1. Lithium: Mechanism of Action
Flavio Guzman, MD

2. Lithium: multiple levels of action
Brain structure
Neurotransmitter modulation
Intracellular changes

3. Changes in brain structure
Abnormalities found in bipolar disorder:
Hippocampus
Amygdala
Striatum
Fronto-limbic network
Malhi, G. S., Tanious, M., Das, P., Coulston, C. M., & Berk, M. (2013). Potential mechanisms of action of lithium in bipolar disorder. CNS drugs, 27(2),

4. Lithium and neuroprotective effects
Anterior Cingulate Cortex (ACC)
Malhi, G. S., Tanious, M., Das, P., Coulston, C. M., & Berk, M. (2013). Potential mechanisms of action of lithium in bipolar disorder. CNS drugs, 27(2),

5. Lithium and neuroprotective effects
Superior temporal gyrus
Malhi, G. S., Tanious, M., Das, P., Coulston, C. M., & Berk, M. (2013). Potential mechanisms of action of lithium in bipolar disorder. CNS drugs, 27(2),

6. Lithium and neuroprotective effects
Ventral prefrontal cortex
Malhi, G. S., Tanious, M., Das, P., Coulston, C. M., & Berk, M. (2013). Potential mechanisms of action of lithium in bipolar disorder. CNS drugs, 27(2),

7. Lithium and neuroprotective effects
Other regions
Paralimbic association cortex
Left amygdala
Hippocampus
Malhi, G. S., Tanious, M., Das, P., Coulston, C. M., & Berk, M. (2013). Potential mechanisms of action of lithium in bipolar disorder. CNS drugs, 27(2),

8. Lithium and neuroprotective effects
Neuroimaging findings:
Neuroprotective and neuroproliferative effects (preservation of grey matter)
Mechanism unknown
Clinical implications not clear
Malhi, G. S., Tanious, M., Das, P., Coulston, C. M., & Berk, M. (2013). Potential mechanisms of action of lithium in bipolar disorder. CNS drugs, 27(2),

9. Lithium modulates neurotransmission
Dopamine receptors
NMDA receptors (Glutamate)
GABA receptors

10. Lithium inhibits dopamine neurotransmission
Cyclical dysregulation hypothesis:
Decreased neurotransmission associated with clinical depression
Downregulation
Mania: dopamine NT is increased
Malhi, G. S., Tanious, M., Das, P., Coulston, C. M., & Berk, M. (2013). Potential mechanisms of action of lithium in bipolar disorder. CNS drugs, 27(2),

11. Lithium inhibits dopamine neurotransmission
Postsynaptic activation is mediated by GPCR Lithium alters the functionality of GPCR subunits

12. Lithium downregulates the NMDA receptor
NMDA receptor: glutamate receptor
Glutamate: excitatory neurotransmitter elevated during mania
Malhi, G. S., Tanious, M., Das, P., Coulston, C. M., & Berk, M. (2013). Potential mechanisms of action of lithium in bipolar disorder. CNS drugs, 27(2),

13. Lithium downregulates the NMDA receptor
Acute stimulation
Chronic administration: NMDA downregulation
Glutamate NT modulation
Malhi, G. S., Tanious, M., Das, P., Coulston, C. M., & Berk, M. (2013). Potential mechanisms of action of lithium in bipolar disorder. CNS drugs, 27(2),

14. Lithium promotes GABAergic neurotransmission
Inhibitory neurotransmitter
Modulates dopamine and glutamate NT
Patients with BD: reduced GABAergic neurotransmission
Malhi, G. S., Tanious, M., Das, P., Coulston, C. M., & Berk, M. (2013). Potential mechanisms of action of lithium in bipolar disorder. CNS drugs, 27(2),

15. Lithium promotes GABAergic neurotransmission
Increases GABA levels in CSF
Presynaptic: facilitates GABA release
Postsynaptic: upregulates GABAB receptors
Malhi, G. S., Tanious, M., Das, P., Coulston, C. M., & Berk, M. (2013). Potential mechanisms of action of lithium in bipolar disorder. CNS drugs, 27(2),

16. Cellular mechanisms Lithium modulates cellular signaling systems:
AC/cAMP
ImPase - IPPase
PKC
GSK-3
BDNF and Bcl-2

17. Lithium inhibits IPPase and IMPase
Phosphoinositide cycle:
Phosphoinositides: precursor of signaling molecules
Enzymes IPPase and IPPase: synthesis of myoinositol (mI)
Lithium MOA: “mI depletion hypothesis”
Schloesser, R. J et al (2007). Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder.Neuropsychopharmacology, 33(1),

18. Lithium inhibits PKC, MARCKS and GSK-3
PKC: Protein Kinase C
MARCKS: Myristoylated Alanine-Rich C Kinase Substrate
Lithium inhibits PKC and MARCKS: antimanic effects
Schloesser, R. J et al (2007). Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology, 33(1),

19. Lithium inhibits PKC, MARCKS and GSK-3
Lithium inhibits GSK-3
GSK-3: Glycogen Synthase Kinase 3
Gene transcription
Synaptic plasticity
Activated under conditions of chronic stress
Schloesser, R. J et al (2007). Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology, 33(1),

20. Lithium facilitates the production of neuroprotective factors
CREB transcription factor:
Downstream target of AC
Activated by lithium
CREB facilitates the production of:
BDNF (neuroprotective)
Bcl-2 (neuroprotective)
Malhi, G. S., Tanious, M., Das, P., Coulston, C. M., & Berk, M. (2013). Potential mechanisms of action of lithium in bipolar disorder. CNS drugs, 27(2),

21. Key points Lithium acts on multiple levels
Neuroprotective effect (BDNF, Bcl-2)
Changes in brain structure: anterior cingulate cortex ventral prefrontal cortex, hippocampus, amygdala
Modulates neurotransmitters: dopamine, glutamate and GABA
Inhibits intracellular proteins: PKC, MARCKS , GSK-3, IPPase, IMPase