PHM142 Fall 2015
Instructor: Dr. Jeffrey Henderson
Neuropharmacology of
Lithium
By: Kathryn Carson, Brandon LeBlanc, Daniel Greco, Ashour Barkho
What is Lithium?
 Monovalent cation
 Competes for monovalent/divalent cellular sites
 Often sites involved in the synthesis, storage, release and
reuptake of neurotransmitters (NTs)
 Ex. alters Na+ transport in neurons
 Drug Class: antimanic – mood stabilizer
 Non-pharmacological use = lithium batteries
What is it used for?
Indications:
Health Canada Approved
 Management of acute manic episodes
 Maintenance treatment of bipolar disorder
Off-Label Uses
• Augmentation therapy in patients with treatment-resistant
depression
• Prophylactic management of chronic cluster headaches
Formulations
Lithium carbonate
 Extended release tablet
 Immediate release capsule
Lithium citrate
• Syrup
Oral Administration
 Well absorbed from the GI tract
 Crosses the blood brain barrier (BBB)
 Css reached within 4 days
 Full effect may take 10-21 days following initiation of therapy
What exactly is Bipolar Disorder?
Bipolar disorder is a complex, recurrent mood disorder
• Formerly called manic depression
• Patients experience manic episodes and major depressive
episodes
• Affects 1-2% of the population
Patients experience reocurring episodes:
• Manic episodes
• Major depressive episodes
Clinical Role of Lithium
Lithium is a first line treatment for bipolar disorder
• Exerts its effects primarily on manic episodes
• Functions to manage deppresive episodes
In Canada Lithium is sold under the brand names
Carbolith, Lithmax, Lithane, Duralith
Goals for therapy:
• Control symptoms of episodes
• Prevent reoccurence
Important Considerations
Lithium has a very narrow therapeutic window
• Patients must be monitored regularly while on treatment
Lithium is a teratogen
• Capable of passing the placenta and present in breast milk
• Causes heart defects in developing fetus
Primarily excreted renally
• Issues arise when renal function is impaired
Mechanism of Action
• Many hypothesized mechanisms:
- Telomere shortening prevention, increased mitochondrial function,
and regulation of circadian rhythm.
• Li+ and Mg2+ competition:
- Diagonal relationship.
- Electronegativity and atomic radii.
http://ch301.cm.utexas.edu/svg/atomic-ionic-radii.svg
Mota de Freitas, D., et al, Acc. Chem. Res., 39, 2006, 283-291.
+
Li
competition of
• Glycogen synthase kinase 3β:
- Inhibition promotes
neuroprotection.
- GSK-3β is pro-apoptotic.
Interest: Pharmacological
inhibition led to anti-manic and
anti-depressant effects.
Chuang, D-M. et al, Frontiers in Mol. Neuroscience, 4(15), 2011, 1-12
Mota de Freitas, D., et al, Acc. Chem. Res., 39, 2006, 283-291.
2+
Mg
+
Li
competition with
• IMPase and IPPase:
- Inhibition reduces inositol levels.
- Decreased Ca2+ release.
- Increased expression in the
cerebellum.
- Inositol transporter found to be
overexpressed in BD.
Mota de Freitas, D., et al, Acc. Chem. Res., 39, 2006, 283-291.
Alda, M., Molecular Psychiatry, 20, 2015, 661-670.
Harwood, A.J., Molecular Psychiatry, 10, 2005, 117-126.
2+
Mg
+
Li
competition of
• Adenylyl Cyclase:
- Inhibition decreases production
of cAMP.
- Individuals with BP show
increased Gsα and cAMP in the
cerebral cortex.
Interest: Addition of Mg2+ reverses
effects of Li+.
Zimmerman, G., et al, J. Biol. Chem., 273(31), 1998, 19650-19655.
Mota de Freitas, D., et al, Acc. Chem. Res., 39, 2006, 283-291.
Alda, M., Molecular Psychiatry, 20, 2015, 661-670.
2+
Mg
Current Difficulties
Lithium Treatment for Bipolar disorder
• 1st line treatment
• Lack of Compliance
• Discontinuation can be fatal
Anticonvulsant Drugs
• Valproate, gabapentin
• More effective for “kindlers”
Future Treatments
Signal Transduction
• Control mood by targeting specific enzymes
• Future research on pathophysiology
Genetics
• Gene manipulation
• Eliminate factors causing the illness
Summary Slide
• Belongs to the drug class: antimanic – acts as a mood stabilizer.
• Is approved by health canada for the treatment of acute manic episodes and as
maintenance therapy of bipolar disorder .
• Is administered orally either as: lithium carbonate or lithium citrate.
• Lithium has a narrow therapeutic window.
• Mechanism of action not fully understood, but competition with Mg2+ viable option.
• Current Lithium treatment for Bipolar disorder causes hand tremors, weight gain,
cognitive impaired function.
• Gene manipulation and targeting enzymes in signal transduction pathway are future
methods to treat bipolar disorder.