Residency · Residency · Psychiatry

Mood Stabilizers: Lithium and Anticonvulsants

Lithium

Pharmacology and Mechanism of Action

Monovalent cation; exact mechanism incompletely understood. Inhibits inositol monophosphatase (inositol depletion hypothesis) Inhibits glycogen synthase kinase-3beta (GSK-3beta), involved in neuroplasticity and cell survival. Modulates glutamate neurotransmission. Upregulates BDNF and Bcl-2 (neuroprotective and potentially neurotrophic) Alters intracellular signaling cascades involving protein kinase C.

Pharmacokinetics

Absorbed rapidly from GI tract; peak levels in 1-2 hours (immediate release) or 4-5 hours (extended release) Not protein-bound, not metabolized; excreted entirely by the kidneys. Half-life: 18-24 hours in adults; longer in elderly. Steady state achieved in 5 days. Renal handling: freely filtered at glomerulus, 80% reabsorbed in proximal tubule (competes with sodium) Factors that increase lithium levels: dehydration, low-sodium diet, NSAIDs, ACE inhibitors, thiazide diuretics, renal impairment. Factors that decrease lithium levels: increased sodium intake, osmotic diuretics, theophylline, pregnancy (increased GFR)

Therapeutic Monitoring

Acute mania target: 0.8-1.2 mEq/L. Maintenance target: 0.6-0.8 mEq/L (some patients respond at 0.4-0.6 mEq/L) Draw trough levels (12 hours post-dose) Monitor levels every 5-7 days during titration, then every 3-6 months at steady state. Toxicity threshold: >1.5 mEq/L (mild-moderate: 1.5-2.5; severe: >2.5) Signs of toxicity: coarse tremor, ataxia, slurred speech, vomiting, diarrhea, confusion, seizures, coma.

Adverse Effects

Renal: nephrogenic diabetes insipidus (polyuria/polydipsia) due to impaired aquaporin-2 expression; chronic kidney disease with long-term use (tubulointerstitial nephropathy); monitor creatinine/eGFR every 6 months. Thyroid: hypothyroidism (up to 20% of patients), goiter; monitor TSH every 6 months; treat with levothyroxine supplementation (lithium continuation generally appropriate) Parathyroid: hyperparathyroidism and hypercalcemia; monitor calcium. Neurological: fine tremor (beta-blockers for management), cognitive dulling, ataxia at higher levels. GI: nausea, diarrhea (often dose-related; may improve with extended-release formulation) Cardiac: T-wave flattening or inversion, sinus node dysfunction (rare); baseline ECG recommended in patients >40 years. Dermatologic: acne, psoriasis exacerbation, alopecia. Weight gain: common, averaging 4-6 kg. Teratogenicity: Ebstein anomaly (tricuspid valve malformation); risk is real but historically overestimated (~0.1-0.2% vs. baseline 0.005%); requires careful risk-benefit discussion in pregnancy.

Baseline Workup Before Starting Lithium

Renal function: BMP (creatinine, BUN, electrolytes), eGFR. Thyroid function: TSH, free T4. Calcium level. Pregnancy test in reproductive-age women. ECG in patients >40 or with cardiac history. CBC (baseline) Urinalysis (baseline for concentrating ability)

Clinical Indications

Acute mania (Level 1 evidence) Bipolar maintenance (strongest evidence for long-term relapse prevention, particularly for manic episodes) Bipolar depression (moderate evidence, less robust than for mania) Augmentation of antidepressants in unipolar TRD. Anti-suicidal properties: unique among mood stabilizers; meta-analyses demonstrate reduced suicide risk in both bipolar and unipolar depression.

Valproate (Valproic Acid / Divalproex Sodium)

Mechanism of Action

Increases GABA levels by inhibiting GABA transaminase and enhancing GABA synthesis. Blocks voltage-gated sodium channels. Modulates intracellular signaling via HDAC inhibition (histone deacetylase) -- epigenetic effects. May have neuroprotective properties.

Pharmacokinetics

Highly protein-bound (90%); free levels increase when albumin is low or with drug displacement interactions. Hepatic metabolism via glucuronidation and beta-oxidation; inhibits CYP2C9. Therapeutic level: 50-125 mcg/mL (some sources cite 50-100 mcg/mL) Half-life: 9-16 hours. Divalproex sodium (Depakote) is an enteric-coated formulation with less GI irritation.

Clinical Use

Acute mania: effective; can be loaded rapidly (20-30 mg/kg/day) for faster onset. Maintenance: effective for relapse prevention, particularly mixed episodes. Less effective than lithium for classic euphoric mania and long-term suicide prevention. Used in rapid cycling bipolar disorder.

Adverse Effects

Hepatotoxicity: rare idiosyncratic fatal hepatotoxicity (highest risk in children <2 on polytherapy); monitor LFTs at baseline, frequently in first 6 months, then every 6-12 months. Pancreatitis: rare but potentially fatal. Hematologic: thrombocytopenia (dose-related), platelet dysfunction. Metabolic: weight gain, insulin resistance, hyperandrogenism. GI: nausea, vomiting, diarrhea. Neurological: tremor, sedation, cognitive dulling. Hair loss: sometimes responsive to zinc and selenium supplementation. Teratogenicity: MAJOR concern; neural tube defects (1-2% risk, 10-20x baseline), decreased IQ (8-9 points lower than lithium or carbamazepine exposure), autism risk increased; absolutely contraindicated in pregnancy when alternatives exist; requires effective contraception in reproductive-age women; folic acid supplementation does NOT reliably prevent VPA-related NTDs.

Monitoring

Serum valproic acid level, LFTs, CBC with platelets at baseline and periodically. Pregnancy test in reproductive-age women.

Carbamazepine

Mechanism of Action

Voltage-gated sodium channel blocker (stabilizes inactivated state) Reduces glutamate release. May modulate adenosine receptors.

Pharmacokinetics

Strong CYP3A4 inducer and auto-inducer (increases its own metabolism over 2-4 weeks) Metabolized to carbamazepine-10,11-epoxide (active metabolite, contributes to toxicity) Therapeutic level: 4-12 mcg/mL. Half-life: 12-17 hours at steady state (initially much longer) Multiple significant drug interactions due to CYP induction: reduces levels of oral contraceptives, warfarin, many antipsychotics, lamotrigine.

Clinical Use

Second-line mood stabilizer for bipolar disorder. May be particularly effective in mixed episodes and rapid cycling. Used when lithium and valproate have failed or are not tolerated.

Adverse Effects

Hematologic: leukopenia (benign, common), aplastic anemia and agranulocytosis (rare but serious -- 1 in 200,000) Dermatologic: rash (up to 10%), Stevens-Johnson syndrome/toxic epidermal necrolysis (risk increased in HLA-B*1502 carriers -- screen patients of Asian ancestry before initiation) Hepatic: hepatitis, elevated liver enzymes. Neurological: dizziness, ataxia, diplopia, sedation. Hyponatremia: SIADH, especially in elderly. Teratogenicity: neural tube defects (0.5-1% risk), craniofacial anomalies.

Monitoring

HLA-B*1502 testing before initiation in at-risk populations. CBC, LFTs, electrolytes (sodium), carbamazepine levels at baseline and periodically. Repeat levels after dose changes (auto-induction)

Lamotrigine

Mechanism of Action

Voltage-gated sodium channel blocker. Inhibits presynaptic glutamate and aspartate release. Does not have significant effects on GABA.

Pharmacokinetics

Hepatic metabolism via glucuronidation (UGT1A4) Half-life: ~25 hours as monotherapy. Critical interaction with valproate: VPA inhibits lamotrigine metabolism, doubling levels and increasing SJS risk (halve the lamotrigine dose when co-prescribed with VPA) Carbamazepine induces lamotrigine metabolism (double the dose needed) Estrogen-containing oral contraceptives reduce lamotrigine levels.

Clinical Use

Bipolar depression: strongest evidence among mood stabilizers for acute bipolar depression and depressive episode prevention. Bipolar maintenance: primarily prevents depressive relapse; less effective for preventing manic episodes. Not effective for acute mania. Particularly useful in bipolar II disorder (depressive-predominant course)

Adverse Effects

Stevens-Johnson syndrome / toxic epidermal necrolysis: risk ~0.1% in adults, higher in children and with rapid titration or valproate co-administration. MUST follow slow titration schedule: 25 mg/day for weeks 1-2, 50 mg/day for weeks 3-4, then increase by 50 mg every 1-2 weeks; target 200-400 mg/day. If valproate is co-prescribed: start at 25 mg every other day, halve all titration steps. Benign rash is common (up to 10%) but any rash requires careful evaluation. Generally well tolerated: minimal weight gain, cognitive side effects, or sedation. Headache, dizziness, GI upset possible but generally mild.

Oxcarbazepine

Active metabolite (MHD) is the primary active compound. Fewer drug interactions than carbamazepine (weaker CYP inducer) Similar sodium channel mechanism. Higher risk of hyponatremia than carbamazepine. Limited evidence in bipolar disorder; sometimes used as alternative to carbamazepine. HLA-B*1502 screening also recommended.

Comparison of Mood Stabilizers

<image> A diagram showing the intracellular signaling pathways targeted by lithium. Depict a neuronal cell with the cell membrane, cytoplasm, and nucleus. Show the phosphatidylinositol signaling pathway with PIP2, IP3, and DAG. Illustrate lithium blocking inositol monophosphatase (IMPase) leading to inositol depletion. In a parallel pathway, show lithium inhibiting GSK-3beta, with downstream effects on beta-catenin, BDNF transcription, and Bcl-2 (cell survival). Label all enzymes and second messengers. Use arrows to show activation and flat-headed arrows for inhibition. Medical textbook illustration style. </image>

<image> A clinical monitoring timeline infographic for lithium therapy. Show a horizontal timeline from "Pre-treatment" through "Month 1", "Month 3", "Month 6", and "Annually". At each time point, list the required labs and assessments using icons: blood drop for serum lithium level, kidney for renal function (creatinine/eGFR), butterfly/thyroid shape for TSH, heart for ECG, bone for calcium. Include a toxicity alert zone showing symptoms at different lithium levels: 1.5-2.0 (mild: tremor, GI), 2.0-2.5 (moderate: ataxia, confusion), >2.5 (severe: seizures, coma). Clean medical infographic style. </image>

<image> A comparative teratogenicity risk diagram for mood stabilizers. Show four panels, one for each agent (lithium, valproate, carbamazepine, lamotrigine). Each panel shows a developing fetus with the specific malformation risk highlighted: Ebstein anomaly (tricuspid valve) for lithium, neural tube defect (spina bifida) for valproate and carbamazepine, with relative risk ratios displayed. Include a bar graph below comparing absolute risk percentages for major congenital malformations from pregnancy registry data. Color-code by risk level (green for low, yellow for moderate, red for high). Medical illustration style. </image>

Clinical Pearls

Lithium remains the gold standard mood stabilizer with the broadest evidence base; it is the only agent with robust anti-suicidal evidence. Always check drug interactions before starting lithium -- NSAIDs, ACE inhibitors, and thiazide diuretics are the most common culprits for toxicity. Valproate is absolutely contraindicated in women of reproductive potential unless no alternative exists and effective contraception is confirmed; this is a medicolegal issue. Lamotrigine is the preferred mood stabilizer for bipolar depression and bipolar II disorder maintenance; its favorable side effect profile supports adherence. Never rush lamotrigine titration -- the SJS risk is directly related to rapid dose escalation; if a patient misses more than 5 days of lamotrigine, restart from the beginning of the titration schedule. When valproate and lamotrigine are co-prescribed, halve all lamotrigine doses and titrate even more slowly. HLA-B*1502 testing is mandatory before starting carbamazepine or oxcarbazepine in patients of Southeast Asian, South Asian, or Han Chinese ancestry. Lithium's neuroprotective effects (reduced dementia risk in some studies) are an emerging area of research that may expand its indications. Educate patients on lithium toxicity signs and the importance of maintaining hydration, especially during illness, exercise, or hot weather.

References

• Yatham LN, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170.
• Cipriani A, et al. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646.
• Meador KJ, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study). Lancet Neurol. 2013;12(3):244-252.
• Stahl SM. Stahl's Essential Psychopharmacology. 5th ed. 2021.
• APA Practice Guidelines for Bipolar Disorder. 2nd ed. American Psychiatric Association; 2002 (with 2019 guideline watch).
• Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381(9878):1672-1682.

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