Neuropharmacology of Lithium

By: Kathryn Carson, Brandon LeBlanc, Daniel Greco, Ashour Barkho

PHM142 Fall 2015Instructor: Dr. Jeffrey Henderson

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

FormulationsLithium 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 LithiumLithium 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 namesCarbolith, 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.svgMota de Freitas, D., et al, Acc. Chem. Res., 39, 2006, 283-291.

Li+ competition of Mg2+

• 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, 1-12Mota de Freitas, D., et al, Acc. Chem. Res., 39, 2006, 283-291.

Li+ competition with Mg2+

• 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.

Li+ competition of Mg2+

• 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.

Current DifficultiesLithium Treatment for Bipolar disorder• 1st line treatment• Lack of Compliance• Discontinuation can be fatal

Anticonvulsant Drugs• Valproate, gabapentin• More effective for “kindlers”

Future TreatmentsSignal 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.