Pharmacology of Lithium

What factors might influence a patients bipolar disorder disease course?

• age

• sex

• seasonal variation

• hormonal variation (menstrual cycle, postpartum)

• genetics

• diet? (association with nitrates in cured meats?)

• environmental triggers - stress, sleep disruption, substance use

What is the etiology of bipolar disorder?

Is an interaction of neurocircuitry, intracellular signaling, genetics and cellular resilience 

• Genetics 

  • heritability 70-85% (highest of psychiatric conditions) 

  • polygenic risk

• Electrophysiology/neurotransmission pathways 

• Second Messenger pathways

• Cellular Resilience/Neurotrophic pathways 

How does electrophysiologic and neurotransmitter dysregulation play a role in bipolar disorder?

• neuronal hyperexcitability in limbic and prefrontal cortex → mood lability

• neurotransmitter imbalance

  • mania: increased DA and glutamate, decreased GABA

  • depression: decreased DA, NE, 5-HT

• ion-channel gene variants alter Na/Ca currents

Net effect: unstable firing patterns and excessive network synchrony

How does secondary messenger pathway dysfunction play a role in bipolar disorder?

• overactivation of intracellular signaling cascades

  • can amplify neuronal responsiveness

  • abnormal G-protein coupling can alter cAMP, IP3 and cause neuronal hyperexcitability and oxidative stress

Net effect: exaggerated neurotransmission, unstable mood-state switching and impaired feedback control of signaling networks.

How does gene expression and neurotrophic mechanisms play a role in bipolar disorder?

• a result of second messenger dysfunction, gene expression changes impact many neurotrophic mechanisms

  • decrease BDNF → impaired neurogenesis and synaptic maintenance 

  • mitochondrial dysfunction → less ATP and more oxidative stress 

  • neuroinflammation → increase in cytokines during mood episodes

• many brain regions affected: 

  • decreased prefrontal cortex → poor emotion regulation 

  • increased amygdala → emotional hyperactivity 

  • decreased hippocampal volume → impaired stress modulation 

Net effect: long-term illness can cause structural and functional brain changes 

What is the mitochondrial, circadian and inflammatory integrative model?

• circadian rhythm disruption: altered genes impacting → sleep disturbances trigger mood episodes

• HPA axis hyperactivity: increase cortisol → hippocampal damage, relapse risk 

• treatment implication: mood stabilizers act by normalizing intracellular signaling, enhancing neurotrophic factors and stabilizing circadian-neural rhythms

What is lithium?

• alkali metal

• natural Li is mainly Li-7, with minimal Li-6 (lacking 1 neutron)

  • appears to be differences in in-vitro and animal studies b/w the 2 

  • different levels vary from region to region 

How do different Li levels in various regions change prevalence/severity of psychiatry disorders?

• populations with higher-than-average Li amounts in drinking water

  • significantly lower suicide/homicide rates 

  • reduced rates of psychotic experiences in adolescents 

*note levels in drinking water and ~100x lower than treatment for bipolar disorder doses 

What is the MOA of lithium for bipolar disorder?

*really unknown

• competition with Na and Mg 

  • various number of effects throughout the body 

How does lithium work on sodium channels?

• almost all Na channels allow unregulated passage of Li+ 

• Li+ competes with Na+ throughout the body

• Na/K ATPase can’t move Li across membranes 

• unlike Na, Li does not sequester to once side of excitable membranes 

How does Li work when competing with Mg?

• Mg2+ binds preferentially to beta and gamma phosphates of ATP

• Li+ competes with Mg2+ causes small conformation change

  • ATP-Mg can still fit in ATP-binding sites and affect signaling 

  • intracellularly Li+ compete with Mg2+ in many biochem mechanisms that use ATP-Mg complex

• over 3000 known kinases use ATP-Mg and could be affected by Li+ competition 

What is the preclinical evidence of Li in quantum mechanics?

• differential rat behaviour

  • opposite behavioural effects in Li-6 cs Li-7 despite identical dosing

• developmental delays

  • offspring exposed to Li-6 showed delayed motor or sensory development vs Li-7

• isotopic differences in effects on Ca in mitochondria 

  • opposite effects on Ca capacity and permeability in mitochondria 

• opposite hippocampal electrophysiology 

  • opposite effects on excitatory postsynaptic potentials

How does Li play a role in the electrophysiologic and neurotransmitter systems? 

• Li competes with Na at voltage-gates Na channels → reducing neuronal excitability 

• Li alters biogenic amine metabolism and activity → inhibits synaptic release of NE/DA, may increase non-synaptically-evoked release of 5-HT

Net effects: normalizes the hyperdopaminergic, hyperglutamatergic and hyperexcitability state seen in mania 

How does Li affect secondary messengers?

• inhibits IMPase cycle → decreases Ca-dependent intracellular signaling 

• inhibits adenylate cyclase pathway → decreased cAMP and PKA signaling 

• protein kinase modulation → general increase in cell resilience, growth and repair

Net effect: dampens overactive intracellular signaling cascades that amplify mood states.

How does Li play role in gene regulation and neurotrophic mechanisms?

• altered gene regulation

• neuropretection 

Net effect: promoted neurogenesis and gray-matter recovery 

How does Li play a role in the cellular, mitochondrial and circadian mechanisms?

• mitochondrial stabilization:

  • enhances ATP production, increased expression of anti-apoptotic proteins and mitochondrial protective factors

• reduction of oxidative stress:

  • decreased ROS generation and increase antioxidant enzyme activity 

  • protects neurons from oxidative and metabolic injury

• circadian rhythm regulation: 

  • modulated gene expression that may normalize abnormal circadian signaling 

Net effect:  restores cellular energy balance, reduces oxidative and inflammatory burden, and stabilizes biological rhythms → supports long-term mood stabilization 

Is there patient factors that alter lithium efficacy?

• polymorphism of GSK3B genes correlate with lithium efficacy

• other lifestyle and health factors can affect efficacy and tolerance

What are the PKs of lithium?

• absorption 

  • nearly 100% absorbed 

  • peak in 2-4 hours 

• distribution 

  • initially to ECF, then slowly into tissues and intracellular compartments 

  • BBB partially restrictive → CSF ~ 50% of plasma 

  • crosses placenta and enters breast milk 

• elimination 

  • >95% renal excretion (minor sweat losses) 

    • parallels Na 

  • half-life 24h 

    • shorter in youth, and longer in older adults

What are drug interactions with Li? 

• thiazide diuretics → reduce Li clearance 

• osmotic diuretics → increase Li excretion 

• ACE/ARBs → reduce Li clearance 

• NSAIDs → increase Li reabsorption from proximal tubules

• serotonergic agents → may increase risk of serotonin syndrome

Which patient/diet factors may increase Li levels?

• sodium restriction

• dehydration

• vomiting

• diarrhea

• age > 50

• CHF

• renal disease

Which patient/diet factors may decrease Li levels?

• pregnancy 

• manic episodes 

• heavy exercise/sauna (insensible losses) 

What is the therapeutic range for Li?

• The therapeutic range for lithium is typically between 0.6 and 1.2 mEq/L

When do you typically see mild Li toxicity, and what are symptoms?

• mild toxicity begins around 1.2-1.5 - 2.5

• symptoms: 

  • nausea

  • vomiting

  • lethargy

  • tremor

  • fatigue 

hen do you typically see severe Li toxicity, and what are symptoms?

• start seeing around 3.5

• symptoms: 

  • confusion 

  • agitation 

  • delirium 

  • tachycardia 

  • hypertonia 

  • coma 

What symptoms are seen with lithium overdose? 

• vomiting and diarrhea 

• tremor - “coarse” vs. “fine” 

• seizure

• ataxia 

• coma 

How does Li cause kidney toxicity?

• ionic strength

• intracellular apoptotic signaling 

What type of kidney damage is caused from Li?

• nephrogenic diabetes insipidus

  • damaged tubules cannot respond to antidiuretic hormone 

  • leads to dehydration, excessive thirst, large amounts of urine output 

• sodium-losing nephritis 

  • damaged tubules cannot reuptake sodium 

  • leads to hyponatremia, hypochloremia, dehydration, fatigue

• nephrotic syndrome

  • damaged tubules cause protein to leak into urine (proteinuria)

  • leads to low levels of albumin in blood, edema, hyperlipidemia

What else do you see with chronic lithium toxicity?

• endocrine system disruption → often slightly low T4/T3 even at non-toxic levels 

  • hypothyroidism 

  • hyperthyroidism 

  • hyperparathyroidism 

What are the ADEs seen with lithium?

• hand tremor (very common and dose-dependent)

• incoordination, slurred speech

• seizures

• worsening EPS

• polyuria, polydipsia

• hypercalcemia, hypokalemia, diabetes insipidus 

• thyroid enlargement w/o changes in thyroid levels 

• changes in ECG, w/ bradycardia at high concentrations 

• dermatitis, acne 

• fetal cardiotoxicity (highest in first trimester) 

What is the risk of using lithium in pregnancy? 

• small teratogenic risk in 1st trimester

  • ~1-2% increase in cardiac malformations

  • dose-dependent

• d/c significantly increases relapse rate, suicide and poor obstetric outcomes

  • need for individualization of therapy

  • if continuing monitor levels closely

What is the risk of lithium in lactation? 

• does transfer to breast milk 

  • infant serum ~20-50% maternal levels

• neonatal risks:

  • hypotonia

  • poor feeding

  • dehydration

  • rare toxicity → risk higher with high maternal levels or dehydration

• historically CI

  • may be considered case-by-case in healthy full-term infants with close infant + maternal monitoring (Li level, renal, thyroid)