Pharmacology of Mood Stabilizers

Introduction/Overview

The pharmacological management of bipolar spectrum disorders represents a cornerstone of modern neuropsychiatric therapeutics. Mood stabilizers constitute a heterogeneous class of psychotropic agents primarily employed to treat and prevent episodes of mania, hypomania, and depression in bipolar disorder. Their clinical application extends beyond this core indication to include adjunctive treatment in major depressive disorder, schizoaffective disorder, and certain impulse-control disorders. The therapeutic goal is not merely acute symptom suppression but the long-term stabilization of mood, reduction in episode frequency and severity, and prevention of disease progression. The historical introduction of lithium carbonate in the mid-20th century marked a paradigm shift, demonstrating that a chronic, recurrent psychiatric illness could be effectively managed with pharmacotherapy. Subsequent development has incorporated several anticonvulsants and atypical antipsychotics into the mood stabilizer armamentarium, each with distinct pharmacological profiles and risk-benefit considerations.

The clinical relevance of these agents is underscored by the significant global burden of bipolar disorders, which are associated with high rates of morbidity, mortality, and functional impairment. Mastery of their pharmacology is essential for safe and effective prescribing, given their narrow therapeutic indices, complex pharmacokinetics, and potential for serious adverse effects and drug interactions. Rational therapeutic selection requires an integrated understanding of mechanism of action, individual patient factors, and the phase of the illness being treated (e.g., acute mania versus maintenance).

Learning Objectives

• Classify the primary agents used as mood stabilizers and describe their fundamental chemical and pharmacological categories.
• Explain the proposed neurobiological mechanisms of action for lithium, valproate, carbamazepine, and lamotrigine, including effects on intracellular signaling, neurotransmission, and neuroplasticity.
• Analyze the pharmacokinetic properties, including absorption, distribution, metabolism, and elimination, of major mood stabilizers and their implications for dosing, monitoring, and drug interactions.
• Evaluate the therapeutic applications, common and serious adverse effect profiles, and major drug interactions for each class of mood stabilizer.
• Apply knowledge of special considerations, including use in pregnancy, renal or hepatic impairment, and overdose management, to clinical decision-making.

Classification

Mood stabilizers are not defined by a shared chemical structure but by a common therapeutic action. They are conventionally categorized based on their primary historical use and chemical properties.

Classical Mood Stabilizers

This category includes the prototypical agent, lithium, a monovalent cation. Lithium salts, primarily lithium carbonate and lithium citrate, are the only agents in this unique class. Their mechanism is distinct from all other psychotropic drugs.

Anticonvulsant-Derived Mood Stabilizers

Several antiepileptic drugs have demonstrated efficacy in bipolar disorder and are now fundamental to its treatment. They are further subdivided by chemical structure:

• Fatty Acid Derivatives: Valproic acid and its salts (divalproex sodium, sodium valproate).
• Iminostilbene Derivatives: Carbamazepine and its analogue oxcarbazepine.
• Phenyltriazine Derivatives: Lamotrigine.
• Other Anticonvulsants: Certain second-generation agents like topiramate and gabapentin are sometimes used, though evidence for efficacy as primary mood stabilizers is less robust.

Atypical Antipsychotics

While primarily classified as antipsychotics, several second-generation (atypical) antipsychotics have proven mood-stabilizing properties and are approved for acute and maintenance treatment of bipolar disorder. These include olanzapine, quetiapine, risperidone, aripiprazole, ziprasidone, lurasidone, cariprazine, and asenapine. Their pharmacology is detailed in dedicated antipsychotic chapters; this chapter will focus on their role and specific considerations within mood stabilization protocols, often in comparison to classical and anticonvulsant agents.

Mechanism of Action

The precise mechanisms by which mood stabilizers exert their therapeutic effects remain incompletely elucidated. Current models suggest they modulate dysregulated neural circuits and cellular pathways implicated in the pathophysiology of bipolar disorder, rather than correcting a single neurotransmitter deficit. Proposed actions converge on intracellular signaling cascades, gene expression, neuroprotection, and circadian rhythm regulation.

Lithium

Lithium’s actions are pleiotropic, stemming from its ability to substitute for other monovalent cations (Na⁺, K⁺) and divalent cations (Mg²⁺, Ca²⁺) at various biological sites due to its small ionic radius.

• Inositol Depletion Hypothesis: Lithium is a non-competitive inhibitor of inositol monophosphatase (IMPase) and other enzymes in the phosphoinositide cycle. This inhibition depletes neuronal inositol, a precursor for phosphatidylinositol 4,5-bisphosphate (PIP₂), thereby dampening the activity of G_q-protein coupled receptor signaling (e.g., for muscarinic M₁, M₃, α₁-adrenergic, and certain metabotropic glutamate receptors). This may reduce neuronal hyperexcitability.
• Glycogen Synthase Kinase-3 (GSK-3) Inhibition: Lithium directly and indirectly inhibits GSK-3β, a serine/threonine kinase involved in numerous cellular processes. GSK-3 inhibition may promote neurotrophic effects (e.g., increased β-catenin activity), enhance mitochondrial function, reduce apoptosis, and exert anti-inflammatory actions.
• Modulation of Monoaminergic and Glutamatergic Neurotransmission: Chronic lithium administration may increase serotonin synthesis and release, enhance presynaptic norepinephrine reuptake, and modulate postsynaptic sensitivity. It also appears to reduce excessive glutamate activity, potentially via effects on NMDA receptor signaling and glutamate release.
• Neuroprotective and Neurotrophic Effects: Lithium upregulates the expression of neuroprotective proteins like B-cell lymphoma 2 (Bcl-2) and brain-derived neurotrophic factor (BDNF), while reducing markers of oxidative stress and inflammation. These effects may counteract the cellular resilience deficits observed in bipolar disorder.

Valproate

Valproate’s mood-stabilizing effects are attributed to multiple mechanisms, many overlapping with its anticonvulsant properties.

• Enhancement of GABAergic Inhibition: Valproate increases brain levels of gamma-aminobutyric acid (GABA) by inhibiting GABA transaminase and succinic semialdehyde dehydrogenase, enzymes responsible for GABA catabolism. It may also stimulate glutamic acid decarboxylase (GAD), the GABA-synthesizing enzyme, and potentiate postsynaptic GABA responses.
• Modulation of Voltage-Gated Ion Channels: Valproate inhibits voltage-gated sodium channels, reducing neuronal firing and high-frequency repetitive firing. It may also modulate T-type calcium channels.
• Histone Deacetylase (HDAC) Inhibition: Valproate is a broad-spectrum HDAC inhibitor, leading to chromatin remodeling and altered gene expression. This epigenetic mechanism may contribute to its long-term neurotrophic and neuroplastic effects.
• Mitigation of Kindling: Valproate may suppress limbic kindling, a model of progressive neuronal sensitization thought to be relevant to the episodic and progressive nature of bipolar disorder.

Carbamazepine and Oxcarbazepine

These agents share a primary mechanism centered on ion channel modulation.

• Use-Dependent Blockade of Voltage-Gated Sodium Channels: Both drugs bind preferentially to inactivated sodium channels, stabilizing the neuronal membrane and inhibiting the propagation of high-frequency action potentials. This is considered their principal mechanism for controlling neuronal excitability.
• Modulation of Neurotransmitter Release: By blocking sodium channels, they reduce the release of various neurotransmitters, including glutamate.
• Additional Mechanisms: Carbamazepine may also inhibit L-type calcium channels and potentiate adenosine receptors. Oxcarbazepine and its active metabolite have a similar profile but with a lower propensity for enzyme induction.
• Anti-Kindling Effects: Like valproate, carbamazepine exhibits anti-kindling properties in animal models.

Lamotrigine

Lamotrigine’s mechanism is distinct and appears particularly relevant to the prevention of depressive episodes.

• Use-Dependent Blockade of Voltage-Gated Sodium Channels: Similar to carbamazepine, lamotrigine inhibits voltage-gated sodium channels in a use-dependent manner, stabilizing neuronal membranes and reducing the release of excitatory neurotransmitters.
• Inhibition of Glutamate Release: A key postulated action is the presynaptic inhibition of glutamate release, particularly from pyramidal neurons. This may involve an effect on P/Q-type calcium channels.
• Other Potential Actions: Lamotrigine may have mild effects on calcium channels and serotonin systems, though their clinical significance is uncertain.

Atypical Antipsychotics

The mood-stabilizing effects of atypical antipsychotics are primarily linked to their receptor binding profiles, particularly dopamine D₂ and serotonin 5-HT_2A receptor antagonism. Additional actions at other serotonin receptors (e.g., 5-HT_1A partial agonism by some agents), adrenergic receptors, and effects on intracellular signaling cascades likely contribute. Their efficacy in acute mania correlates with D₂ receptor occupancy, while broader receptor profiles may underpin antidepressant and maintenance effects.

Pharmacokinetics

The pharmacokinetic profiles of mood stabilizers are complex and have direct, critical implications for clinical management, particularly regarding dosing regimens, therapeutic drug monitoring, and interaction potential.

Lithium

Lithium exhibits simple pharmacokinetics as an ion, but its handling by the body requires careful attention.

• Absorption: Lithium salts are rapidly and completely absorbed from the gastrointestinal tract, with peak plasma concentrations (C_max) occurring 1-4 hours post-dose. Standard and sustained-release formulations are available.
• Distribution: Lithium distributes throughout total body water without binding to plasma proteins. Its volume of distribution is approximately 0.7-0.9 L/kg. It crosses the blood-brain barrier slowly, resulting in a lag between serum and cerebrospinal fluid concentrations. Steady-state brain concentrations are roughly 40-50% of serum levels.
• Metabolism: Lithium is not metabolized.
• Excretion: Elimination is almost exclusively renal. Approximately 95% of a single dose is excreted unchanged in urine. Renal clearance (about 20% of creatinine clearance) is influenced by glomerular filtration rate and sodium balance. Sodium depletion promotes proximal tubular reabsorption of lithium, increasing serum levels and risk of toxicity.
• Half-life and Dosing: The elimination half-life (t_1/2) in adults is 18-36 hours, allowing for once- or twice-daily dosing. Steady-state is achieved in 5-7 days. Dosing is highly individualized, guided by serum lithium levels. The typical therapeutic range for maintenance is 0.6-1.0 mmol/L, and for acute mania 0.8-1.2 mmol/L. Levels should be drawn 12 hours post-dose.

Valproate

• Absorption: Valproic acid is rapidly absorbed, with C_max in 1-4 hours. Enteric-coated and extended-release formulations delay absorption and smooth the concentration-time profile.
• Distribution: It is highly protein-bound (80-90%), primarily to albumin. Binding is saturable within the therapeutic range (50-100 µg/mL), leading to a disproportionate increase in free, pharmacologically active drug as total concentration rises. Volume of distribution is small (0.1-0.4 L/kg).
• Metabolism: Valproate undergoes extensive hepatic metabolism via glucuronidation, β-oxidation, and cytochrome P450 (CYP)-mediated oxidation (CYP2C9, 2C19, 2A6). Several metabolites are active and may contribute to efficacy and toxicity.
• Excretion: Metabolites are primarily excreted in urine; less than 3% is excreted unchanged.
• Half-life and Dosing: The t_1/2 is 9-16 hours but can be shorter when co-administered with enzyme-inducing drugs. Dosing is typically twice or three times daily, though extended-release formulations allow once-daily administration. Therapeutic drug monitoring is common, with a typical target range of 50-125 µg/mL for bipolar disorder.

Carbamazepine

• Absorption: Absorption is slow and variable, with C_max at 4-8 hours post-dose. It exhibits autoinduction of its own metabolism.
• Distribution: It is 75-80% protein-bound and distributes widely (V_d ≈ 1 L/kg).
• Metabolism: Carbamazepine is metabolized almost exclusively in the liver by CYP3A4 to its active metabolite, carbamazepine-10,11-epoxide, which is further hydrolyzed. Carbamazepine is a potent inducer of CYP3A4 and other enzymes (e.g., CYP1A2, UGT), leading to complex drug interactions and autoinduction, where its own clearance increases over 2-4 weeks of therapy.
• Excretion: Metabolites are excreted in urine and feces.
• Half-life and Dosing: The initial t_1/2 is 25-65 hours but decreases to 12-17 hours with autoinduction. Dosing must often be increased gradually over weeks to maintain therapeutic levels (typically 4-12 µg/mL). Twice-daily dosing is standard.

Lamotrigine

• Absorption: Rapid and complete oral absorption, with C_max at 1-3 hours. Food does not affect bioavailability.
• Distribution: Approximately 55% protein-bound. Volume of distribution is 0.9-1.3 L/kg.
• Metabolism: Metabolized primarily by hepatic glucuronidation via UGT1A4. It is not a significant inducer or inhibitor of CYP enzymes.
• Excretion: Over 90% of a dose is excreted as glucuronide conjugates in urine.
• Half-life and Dosing: The mean t_1/2 in adults is 25-33 hours. Dosing is once or twice daily. A critical consideration is the need for a very slow titration schedule to minimize the risk of serious rash (Stevens-Johnson syndrome). The final maintenance dose is highly dependent on concomitant medications: higher with enzyme inducers (e.g., carbamazepine), lower with valproate (a UGT inhibitor), and intermediate when used as monotherapy.

Therapeutic Uses/Clinical Applications

The selection of a mood stabilizer is guided by the phase of bipolar disorder (mania, depression, maintenance), evidence from clinical trials, side effect profiles, and patient-specific factors.

Approved Indications

• Lithium: Approved for the treatment of acute manic episodes and as maintenance therapy to prevent or diminish the frequency and severity of subsequent episodes in bipolar I disorder. It is considered a first-line agent for classic euphoric mania and for long-term maintenance, where it has the strongest evidence for reducing suicide risk.
• Valproate: Approved for the treatment of acute manic or mixed episodes associated with bipolar I disorder. It is often preferred in mixed states, rapid cycling, and comorbid substance use. Its role in maintenance therapy and bipolar depression is supported but may be less robust than for lithium in certain presentations.
• Carbamazepine: Approved for the treatment of acute manic and mixed episodes. It may be particularly useful in patients who do not respond to or tolerate lithium or valproate.
• Lamotrigine: Approved for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed). It has proven particularly effective in preventing depressive relapse and is often a first-line choice for the maintenance phase with a predominant depressive course.
• Atypical Antipsychotics: Most have approvals for acute mania/mixed states. Several (olanzapine, aripiprazole, quetiapine, risperidone long-acting injection) are also approved for maintenance treatment. Quetiapine, lurasidone, cariprazine, and the combination of olanzapine/fluoxetine are approved for the treatment of bipolar depression.

Off-Label and Adjunctive Uses

• Adjunctive Treatment in Major Depressive Disorder: Lithium and certain atypical antipsychotics are used to augment antidepressants in treatment-resistant unipolar depression.
• Schizoaffective Disorder: Mood stabilizers are frequently combined with antipsychotics.
• Impulse-Control and Aggression: Lithium, valproate, and carbamazepine may be used to manage aggression in disorders such as intermittent explosive disorder and in certain neurodevelopmental disorders.
• Preventive Treatment in Cyclothymia and Bipolar II Disorder: While formal approvals may be lacking, mood stabilizers are commonly employed based on clinical guidelines.
• Migraine Prophylaxis: Valproate and topiramate have established roles.
• Neuropathic Pain: Carbamazepine (specifically for trigeminal neuralgia), oxcarbazepine, and lamotrigine are sometimes used.

Adverse Effects

The adverse effect profiles of mood stabilizers are diverse and often dictate drug selection and monitoring requirements.

Lithium

Adverse effects are common and often correlate with serum concentration.

• Common Side Effects: Polyuria and polydipsia (due to nephrogenic diabetes insipidus), fine tremor, weight gain, gastrointestinal distress (nausea, diarrhea), fatigue, and cognitive dulling. Acne and psoriasis exacerbation may occur.
• Serious Adverse Reactions:
  • Renal Toxicity: Chronic lithium use can lead to nephrogenic diabetes insipidus and, in a minority of patients, chronic interstitial nephritis with a gradual decline in glomerular filtration rate.
  • Thyroid Dysfunction: Can cause hypothyroidism (often subclinical) and rarely hyperthyroidism. It inhibits thyroid hormone release and may induce autoimmune thyroiditis.
  • Cardiac Effects: Benign T-wave flattening on ECG is common. Sinus node dysfunction and other arrhythmias are risks in overdose or susceptible individuals.
  • Hyperparathyroidism: Can cause elevated calcium levels.
  • Lithium Toxicity: A medical emergency occurring at levels >1.5 mmol/L. Symptoms progress from worsening tremor, nausea, and diarrhea to confusion, ataxia, nystagmus, seizures, coma, and death.
• Black Box Warnings: Lithium toxicity. Close monitoring of serum levels is required.

Valproate

• Common Side Effects: Gastrointestinal upset (minimized with enteric-coated forms), tremor, weight gain, alopecia (often transient), and sedation.
• Serious Adverse Reactions:
  • Hepatotoxicity: Rare but potentially fatal, especially in children under two years on multiple anticonvulsants and those with metabolic disorders. Monitoring of liver enzymes is recommended early in therapy.
  • Pancreatitis: Hemorrhagic pancreatitis can occur and may be fatal.
  • Hyperammonemic Encephalopathy: Can occur with or without elevated liver enzymes, presenting with lethargy, vomiting, and confusion.
  • Teratogenicity: High risk of neural tube defects and other major congenital malformations.
  • Thrombocytopenia and Platelet Dysfunction: Dose-related effect on platelet count and function.
• Black Box Warnings: Hepatotoxicity, teratogenicity, and pancreatitis.

Carbamazepine

• Common Side Effects: Dizziness, drowsiness, ataxia, diplopia, nausea, vomiting, and hyponatremia (due to SIADH).
• Serious Adverse Reactions:
  • Dermatological Reactions: Benign maculopapular rash occurs in 5-10% of patients. Life-threatening Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is associated with the HLA-B*1502 allele in certain Asian populations.
  • Hematological Toxicity: Dose-related leukopenia is common. Aplastic anemia and agranulocytosis are rare but serious.
  • Hepatotoxicity.
  • Teratogenicity: Increased risk of congenital malformations (neural tube defects, craniofacial abnormalities).
• Black Box Warnings: Aplastic anemia, agranulocytosis, SJS/TEN (with HLA-B*1502 recommendation), and teratogenicity.

Lamotrigine

• Common Side Effects: Headache, dizziness, ataxia, somnolence, nausea, diplopia. Rash is common but usually benign.
• Serious Adverse Reactions:
  • Serious Rashes: The risk of SJS/TEN is estimated at 0.1% in adults and is higher in children and with rapid dose escalation. Concomitant valproate use and exceeding recommended titration schedules significantly increase risk.
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): A multiorgan hypersensitivity reaction.
  • Aseptic Meningitis: A rare but reported association.
• Black Box Warning: Serious skin rashes (SJS/TEN).

Drug Interactions

Drug interactions with mood stabilizers are frequent and can be clinically significant, often necessitating dose adjustments and careful monitoring.

Major Drug-Drug Interactions

• Lithium:
  • Diuretics: Thiazide diuretics reduce renal lithium clearance by 20-40%, markedly increasing serum levels and risk of toxicity. Loop diuretics pose a lower risk but still require caution.
  • NSAIDs and COX-2 Inhibitors: Ibuprofen, indomethacin, and others can decrease lithium clearance by inhibiting renal prostaglandin synthesis, leading to elevated levels.
  • ACE Inhibitors and ARBs: Can reduce lithium clearance and increase levels.
  • Metronidazole and Tetracyclines: May increase lithium levels.
  • Serotonergic Drugs: Concomitant use with SSRIs/SNRIs may increase the risk of serotonin syndrome, though this is rare.
• Valproate:
  • Enzyme Inducers: Carbamazepine, phenytoin, phenobarbital, and rifampin increase valproate metabolism, reducing its serum concentration.
  • Enzyme Inhibitors: Valproate inhibits UGT and CYP2C9, increasing levels of lamotrigine (requires a 50% dose reduction of lamotrigine), phenobarbital, and certain benzodiazepines. It displaces phenytoin from protein-binding sites.
  • Aspirin and other highly protein-bound drugs: Can displace valproate from albumin, increasing free fraction.
  • Clozapine and Lamotrigine: Valproate may increase the risk of bone marrow suppression with clozapine and dramatically increases lamotrigine levels.
• Carbamazepine:
  • Enzyme Inducers: As a potent inducer, carbamazepine decreases serum levels of many drugs, including oral contraceptives (risk of contraceptive failure), warfarin, many antipsychotics, antidepressants, benzodiazepines, and other anticonvulsants (including itself—autoinduction).
  • Enzyme Inhibitors: Drugs that inhibit CYP3A4 (e.g., fluoxetine, fluvoxamine, erythromycin, clarithromycin, ketoconazole, valproate, cimetidine) can increase carbamazepine levels and risk of toxicity.
  • Other Interactions: May decrease the efficacy of hormonal contraceptives and non-nucleoside reverse transcriptase inhibitors.
• Lamotrigine:
  • Valproate: Inhibits lamotrigine glucuronidation, doubling its half-life and increasing serum levels 2-3 fold. This necessitates a very low starting dose and slow titration.
  • Enzyme Inducers: Carbamazepine, phenytoin, phenobarbital, and rifampin increase lamotrigine metabolism, reducing its half-life by approximately 50%, requiring a higher maintenance dose.
  • Oral Contraceptives: Estrogen-containing contraceptives can increase lamotrigine clearance by inducing glucuronidation, reducing lamotrigine levels by up to 50%. Dose adjustments may be needed during pill cycles and withdrawal.

Contraindications

Absolute contraindications are often related to serious adverse effect profiles.

• Lithium: Severe renal impairment, significant cardiovascular disease with rhythm disturbances, untreated hypothyroidism, Addison’s disease, and severe dehydration or sodium depletion.
• Valproate: Known hypersensitivity, significant hepatic disease, urea cycle disorders, and pregnancy (relative contraindication due to high teratogenic risk).
• Carbamazepine: History of bone marrow depression, hypersensitivity to tricyclic compounds, concomitant use of monoamine oxidase inhibitors (MAOIs), and presence of the HLA-B*1502 allele in at-risk populations (for Asian patients).
• Lamotrigine: Known hypersensitivity.

Special Considerations

Use in Pregnancy and Lactation

Management of bipolar disorder in women of childbearing potential requires careful planning due to high teratogenic risks.

• Lithium: Associated with a 0.05-0.1% risk of Ebstein’s anomaly (tricuspid valve malformation), which is 10-20 times the general population risk. The overall risk of major congenital malformations is estimated to be 4-12%, compared to 2-4% in the general population. It is excreted in breast milk, with infant serum levels reaching 10-50% of maternal levels; monitoring of the infant is recommended.
• Valproate: Contraindicated in pregnancy if possible. Associated with a 1-2% risk of neural tube defects (spina bifida), along with increased risks of craniofacial, cardiovascular, and skeletal abnormalities, and neurodevelopmental disorders (e.g., lower IQ, autism spectrum disorders). It is excreted in breast milk, but infant exposure is considered low; use requires caution.
• Carbamazepine: Associated with neural tube defects (0.5-1% risk), craniofacial abnormalities, and fingernail hypoplasia. It is a weak folic acid antagonist. Excreted in breast milk, but infant exposure is generally low.
• Lamotrigine: Appears to have a lower teratogenic risk profile than other mood stabilizers. Data from pregnancy registries suggest a possible small increased risk of oral clefts, though absolute risk remains low. Lamotrigine clearance increases significantly during pregnancy (especially in the second and third trimesters), often requiring dose increases by 50% or more to maintain therapeutic effect. Levels must be monitored closely and doses reduced rapidly postpartum to avoid toxicity. It is excreted in breast milk, but infant serum levels are typically low.
• General Principle: The risks of medication must be balanced against the high risk of relapse from discontinuing treatment, which can also harm the fetus. Preconception counseling and folic acid supplementation are essential.

Pediatric and Geriatric Considerations

• Pediatric: Use of mood stabilizers in children and adolescents is often off-label and requires caution. Children may be more susceptible to certain adverse effects (e.g., valproate hepatotoxicity, behavioral activation with lamotrigine). Dosing is typically weight-based. Lithium clearance is higher in children, often requiring higher mg/kg doses, but they may also be more sensitive to neurotoxic effects.
• Geriatric: Age-related physiological changes significantly impact pharmacokinetics and pharmacodynamics. Reduced renal function mandates lower lithium doses and more frequent level monitoring. Increased sensitivity to CNS side effects (sedation, ataxia, confusion), drug interactions (due to polypharmacy), and medical comorbidities (e.g., cardiac, metabolic) necessitate lower starting doses, slower titration, and careful monitoring for all agents.

Renal and Hepatic Impairment

• Renal Impairment:
  • Lithium: Contraindicated in severe impairment. Dose must be reduced proportional to the decrease in creatinine clearance. Frequent serum level monitoring is critical. Hemodialysis is effective in removing lithium and is used in overdose or severe toxicity.
  • Other Agents: Valproate, carbamazepine, and lamotrigine require caution. Dose adjustments may be needed for renally excreted active metabolites (e.g., lamotrigine’s glucuronide conjugate accumulates in severe renal failure).
• Hepatic Impairment:
  • Valproate and Carbamazepine: Contraindicated in significant hepatic disease due to extensive metabolism and risk of hepatotoxicity. Should be used with extreme caution and close monitoring in mild-to-moderate impairment.
  • Lamotrigine: Metabolism may be impaired; dose reduction may be necessary in moderate-to-severe impairment.
  • Lithium: Not metabolized by the liver; no dose adjustment needed for hepatic impairment alone.

Summary/Key Points

• Mood stabilizers are a pharmacologically diverse class of agents essential for the acute and long-term management of bipolar disorder and related conditions.
• Lithium remains a first-line treatment with a unique mechanism involving inositol depletion and GSK-3 inhibition, but its use is constrained by a narrow therapeutic index requiring regular serum level monitoring and vigilance for renal, thyroid, and cardiac effects.
• Anticonvulsant-derived mood stabilizers (valproate, carbamazepine, lamotrigine) offer alternative mechanisms, primarily involving ion channel modulation and enhanced GABAergic inhibition. Each possesses a distinct efficacy profile (e.g., lamotrigine for depression prevention, valproate for mixed states) and a characteristic set of serious adverse effects requiring specific monitoring protocols.
• Atypical antipsychotics are now integral to the treatment landscape, with several agents approved for all phases of bipolar illness, often used in combination with classical mood stabilizers.
• Pharmacokinetic properties are complex and clinically critical. Lithium has renal excretion sensitive to sodium balance. Valproate and carbamazepine undergo extensive hepatic metabolism, with carbamazepine acting as a potent enzyme inducer. Lamotrigine metabolism is highly susceptible to drug interactions via glucuronidation.
• Drug interactions are extensive, particularly for carbamazepine (as an inducer) and valproate (as an inhibitor), necessitating careful review of concomitant medications.
• Special populations require tailored approaches: significant teratogenic risks (especially with valproate), dose adjustments in renal/hepatic impairment, and cautious use in pediatric and geriatric patients due to altered pharmacokinetics and increased sensitivity to adverse effects.

Clinical Pearls

• The therapeutic serum lithium range is 0.6-1.0 mmol/L for maintenance, with levels drawn 12 hours post-dose. Toxicity can occur with levels >1.5 mmol/L and is a medical emergency.
• When initiating lamotrigine, the titration schedule is paramount. It must be slowed by approximately 50% when co-administered with valproate and may be accelerated when given with enzyme inducers like carbamazepine.
• Valproate levels reflect total drug (bound + free); at higher concentrations, protein binding becomes saturated, leading to a disproportionate increase in free, active drug not reflected in the total level.
• Carbamazepine therapy requires baseline and periodic monitoring of CBC, LFTs, and sodium due to risks of hematological toxicity, hepatotoxicity, and hyponatremia. HLA-B*1502 screening should be considered for patients of Asian ancestry.
• In women of childbearing potential, the choice of a mood stabilizer must involve a detailed discussion of teratogenic risks (highest with valproate), the need for effective contraception, and the importance of preconception folic acid supplementation.

References

1. Stahl SM. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 5th ed. Cambridge: Cambridge University Press; 2021.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
4. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
5. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
6. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
7. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.