1. Neuropharmacology of Lithium By: Kathryn Carson, Brandon LeBlanc, Daniel Greco, Ashour Barkho PHM142 Fall 2015 Instructor: Dr. Jeffrey Henderson

2. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. Mechanism of Action Many hypothesized mechanisms: -Telomere shortening prevention, increased mitochondrial function, and regulation of circadian rhythm. Li + and Mg 2+ 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.

10. Li + competition of Mg 2+ 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.

11. Li + competition with Mg 2+ IMPase and IPPase: -Inhibition reduces inositol levels. -Decreased Ca 2+ 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.

12. Li + competition of Mg 2+ Adenylyl Cyclase: -Inhibition decreases production of cAMP. -Individuals with BP show increased G sα and cAMP in the cerebral cortex. Interest: Addition of Mg 2+ 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.

13. Current Difficulties Lithium Treatment for Bipolar disorder 1 st line treatment Lack of Compliance Discontinuation can be fatal Anticonvulsant Drugs Valproate, gabapentin More effective for “kindlers”

14. Future Treatments Signal Transduction Control mood by targeting specific enzymes Future research on pathophysiology Genetics Gene manipulation Eliminate factors causing the illness

15. 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 Mg 2+ 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.