Potential mechanisms of action of lithium in bipolar disorder : current understanding

TLDR: It is clear that the processes which underpin the therapeutic actions of lithium are sophisticated and most likely inter-related.

Abstract: Lithium has been used for over half a century for the treatment of bipolar disorder as the archetypal mood stabilizer, and has a wealth of empirical evidence supporting its efficacy in this role. Despite this, the specific mechanisms by which lithium exerts its mood-stabilizing effects are not well understood. Given the inherently complex nature of the pathophysiology of bipolar disorder, this paper aims to capture what is known about the actions of lithium ranging from macroscopic changes in mood, cognition and brain structure, to its effects at the microscopic level on neurotransmission and intracellular and molecular pathways. A comprehensive literature search of databases including MEDLINE, EMBASE and PsycINFO was conducted using relevant keywords and the findings from the literature were then reviewed and synthesized. Numerous studies report that lithium is effective in the treatment of acute mania and for the long-term maintenance of mood and prophylaxis; in comparison, evidence for its efficacy in depression is modest. However, lithium possesses unique anti-suicidal properties that set it apart from other agents. With respect to cognition, studies suggest that lithium may reduce cognitive decline in patients; however, these findings require further investigation using both neuropsychological and functional neuroimaging probes. Interestingly, lithium appears to preserve or increase the volume of brain structures involved in emotional regulation such as the prefrontal cortex, hippocampus and amygdala, possibly reflecting its neuroprotective effects. At a neuronal level, lithium reduces excitatory (dopamine and glutamate) but increases inhibitory (GABA) neurotransmission; however, these broad effects are underpinned by complex neurotransmitter systems that strive to achieve homeostasis by way of compensatory changes. For example, at an intracellular and molecular level, lithium targets second-messenger systems that further modulate neurotransmission. For instance, the effects of lithium on the adenyl cyclase and phospho-inositide pathways, as well as protein kinase C, may serve to dampen excessive excitatory neurotransmission. In addition to these many putative mechanisms, it has also been proposed that the neuroprotective effects of lithium are key to its therapeutic actions. In this regard, lithium has been shown to reduce the oxidative stress that occurs with multiple episodes of mania and depression. Further, it increases protective proteins such as brain-derived neurotrophic factor and B-cell lymphoma 2, and reduces apoptotic processes through inhibition of glycogen synthase kinase 3 and autophagy. Overall, it is clear that the processes which underpin the therapeutic actions of lithium are sophisticated and most likely inter-related.

Figures

Table 1. The actions of lithium on second messenger systems

Full text

1
CNS Drugs 2013; 27 (2)
Review Article
Running title: Potential Mechanisms of Action of Lithium in Bipolar Disorder
Potential Mechanisms of Action of Lithium in Bipolar Disorder
Current Understanding
Gin S. Malhi
1,2
, Michelle Tanious
1,2
, Pritha Das
1,2
, Carissa Coulston
1,2
and Michael Berk
3-6
1
Discipline of Psychiatry, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
2
CADE Clinic, Department of Psychiatry, Royal North Shore Hospital, St. Leonards, Sydney, NSW,
Australia
3
Deakin University, School of Medicine, Barwon Health, Geelong, VIC, Australia
4
Orygen Youth Health Research Centre, Parkville, VIC, Australia
5
Mental Health Research Institute, University of Melbourne, Kenneth Myer Building, Parkville, VIC,
Australia
6
University of Melbourne, Department of Psychiatry, Royal Melbourne Hospital, Parkville, VIC,
Australia
Correspondence: Gin S. Malhi, CADE Clinic, Level 5, Building 36, Royal North Shore
Hospital, St Leonards, Sydney, NSW 2065, Australia.
Email: gin.malhi@sydney.edu.au

2
Fig. 1 Lithium actions. Lithium exerts its effects at multiple levels beginning with clinical changes to
mood by counteracting mania and depression and diminishing suicidality. Evidence for the effects of
lithium on cognition from neuropsychological and functional magnetic resonance imaging studies point
overall towards cognitive compromise; however, evidence for this has been mixed. Structural imaging
studies have provided evidence of neuroprotection with increased grey matter volumes in particular in the
amydgala, hippocampus and prefrontal cortical regions in lithium-treated patients. Changes to
neurotransmission that have clinical impact may be explained through increased inhibitory and decreased
excitatory neurotransmission in lithium-treated patients. At the intracellular level, lithium influences
second messenger systems, which modulate neurotransmission and facilitate cellular viability by
promoting anti-oxidant defences, decreasing apoptosis and increasing neuroprotective proteins. AC adenyl
cyclase, bcl-2 B-cell lymphoma 2, BDNF brain-derived neurotrophic factor, GSK glycogen synthase
kinase, MARCKS myristoylated alanine-rich c kinase substrate, PKC protein kinase C, ↑ indicates
increased, ↓ indicates decreased
Fig. 2 The actions of lithium on pre- and post-synaptic neurotransmission. The facilitatory actions of
lithium are depicted in green, and its inhibitory actions in red. Lithium inhibits excitatory
neurotransmission by decreasing pre-synaptic dopamine activity and inactivating post-synaptic G-
proteins. It also exerts an inhibitory effect downstream on the AC system, and via effects on cAMP,
modulates further neurotransmission. Similarly, lithium promotes inhibitory neutrotransmission through
its modulation of glutamatergic neurotransmission by downregulating the NMDA receptor and inhibiting
the mI second messenger system, which is responsible for maintaining signalling efficiency. When
activated, the mI system leads to phosphorylation of PI, which in turn initiate two second messenger
pathways involving DAG and IP
3
. These components of the phosphorylation cycle are responsible for
modulating neurotransmission and regulating genetic transcription. Chronic modulation of this cycle
through lithium exposure eventually alters gene transcription, which ultimately produces long-term
changes in neurotransmission. Lithium additionally inhibits neurotransmission by facilitating the release
of GABA and upregulating the GABA
B
receptor. AC adenyl cyclase, cAMP cyclic adenosine
monophosphate, DAG diaglycerol, IP
3
inositol triphosphate, mI myo-inositol, PI phosphoinositides, ↑
indicates increased, ↓ indicates decreased
Fig. 3 The effects of lithium on second messenger pathways. The inhibitory actions of lithium are
depicted in red, and its facilitatory actions are depicted in green. (a) AC/cAMP system. Lithium
modulates this system in several ways: initially, basal levels of AC and cAMP are increased.
Consequently, when a cell is stimulated, large fluctuations of AC and cAMP that would normally occur

3
are minimized, therefore stabilizing the system. The CREB transcription factor is an important
downstream target of the AC system and is activated by lithium, which facilitates the production of
neuroprotective factors including BDNF and bcl-2. (b) The PI cycle. Lithium inhibits the PI cycle: the PI
cycle is activated following stimulation of the cell surface receptor by a neurotransmitter. PLC mediates
the hydrolysis of PIP
2
to the secondary messengers DAG and IP
3.
These then activate downstream
signalling pathways. ImPase and IPPase facilitate recycling of IP
3
back into mI, which then allows the PI
cycle to continue. Lithium inhibits cellular mI by: (1) blocking the reuptake of inositol via inhibition of
the SMIT and (2) via direct inhibition of IPPase and ImPase. Overall, this results in the inhibition of
transmembrane signalling and triggering of autophagy. (c) PKC, MARCKS, GSK-3: lithium inhibits
PKC, MARKS and GSK-3: PKC and MARCKS are downstream targets of DAG, and thus direct
inhibition by lithium reduces pre- and post-synaptic excitatory neurotransmission. GSK-3 plays a major
role in cellular structure and resilience. Direct and indirect inhibition of this kinase by lithium activates
the Akt neuroprotective pathway. (d) Autophagy: lithium ultimately inhibits this process. Autophagy is
induced by the intracellular calcium released from the mitochondria by IP
3.
The mTOR protein is
activated by lithium and is a negative regulator of autophagy and therefore inhibits this process. Lithium-
induced depletion of IP
3
also induces autophagy; however, its inhibitory effects through the mTOR
protein are more potent. AC adenyl cyclase, bcl-2 B-cell lymphoma 2, BDNF brain-derived neurotrophic
factor, cAMP cyclic adenosine monophosphate, CREB cAMP response element binding, DAG
diaglycerol, GSK-3 glycogen synthase kinase 3, ImPase inositol monophosphate 1-phosphatase, IPPase
inositol phosphate 1-phosphatase, IP
3
inositol triphosphate, MARCKS myristoylated alanine-rich c kinase
substrate, mI myoinositol, mTOR mammalian target of rapamycin, PI phosphoinositide, PIP
2
phosphoinositol 4-5-biphosphate, PKC protein kinase C, PLC phospholipase C, SMIT sodium myo-
inositol transporter

4
Keywords: BDNF; Bipolar-disorders; Depression; Dopamine; Gamma-aminobutyric-acid; Lithium;
Mania; Neuroprotection.

5
Abstract
Lithium has been used for over half a century for the treatment of bipolar disorder as the archetypal mood
stabilizer and has a wealth of empirical evidence supporting its efficacy in this role. Despite this, the
specific mechanisms by which lithium exerts its mood-stabilizing effects are not well understood. Given
the inherently complex nature of the pathophysiology of bipolar disorder, this paper aims to capture what
is known about the actions of lithium ranging from macroscopic changes in mood, cognition and brain
structure to its effects at the microscopic level on neurotransmission and intracellular and molecular
pathways. A comprehensive literature search of databases including MEDLINE, EMBASE and
PsychINFO was conducted using relevant keywords and the findings from the literature were then
reviewed and synthesized. Numerous studies report that lithium is effective in the treatment of acute
mania and for the long-term maintenance of mood and prophylaxis; in comparison, evidence for its
efficacy in depression is modest. However, lithium possesses unique anti-suicidal properties that set it
apart from other agents. With respect to cognition, studies suggest that lithium may reduce cognitive
decline in patients; however, these findings require further investigation using both neuropsychological
and functional neuroimaging probes. Interestingly, lithium appears to preserve or increase the volume of
brain structures involved in emotional regulation such as the prefrontal cortex, hippocampus and
amygdala possibly reflecting its neuroprotective effects. At a neuronal level, lithium reduces excitatory
(dopamine and glutamate) but increases inhibitory (GABA) neurotransmission; however, these broad
effects are underpinned by complex neurotransmitter systems that strive to achieve homeostasis by way of
compensatory changes. For example, at an intracellular and molecular level, lithium targets second-
messenger systems that further modulate neurotransmission. For instance, the effects of lithium on the
adenyl cyclase and phospho-inositide pathways as well as protein kinase C may serve to dampen
excessive excitatory neurotransmission. In addition to these many putative mechanisms, it has also been
proposed that the neuroprotective effects of lithium are key to its therapeutic actions. In this regard,
lithium has been shown to reduce the oxidative stress that occurs with multiple episodes of mania and

Frequently asked questions

Q1. What are the key kinases that activate apoptosis?

When cells are exposed to an insult such as excessive glutamate excitation, certain kinases are activated through phosphorylation, specifically c-Jun N-terminal kinase and p38 mitogen-activated protein [163, 164] . 

Q2. What contributions have the authors mentioned in the paper "Running title: potential mechanisms of action of lithium in bipolar disorder potential mechanisms of action of lithium in bipolar disorder current understanding" ?

Lithium has been shown to significantly reduce the risk of suicide, and this unique property sets it apart from other medications used for the treatment of bipolar disorder this paper. 

Q3. What are the future works mentioned in the paper "Running title: potential mechanisms of action of lithium in bipolar disorder potential mechanisms of action of lithium in bipolar disorder current understanding" ?

It is therefore important to note that the potential mechanisms of action of lithium that have been detailed in this paper are tentative and that there are many aspects that require replication and further research. By integrating basic sciences research and clinical studies it is hoped that a more complete picture of the actions of this enigmatic element will emerge and that it may also provide insights into the pathophysiology of bipolar disorder. 

Q4. What is the role of mitochondria in the pathophysiology of bipolar disorder?

As well as being the energy centre of the cell, mitochondria play a central role in mediating apoptosis and regulating intracellular calcium, both of which have implications for neurotransmission and neuroprotection [123, 167, 168] . 

Q5. What is the role of GABA in the pathophysiology of bipolar disorder?

anincrease in GABA in response to lithium reduces the level of glutamate and this downregulates the NMDA receptor [108] .5.4 SummaryIt is important to note that whilst specific neurotransmitter systems have been strongly implicated in the pathophysiology of bipolar disorder, these systems are highly interconnected via complex neural networks [102] . 

Q6. What are the key words used to identify relevant articles?

keywords that were used to identify relevant articles included „bipolar disorder‟, „lithium‟, „mechanisms of action‟, „therapeutic actions‟, „efficacy‟, „anti-suicidal‟, „neuroprotection‟, „neuroprogression‟, „brain structure‟, „functional magnetic resonance imaging‟, „neuropsychology‟, „neurocognition‟, „cognition‟, „neurotransmission‟, „dopamine‟, „glutamate‟, „gamma-aminobutyric acid‟, „NMDA‟, „G-protein‟, „second messenger systems‟, „adenylyl cyclase‟, „phosphoinositide‟, „inositol‟, „protein kinase C‟, „myristoylated alanine-rich C kinase substrate‟, „intracellular calcium‟, „brain derived neurotrophic factor‟, „apoptosis‟, „oxidative stress‟, „mitochondria‟, „bcl-2‟, „glycogen synthase kinase 3‟ and „autophagy‟. 

Q7. What regions have shown improvement in grey matter volume?

Regions that have shown improvement include the anteriorcingulate, ventral prefrontal cortex, paralimbic association cortex [78, 80] , superior temporal gyri [81] , left amygdala [82, 83] and hippocampus [61, 84-86] . 

Q8. What is the role of calpain in apoptotic pathways?

Calpain is a protease that has a role in apoptotic pathways, and is activated by intracellular calcium [160] .6.2 Neuroprotective Pathways 

Q9. how much does lithium reduce the risk of suicide?

evidence shows that the risk of suicide in lithium-treated patients is six times less than patients not taking lithium [3] , and that the risk of death by suicide, as well as the risk of self-harm, is reduced by 60 % and 70 %, respectively [5, 45] . 

Q10. In what regions of the brain have reductions been observed in bipolar disorder patients?

Reductions have also been observed in the dorsomedial and left parietal prefrontal cortex in depressed bipolar disorder patients [71] . 

Q11. What is the role of lithium in the neuroprotective role of bipolar disorder?

As previously mentioned, bipolar disorder is increasingly recognized as a degenerative disease for which lithium has been shown to be neuroprotective. 

Q12. how long does lithium take to exert its therapeutic effects?

the effects of lithium on SMIT take approximately 8 days, which is similar to the time lithium takes to exert its therapeutic effects clinically [134] . 

Q13. What is the role of CREB in neuronal plasticity?

CREB is of particular interest because of its effects on brain-derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (bcl-2) genes that are thought to play a key role in neuronal plasticity (see discussion in Sect 6.2.2 and Sect 6.2.3) [9] 

Q14. What does the literature say about the mI depletion hypothesis?

Studies on animals and animal models of mood disorders, as well as investigations of neural cell cultures and brain slices, have produced inconclusive evidence in relation to the mI depletion hypothesis.