Lithium Treatment

1. Lithium Treatment PHM142 Presentation Ghazaleh Darian, Seungjoo Lee, Michelle Rocha, and Liang Sun PHM142 Fall 2013 Instructor: Dr. Jeffrey Henderson

2. Introduction • Lithium is a psychiatric medication that is used to treat patients with bipolar disorder (antimanic agent) • Most commonly prescribed as lithium carbonate • Proposed mechanism of action: upon ingestion, it is widely distributed in the central nervous system to decrease abnormal activity in the brain • When other treatments are not effective, lithium is also used for: • Major depression • Schizophrenia • Mood disorders (bipolar disorder being the most important one)

3. Bipolar Disorder • Bipolar disorder is a complex, recurrent mood disorder • Affects 1-2% of the population • Manifests itself in different ways defined as having either manic, hypomanic, or mixed episode and almost always includes clinical depression • Diagnosis is often difficult as the illness is perhaps the most complex psychiatric disorder

4. Symptoms and Signs • Bipolar disorder is characterized by four episode types that define different types of bipolar disorder: • Manic Episode • abnormally elevated mood lasting at least one week • Hypomania • same as symptoms as mania, but milder lasting for 4 days or more • Depressive • depressed most of the day with diminished interests lasting at least two weeks • Mixed episode • criteria for both manic and depressive episodes met during the same time period for the duration of at least a week

5. Causes Genetic: • likely to be caused by multiple different common alleles Physiological • neuroimaging studies indicate abnormalities in the structure and function of certain brain circuits (i.e. hippocampus, amygdala) • cell loss or atrophy involved (especially cells in critical brain region regulating emotion) • and many more Neurological • Neurotransmitters: abnormalities in norepinephrine, dopamine, serotonin And more!

6. Diagnosis and Treatment Diagnosis • based on self-reported experiences and abnormalities in behaviour • blood tests (CBC, electrolytes, renal function, etc.) and substance screening to rule out other problems • CAT, MRI, EEG for unusual symptoms (i.e. neurological signs) • assess for suicide ideation Treatment • Treatment is directly related to the phase of the episode and severity • Mood stabilizers include anticonvulsants and antipsychotics: • Mania: lithium or divalproex • Depressive: lithium, lamotrigine

7. Neurologic Effects of Lithium • Lithium increases the volume of brain structures involved in emotional regulation (i.e., in the hippocampus, prefrontal cortex and amygdala) • Increase in brain volume leads to improved mental health • During manic phases of bipolar disorder, the brain tissue becomes inflamed, if lithium is ingested, it helps to alleviate the inflammation

8. Neurologic Effects of Lithium II • Lithium inhibits glycogen synthase kinase 3 (Gsk3) and inositol trisphosphate (InsP3) • these enzymes, when overexpressed, can lead to psychiatric disorders

9. Proposed Mechanism of Action • Lithium protects neurons from toxic insults • Lithium modulates the cytoskeleton, which contributes to neural plasticity in mood recovery and stabilization • Lithium influences gene regulation, such that there is an increase in the expression of neuroprotective proteins

10. Proposed Mechanisms of Action II • Lithium balances the activities of neurotransmitters, which result in neuroprotective effects • In particular, lithium affects glutamatergic activity • Excess glutamate uptake by glutamatergic receptors results in seizures, thus, by decreasing their activity, neurons can be protected

11. Absorption, Distribution, and Excretion • Well absorbed in the GI tract • distributed into most body tissues and across the blood brain barrier • not bound to plasma proteins • Elimination half life • 24 hrs • 18 hours in children • 36 hrs in geriatric patients • 40-50 hrs in patients with impaired renalfunction • excreted primarily in urine (50-80% of single dose • in 24 hrs)

12. Contraindications Should be especially monitored in patients with: • Renal Disease • Cardiac Disease • Dehydration or low salt intake • Pregnancy/breastfeeding Toxicity occurs at doses close to the therapeutic range so treatment should begin at a low dose and increased based on daily serum levels

13. Drug Interactions: ACE inhibitors Antiepileptic drugs Calcium channel blockers Diuretics NSAIDS Sodium and many more Side Effects and Major Drug Interactions Mild Adverse Events: • nausea • muscle weakness • vertigo • thirst • fatigue • hand tremors Serious Adverse Events: • ataxia • tinnitus • blurred vision and slurred speech • Seizures, vomiting and diarrhea • Coma, death

14. Summary • Lithium decreases the severity and frequency of manic episodes in bipolar disorder • Bipolar disorder is an affective disorder characterized by the occurrence of alternating manic, hypomanic, or mixed episodes and with major depressive episodes. Lithium carbonate is the most commonly prescribed form of lithium • Lithium modulates the activity of neurotransmitters (primarily glutamate) to protect neurons against excitotoxicity. Lithium inhibits glycogen synthase kinase 3 (Gsk3) and inositol trisphosphate (InsP3). • Lithium decreases inflammation in the brain. • Lithium is absorbed in the GI tract, distributed to body tissues and brain and excreted in urine • Lithium may have a number of adverse effects, thus, plasma concentrations should be monitored regularly to ensure levels stay within the therapeutic range

15. References American Society for Biochemistry and Molecular Biology (2010, May 24). Uncovering lithium's mode of action. ScienceDaily. Retrieved November 24, 2013, from http://www.sciencedaily.com­/releases/2010/05/100521191440.htm. Berk M., Dodd S., Berk L. (2005). The management of bipolar disorder in primary care: a review of existing and emerging therapies. Psychiatry Clinical Neuroscience, 59(3), 229-39. Canadian Pharmacists Association. (2011). Lithium. Compendium of Pharmaceutical and Specialties, online version (e-CPS). Hashimoto K., Sawa A., Iyo M. (2007). Increased levels of glutamate in brains from patients with mood disorders. Biological Psychiatry, 62(11), 1310-6. Houenou J., Frommberger J., Carde S., et al. ( 2011). Neuroimaging-based markers of bipolar disorder: Evidence from two meta-analyses. Journal of Affective Disorders,132(3), 344-55. Hölzel, B. K., Carmody, J., Vangel, M., Congleton, C., Yerramsetti, S. M., Gard, T., & Lazar, S. W. (2011). Mindfulness practice leads to increases in regional brain gray matter density. Psychiatry Research: Neuroimaging, 191(1), 36-43. Jope, R. S. (1999). Anti-bipolar therapy: mechanism of action of lithium.Molecular psychiatry, 4(2), 117-128. Lithium Treatment for Bipolar Disorder: Side Effects and More. (2005, January 3). WebMD. Retrieved November 24, 2013, from http://www.webmd.com/bipolar-disorder/bipolar-disorder-lithium.

16. References Lithium: MedlinePlus Drug Information. (2010, September 1). MedlinePlus. Retrieved November 22, 2013, from http://www.nlm.nih.gov/medlineplus/druginfo/meds/a681039.html. Malhi, G.S., Tanious, M., Das, P., Coulston, C.M., & Berk, M. (2013). Potential mechanisms of action of lithium in bipolar disorder. Current understanding. CNS Drugs, 27(2), 135-53. Williams, R. S. (2005). Pharmacogenetics in model systems: defining a common mechanism of action for mood stabilisers. Progress in Neuro-psychopharmacology and Biological Psychiatry, 29(6), 1029-1037. Yatham L.N., Kennedy S.H. O'Donovan C., et al. (2005). Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: consensus and controversies. Bipolar Disorder, 7(3), 5-69.