Lithium’s Mechanism of Action – A Focus on Neuroprotection

• John Cade rediscovered the use of Lithium for the treatment of Bipolar Disorder (BD) in 1949.
• In the early 20th century, beverages such as Lithia beer and 7-Up contained trace amounts of Lithium. The latter was marketed as a hangover cure.

Mechanism of Action: [4]

1. Glutamate: Glutamate levels are found to be increased in mania and decreased in depression.  Acute administration of Lithium increases levels of glutamate via activation of the NMDA receptor and inhibition of its uptake by inhibiting glutamate transporter. This explains the antidepressant effect. Chronic administration, however, leads to NMDA receptor downregulation with glutamate reuptake upregulation resulting in lowered levels of glutamate which explains the mood stabilisation effect.
2. Dopamine: Lithium reduces the levels of dopamine at the postsynaptic neuron via second messenger pathways i.e. inhibiting G-protein – reduced cyclic AMP (cAMP) – reduced dopamine
3. GABA: GABA is the brain’s inhibitory neurotransmitter, and lithium reduces neuronal excitation by increasing the levels of GABA.
4. Glycogen Synthase Kinase-3 (GSK-3): GSK-3 plays an important role in modulating synaptic plasticity and maintaining cell structure.  Lithium inhibits GSK-3 thus reducing cell death resulting from excitatory neurotransmission.
5. Inositol: Inositol is responsible for the maintenance of myo-inositol levels which inturn maintains cell membrane phospholipid concentrations (phospholipids are important for the binding of second messengers which are responsible for signal transduction within the central nervous system). Lithium reduces excess inositol which inturn stabilises membranes. (Inositol depletion hypothesis).

For a detailed description of Lithium’s mechanism of action along with a visual guide click here.

1. Renal function:

• Lithium limits the ability of the kidney to store free water by reducing the cAMP response to anti-diuretic hormone. This resuts in polyuria and polydisia. Approx. 10% of patients can develop Diabetes Insipidus.
• End-stage renal failure occurs in 0.53% of Lithium treated individuals compared to 0.2% of the general population.
• Review of Lithium-Induced Renal Dysfunction – Pathophysiology | Diagnosis | Management

2. Endocrine Side Effects: 

• Lithium inhibits iodine reuptake, iodotyrosine coupling and thyroxine secretion in the thyroid gland which can result in clincially significant hypothyroidism. (8-19% of patients)
• Lithium decreases parathyroid hormone (PTH) calcitonin binding which reduces urinary calcium clearance. This results in hypercalcaemia due to increased PTH.

3. Cardiac side effects:

• QTc interval prolongation, PR interval prolongation, diffuse T wave inversion and sinus bradycardia.

4. Neurological side effects

• Tremor and changes in cognition.
• Fine tremor is common. Coarse tremor indicates Lithium toxicity.

Researchers from the School of Medicine at Deakin University, the School of Psychological Sciences at Monash University and the Melbourne Neuropsychiatry Centre at the University of Melbourne wanted to examine whether lithium was a better neuroprotective agent than quetiapine following a first episode of mania. [5]

This study involved a cohort of patients with acute first episode mania with psychotic features (n=26) who had been stabilised after a first episode of mania with a combination of lithium and quetiapine. Individuals were then randomly assigned to either lithium (n=20 and a serum level of 0.6 mmol^-1) or quetiapine (n=19 and up to 800 mg per day) monotherapy for 12 months.

In response to treatment over time, white and grey matter volume changes were determined using MRI data acquisition after 3 months and 12 months.

Clinical assessments were also carried out at baseline and then every 2 weeks for the first month and then every 3 months over the following year. Assessments included the Clinical Global Impression Scale in BD; the Montgomery-Asberg Rating Scale for depressive symptoms; YMRS for manic symptoms; and the Brief Psychiatric Rating Scale for severity of psychotic symptoms.

Assessments included the Clinical Global Impression Scale in BD; the Montgomery-Asberg Rating Scale for depressive symptoms; YMRS for manic symptoms; and the Brief Psychiatric Rating Scale for severity of psychotic symptoms.

This study began by determining whether all patients were clinically stabilised after the first episode of mania (with psychotic symptoms) with subsequent treatment with lithium and quetiapine.

The data showed that co-treatment with lithium and quetiapine was successful and that all patients were stabilised at baseline before commencing lithium or quetiapine monotherapy.

Structural MRI showed that all patients had a reduced regional grey and white matter volume in the cortex and the cerebellum at baseline when compared to controls.

After 12 months, the researchers observed that lithium treatment significantly helped to preserve white matter volume when compared to quetiapine treatment. However, both treatment groups had no such effect on grey matter volume changes.

The research group had also shown (published in British Journal of Psychiatry) [6] that in people (61 randomised people) with first episode mania treated with a combination of lithium and quetiapine, continuation treatment with lithium rather than quetiapine is superior in terms of mean levels of symptoms during a 1 year evolution.

This study supports the use of lithium as a neuroprotective agent in the treatment bipolar disorder. This study also showed the benefits of Lithium treatment early in the course of treatment.

According to the authors –

This challenges several guidelines that advocate for lithium use later in the course of the illness.

This study has a small sample size due to the low incidence of first-episode mania patients available at the time of study. As such, the cohort of patients in this study included those with bipolar disorder and schizoaffective disorder.

Since most patients had psychotic symptoms at baseline, this data cannot be extrapolated to non-psychotic individuals.

Drop out rates were high (approx 30%) leading to attrition bias.

Recent advances in neuroimaging analyses have allowed researchers to quantify structural changes in the brain with significant improvements in the acquisition and visualization of imaging data.

Using structural MRI, researchers can now accurately detect white matter hyperintensities (WMHs) in the brain. WMHs are pathological markers of either small vessel vascular disease or areas of focal demyelination.

The hyperintensities viewed on T2-weighted brain MRI images have also been correlated to cognitive and behavioral dysfunction in the ageing brain as well as in some cases of bipolar disorder [7].

Neuroimaging reports suggest that the location and presence of WMHs is indicative of the disruption in white matter microarchitecture and the observed symptoms in patients with bipolar disorder.

1. Reduced glutamate levels and increased GABA – thus reducing neuronal excitation and cell death.
2. Increase neurotrophic factors e.g. Brain-derived neurotrophic factor (BDNF), neuroprotective proteins e.g Bcl-2 group of proteins.
3. Increases N-acetylaspartate (NAA) which is a marker of neuronal health and viability.
4. Lithium competes with magnesium in several enzymatic reactions at substrate sites that require magnesium as a co-factor. In particular, lithium inhibits the enzymes GSK-3B and inositol monophosphatase (IMP), both of which have implications in neurodegenerative diseases such as Alzheimer’s disease as well as being relevant in neuropsychiatric disorders [8].
5. Although bipolar disorder is hypothesized to be a myelin disorder that is not associated with nerve cell loss, WMHs and myelin disruption are suggested to be important in the expression of bipolar symptoms [9]. Here, lithium has been shown to play a protective role in myelin physiology by enhancing the remyelination of peripheral neurons.

All the above mechanisms reflect in larger brain volumes of key areas that regulate cognition and emotions.

Patients treated with Lithium have larger hippocampal and amygdala volumes than healthy controls and those not on Lithium therapy

Read a Visual Guide on Lithium’s Mechanism of Action. 

Read a Visual Guide on Lithium’s Mechanism of Action.