Chapter 26 Lithium

Chapter 26 Lithium

Introduction1970: FDA approved in treating acute maniaInexpensive + Effective: highly cost-effectivePharmacological ProfileMinimal protein boundRenal eliminatedPharmacokineticsAbsorbed from GI, excreted through Renal in 24hrsPeak in 1-2hrs(rapid) or 4-5hrs(sustained)Steady state achieved in 4-5days

Indications and EfficacyBipolar disorderUnipolar depressionSuicide: Is lithium protective?

Lithium in Bipolar Disorder(1)Acute ManiaLithium VS antipsychoticsChlorpromazine > Li with Li less side effects (Prien 1972)Haloperidol / halo + Li > Lithium alone (Garfinkel 1980)Li = haloperidol = risperidone (Segal 1998)Antipsychotics work faster but higher risks for weight gain and other metabolic effectsLithium VS anticonvulsantsCarbamazapine = Li (Small 1991)Valp = Li, 48% achieve response in 3wks (Bowden 1994)Li = Valp = Carbamazepine (Emilien 1996)Anticonvulsants better tolerated than LithiumPatients with EEG abnormalities: Valp > LiCo-occurrence with depression: poor response to Li, better to Valp

Lithium in Bipolar Disorder(2)Bipolar DepressionLi is 1st line treatment (79% had complete/partial response) (Goodwin 1990)Li recommended as monotherapy for mild to moderate bipolar depression (expert consensus in 2004)Rapid CyclingRapid cyclers do poorly with most, Li does improve burden of illnessLi less effective in prevention>1 year of Li: higher % of well time, less severity and duration of episodes

Lithium in Bipolar Disorder(3)Prophylaxis and MaintenanceEffective in long-term use(>1 yr) in decreasing frequency of mood episodes (Tondo 2001)Only 24% free of mood episodes (Kulhara 1999)Patients received valproate remained in treatment significantly longer than did those received lithium. (Bowden 2000)BALANCE: Li + Valp > Valp , Li > ValpDose: QDHS > BID (higher brain-to-serum ratio)

Lithium in Unipolar DepressionLithium augmentation found significant improvement in 56% - 96% (5 controlled trials)15.9% who did not experience remission with citalopram and another medication trial experienced remission after addition of Lithium. (STAR*D)

Lithium in Suicidal ProtectionLower mortality than bipolar population, did not have higher suicide rate than general population. (Schou 1998)Risks of completed and attempted suicides were 8.6-fold higher in patients w/o Li.

Use in Special Populations(1)Children and AdolescentsMore efficacious than placebo for bipolar disorder, but not for major depressionThe ElderlyMore patients > 55 y/o improved with Li than ValpTherapeutic range is similar (>0.8mmol/L)Increase Li level: Volume depletion, NSAIDs, thiazideHD: Li given only after dialysis, need not given dailyNeuroprotective, decrease oxidative damage, prevention of neurocognitive decline, Alzheimers dz

Use in Special Populations(2)Pregnant/Lactating WomenLithium is not a high-risk teratogenAlthough Ebsteins anomaly higher with Li, 0.05%-0.1%The risk is < than neural tube defect of anticonvulsants71% recurrence risk when discontinued mood stabilizer Tx during pregnancy11 times shorter of the time to recurrence if mood stabilizer was discontinued abruptly, not gradually1.6 times higher in women using mood stabilizer other than LiRates of relapse increased sharply during postpartum period prophylactic TxFound in breast milk and infant serum(0.090.3mEg/L)increase in baby TSH, BUN, Cr, w/o evident long-term effects

Side Effects and Toxicology(1)Renal & Thyroid function: twice during the first 6 months, then once every 6 months.Most disturbing: cognitive & weight gainSelf-reported noncompliance: cognition and coordinationNeurotoxicity, delirium, encephalopathyespecially combine with typical antipsychoticsPotentially irreversible

Side Effects and Toxicology(2)TremorTremor may decrease with time, severe tremor indicate toxicityElimination of caffeine may worsen tremorThyroid function14.9% female, 3.4% male developed hypothyroidism (Kirov 1998)Female OR > 50 y/o were more likely

Side Effects and Toxicology(3)Renal ComplicationsTubular dysfunction20% - 40% Nephrogenic diabetes insipidusCKD (10-20 years of lithium administration)Cardiac ChangesSinus bradycardia, sinus node dysfunctionAV block, T-wave change

Drug-Drug Interactions(1)Lithium and AnticonvulsantsLithium + valproate: sedation, tremor, weight gainLithium + carbamazepine: neurotoxicityLithium + CCB: NeurotoxicityLithium and AntipsychoticsNeurotoxicity & TD can occurLow dose antipsychotics, Li level < 1.0mEq/L

Lithium + clozapine: DKA, NMSLithium + risperidone: fever, leukocytosis, increase CPK, deliriumLithium + Gabapentin: safeLithium + BZDs: safe

Drug-Drug Interactions(2)Lithium + serotonergic antidepressants: serotonin syndromeLithium + nonpsychotropic medicationsNSAIDs, thiazide, ACEI