorganisms.
Under normal conditions, there is a balance of production of ROS, and homeostasis exists where energy metabolism is at the appropriate level in the mitochondrion, and the microglia are either at rest, because there is no infection, or are responding normally to an injury or infection.
ROS are essential for the normal function of the cell, and underproduction of ROS would lead to a decrease in energy production and a decrease in the ability of microglia to mount a defence against invading organisms.
The other end of the spectrum appears to be the situation in the ageing brain where increased ROS produced from the mitochondrion, and the microglia can lead to damage to lipids, DNA, and proteins.
The brain is especially susceptible to oxidative stress due to lower levels of antioxidant defences such as superoxide dismutase, catalase and glutathione peroxidase, Vit E and glutathione.
Oxidative stress results when the detoxification mechanisms of the body are overwhelmed by the oxidative reactions resulting in free radical damage.
Oxidative stress is known to play a significant role in bipolar affective disorder. Furthermore, mitochondrial dysfunction is present in bipolar affective disorder.
Lithium stimulates the mitochondrial respiratory chain complexes and in doing so protects against oxidative stress.
It is also known to increase levels of N-acetylaspartate (NAA), the marker of mitochondrial function as neuroprotection.
Watch this video by Prof Berk to learn more about oxidative stress.
BRAIN DERIVED NEUROTROPHIC FACTOR AND B-CELL LYMPHOMA 2 (BCL-2)
- BDNF is an important neuroprotective protein which is known to be decreased in both manic and depressed phases of bipolar affective disorder.
- However, it is found to be increased in patients treated with lithium in combination with other medication. BDNF levels have shown to increase after five days of lithium administration.
- Clinically lithium takes approximately 6 to 10 days to trigger an antimanic effect and some research have suggested this delay is the time needed to to reach to neuroprotective levels.
- Lithium is also known to affect other growth factors such as epidermal growth factor and insulin growth factor, although this mechanism is less well known than BDNF.
- Bcl-2 is another neuroprotective protein that regulates cellular pathways and reduces apoptosis. Lithium increases BDNF and Bcl-2
GLYCOGEN SYNTHASE KINASE 3 (GSK-3)
- GSK-3 is an enzyme responsible for glycogen synthesis. GSK-3 is involved in gene transcription and synaptic plasticity cell structure and resilience.
- GSK-3 increases under chronic stress conditions and can lead to hyperactivity.
- Lithium has been shown to increase synaptic plasticity and decrease GSK expression.
Autophagy is the process that is present in response to cellular stress and is responsible for the creation of intracellular protein.
Autophagy is a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress.
Autophagy plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens.
The mammalian target of rapamycin (mTOR) is a negative regulator of the autophagic process.
GSK-3 activates mTOR and decreases autophagy. However, IMPase inhibition via lithium decreases IP3 levels which in turn induces autophagy.
Hence lithium both inhibits and induces autophagy by reducing GSK-3 and IMPase respectively.
SUMMARY OF INTRACELLULAR SECOND MESSENGER TARGETS AND LITHIUM'S EFFECTS
Thus, lithium acts on several molecules and neurotransmitters that are involved in neurotransmission and intracellular apoptotic and neuroprotective pathways.
By researching the mechanisms of action, a complete picture of the actions is likely to emerge, which may also provide insight into the pathophysiology of bipolar affective disorder.