Lithium Mechanism of Action: 2025 Updated Synopsis and Visual Guide

1. 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.
2. 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. [Malhi et al, 2013]
3. 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.

1. GABA is an inhibitory transmitter that also plays a role in modulating glutamate and dopamine.
2. Patients with bipolar affective disorder have diminished GABA neurotransmission. Thus, low GABA levels can result in excitatory toxicity.
3. Lithium increases the levels of GABA which in turn reduces glutamate and downregulates the NMDA receptor.
4. Lithium also directly activates the GABA receptor.

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.

1. 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.
2. 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).
3. Acute administration of lithium increases basal levels of AC and cAMP by inhibiting the G inhibitory protein.
4. Once cells are stimulated, Lithium transfers stability to the signalling system by reducing Gs activity.
5. Thus, lithium modulates cAMP and AC activity to avoid large fluctuations

Myo-inositol (mI) levels are elevated in patients with mania. Lithium inhibits ImPase and IPPase which reduces the availability of myo-inositol and PI’s.

1. PI’s are precursors for many molecules important in mediating CNS neurotransmission.
2. 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).
3. 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.
4. 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.
5. Lithium-induced inhibition of ImPase and IPPase depletes cellular mI, and this compromises the production of PI.

SMIT

Lithium inhibits the sodium myo-inositol transporter and reduces the availability of inositol and thus myo-inositol.

1. Extracellular inositol can also enter the cell via a high-affinity sodium mI transport (SMIT) system, which also regulates mI levels.
2. Lithium inhibits the expression and activity of the SMIT system, thus limiting the entry of inositol into the cell and produces further depletion.
3. The effects of lithium on SMIT take approximately 8 days,
   which is similar to the onset of Lithium’s clinical onset of action.

1. PKC is a family of calcium- and phospholipid-dependent enzymes involved in mood regulation. Conventional isoforms (α, βI, βII, γ) require calcium and diacylglycerol, while novel isoforms (δ, ε, η, θ, λ) are activated by diacylglycerol alone. [Zarate and Manji,2009].
2. These enzymes are abundant in presynaptic terminals of the prefrontal cortex, amygdala, and hippocampus, where they regulate excitability, neurotransmitter release, glutamate signalling, and neuroplasticity. Dysregulation contributes to neuroinflammation, mitochondrial dysfunction, oxidative stress, and apoptosis.  [Bortolozzi et al., 2024]
3. During mania, increased PKC activity has been observed in both cortical and peripheral regions. [Saxena,et al, 2017].
4. Acute lithium treatment transiently activates PKC, but chronic lithium downregulates PKC and its substrate MARCKS in the hippocampus, an effect linked to neuroprotection. [Malhi et al, 2013], [Bortolozzi et al., 2024]
5. Inhibiting PKC reduces manic-like behaviours and hippocampal degeneration in animal models. A meta-analysis has linked the PKCε locus with suicidality, and genetic studies suggest overlap between PKC signalling and lithium responsiveness. [Khayachi et al, 2021]. 
6. Both lithium and valproate inhibit PKC activity in vitro and in vivo, highlighting PKC as a therapeutic target.
7. Among pharmacological inhibitors, tamoxifen has demonstrated antimanic efficacy but remains unapproved, whereas endoxifen has recently been approved for the treatment of mania in India. [Ahmad et al, 2021].

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.

1. Production of IP3 and DAG via the MI pathway initiates PKC activation and the release of intracellular calcium respectively.
2. Lithium inhibits the PI cycle which reduces intracellular calcium which in turn reduces excitatory toxicity.

NMDA receptor

1. Lithium also blocks the uptake of calcium into cells, and attenuates the calcium activation of the NMDA receptor.

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.

Lithium enhances pro-apoptotic proteins contributing to its neuroprotective effect

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.

Mania is associated with increased mitochondrial respiration and ATP production, while depressive episodes show reduced mitochondrial function. [Bortolozzi et al., 2024]

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.

Lithium enhances mitochondrial biogenesis, improves respiratory chain function, and reduces markers of oxidative stress. [Bortolozzi et al., 2024]

It also modulates the unfolded protein response and promotes autophagy, thereby preserving neuronal integrity under conditions of cellular stress.

These mechanisms collectively support lithium’s role in counteracting neuroprogression in bipolar disorder, where repeated mood episodes are hypothesised to induce cumulative neurobiological injury.

Watch this video by Prof Berk to learn more about oxidative stress.

1. BDNF is an important neuroprotective protein which is known to be decreased in both manic and depressed phases of bipolar affective disorder.
2. 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.
3. 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.
4. 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.
5. Bcl-2 is another neuroprotective protein that regulates cellular pathways and reduces apoptosis. Lithium increases BDNF and Bcl-2
6. In addition to increasing BDNF and Bcl-2, lithium regulates AMPA receptor trafficking and strengthens homeostatic synaptic plasticity, thereby stabilising excitatory-inhibitory balance.
7. Structural neuroimaging studies have corroborated these effects, showing increased grey matter volumes in regions including the hippocampus, amygdala, and prefrontal cortex among lithium-treated patients. These findings support a direct link between lithium’s molecular effects and its clinical profile as both a mood stabiliser and a cognitive protector.[Bortolozzi et al., 2024]

• GSK-3 is an enzyme responsible for glycogen synthesis.  GSK-3 is involved in gene transcription, synaptic plasticity, cell structure, and resilience.
• Lithium directly inhibits glycogen synthase kinase-3 (GSK3), a serine/threonine kinase central to glycogen metabolism and multiple cellular functions [Bortolozzi et al., 2024]
• Lithium acts at the magnesium-binding site of GSK3 and indirectly inhibits its activity via serine phosphorylation at Ser21 (GSK3α) and Ser9 (GSK3β). Inhibition is also achieved through upstream kinases including Akt, PKA, PKC, MAPKs, and mTOR.
• GSK3 is constitutively active, unlike most kinases, and is inhibited by extracellular signals. It interacts with numerous substrates, including transcription factors, glycolytic enzymes, apoptotic regulators, mitochondrial channels, receptors, and cytoskeletal proteins.
• Dysregulation of GSK3 has been implicated in diabetes, insulin resistance, Alzheimer’s disease, Parkinson’s disease, schizophrenia, MDD, and BD.
•  Post-mortem and peripheral studies link impaired inhibitory control of GSK3 with depression, and hyperactivity of GSK3 with mania. [Bortolozzi et al., 2024]
• In BD, decreased serine phosphorylation of GSK3 is observed during acute states, with levels normalising following lithium therapy.
• Preclinical models show that GSK3β downregulation mimics lithium’s behavioural effects, while GSK3β overexpression reverses them.
• GSK3 inhibitory peptides also reproduce lithium’s behavioural outcomes.
• Lithium disrupts β-arrestin 2/Akt/GSK3 signalling and interferes with PP1/I-2 complexes, thereby sustaining Akt activity and prolonging GSK3 inhibition.
• This sensitises cells to weaker extracellular signals, such as neurotrophins and neurotransmitters, potentially explaining lithium’s ability to augment antidepressants in resistant depression.
• Both valproate and antidepressants (including ketamine) suppress GSK3 indirectly via phosphorylation at Ser21/9.
• However, selective GSK3β inhibitors (e.g., AZ1080, compound A) do not fully replicate lithium’s behavioural or molecular effects, nor do they increase BDNF, suggesting that GSK3 inhibition is necessary but not sufficient for lithium’s therapeutic profile.
• Lithium’s efficacy across manic and depressive phases reinforces the central role of GSK3 modulation, though the exact contribution to its mood-stabilising and neuroprotective effects remains incompletely understood.
• Ongoing efforts to develop selective GSK3β inhibitors, aided by machine learning, may help separate therapeutic benefits from lithium’s toxicity profile.

Autophagy is the process that is present in response to cellular stress and is responsible for the creation of intracellular proteins.

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.

An autophagosome, a type of membrane-bound vacuole, exists for only around 10 to 20 minutes before fusing with a lysosome. A lysosome is an active organelle in cells that digests cell components which are no longer needed, as well as bacteria.

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.

Altered autophagy markers, such as beclin-1 and LC3, have also been identified in schizophrenia, suggesting a broader role of impaired autophagy in psychiatric illness. [Bortolozzi et al., 2024]

• Protein homeostasis in neurons depends on balanced synthesis and degradation, with the removal of damaged or misfolded proteins being essential for cellular resilience, given the absence of cell division. [Bortolozzi et al., 2024]

• Lithium influences proteostasis by reducing protein synthesis and enhancing protein degradation, thereby regulating both proteasomal activity and autophagy.

• Lithium can both inhibit and induce autophagy, depending on the pathway being engaged.

• Through GSK-3 inhibition, lithium may reduce autophagic activity, as GSK-3 is one of the regulators of autophagy initiation. [Yu & Greenberg, 2016]

• Unlike rapamycin, which induces autophagy via mTOR inhibition, lithium promotes autophagy through an mTOR-independent pathway. This mechanism involves inositol depletion, mediated by inhibition of IMPase and inositol transporters, which reduces intracellular IP3 levels. [Bortolozzi et al., 2024]

• Lithium-induced inositol depletion exhibits a positive feedback mechanism, becoming more pronounced with higher concentrations of the IMP–IMPase complex. [Yu & Greenberg, 2016].

• These actions may mitigate neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, and dementias, through clearance of abnormal aggregates or by maintaining neuronal protein balance. Lithium facilitates the breakdown of aggregation-prone proteins, including mutant huntingtin, phosphorylated tau, and α-synuclein. [Motoi et al, 2014]. 

• Preclinical studies demonstrate that lithium-induced autophagy enhances clearance of misfolded proteins in animal models of neurodegeneration.

• In bipolar disorder, evidence points to mitochondrial dysfunction linked to impaired autophagy, with mood stabilisers, including lithium, shown to prevent this dysfunction.

• The therapeutic effects of lithium may therefore involve autophagy as a central mechanism underlying both its antimanic and antidepressant properties. Other autophagy-inducing drugs, such as valproate and rapamycin, also display mood-stabilising effects despite being developed for other indications. [Puglisi-Allegra et al, 2021].

A growing body of evidence highlights the role of immune dysregulation in bipolar disorder, with recurrent episodes associated with elevated inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α) and activation of microglial pathways.

Lithium exerts immunomodulatory effects by inhibiting key intracellular regulators such as NF-κB and TLR4, leading to downstream suppression of pro-inflammatory gene transcription [Bortolozzi et al., 2024]

These actions contribute to stabilising glial–neuronal interactions and reducing excitotoxic cascades.

In addition, lithium has been shown to normalise aberrant cytokine profiles, shifting the immune response away from a pro-inflammatory (Th1/Th17) bias toward a more balanced or regulatory phenotype.

This is consistent with clinical findings that lithium may reduce peripheral inflammatory markers in patients with bipolar disorder.

At an epigenetic level, lithium also regulates the expression of microRNA involved in immune signalling, adding another layer to its long-term neuroprotective action.

The concept of neuroinflammation as a driver of neuroprogression is particularly relevant here: chronic low-grade inflammation may accelerate neuronal loss and cognitive decline, analogous to other progressive conditions such as multiple sclerosis.

By attenuating these processes, lithium may function not just as a symptomatic agent but as a disease-modifying treatment in bipolar disorder. These insights integrate clinical and mechanistic observations and may help explain why lithium, when initiated early, is associated with better functional outcomes.

The convergence of lithium’s molecular actions, ranging from GSK3 inhibition and synaptic plasticity regulation to mitochondrial support and immune modulation, places it uniquely within the framework of a disease-modifying agent rather than simply a symptomatic treatment.

Unlike many psychotropics that primarily target neurotransmitter receptors, lithium’s pleiotropic effects span genomic, cellular, and systems-level mechanisms, which may help explain its broad clinical profile and enduring superiority in long-term studies. [Bortolozzi et al., 2024], [Gitlin & Bauer, 2024],

Clinically, this translation manifests in several key domains:

• Neuroprogression: By attenuating neuroinflammation, reducing oxidative stress, and supporting neurotrophic signalling, lithium directly counters processes thought to drive progressive cognitive and functional decline in bipolar disorder.

• Suicide prevention: Lithium’s anti-aggressive and anti-impulsive effects likely stem from its modulation of serotonergic and glutamatergic circuits, as well as its longer-term impact on stress–immune pathways, distinguishing it from other mood stabilisers  [Gitlin & Bauer, 2024],

• Early intervention: Evidence suggests that outcomes are most favourable when lithium is initiated earlier in the illness course, reinforcing the analogy with disease-modifying treatments in neurology. [Post et al, 2025]

• Beyond bipolar disorder: The same mechanisms that provide neuroprotection in mood disorders, such as enhanced autophagy and mitochondrial resilience, are being investigated in conditions including Alzheimer’s disease, Parkinson’s disease, and post-stroke recovery, where lithium shows preliminary but promising benefits. [Bortolozzi et al., 2024],

For psychiatrists, recognising lithium through this mechanistic lens may shift prescribing decisions. Rather than viewing lithium as a ‘last-line’ option, it can be framed as a first-line, disease-modifying agent whose long-term benefits outweigh the practical challenges of monitoring.

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.