Drugs Used as Mood Stabilizers

Introduction

Mood disorders—including bipolar disorder, schizoaffective disorder, and certain forms of unipolar depression—are chronic and debilitating mental health conditions. Characterized by pathologic mood swings, from manic or hypomanic states to severe depressive episodes, they entail significant morbidity, mortality (through suicide), and a profound impact on patient quality of life and functioning. Mood stabilizers constitute a cornerstone of long-term management, aiming to minimize episode frequency and severity, prevent recurrence, and maintain psychosocial well-being.

The evolution of mood stabilizers has transformed psychiatric care—from the serendipitous discovery of lithium’s antimanic properties in the 20th century to the modern use of antiepileptic drugs (valproate, carbamazepine, lamotrigine), and the adoption of atypical antipsychotics for acute manic and long-term maintenance therapy. Understanding their mechanisms, clinical use, monitoring parameters, and adverse effects is essential for evidence-based treatment.

Overview of Mood Stabilizing Drugs

Mood stabilizers are defined by their ability to treat or prevent mood episodes—mania, hypomania, acute depression—without causing, or worsening, the opposite phase (e.g., antidepressant-induced mania).

Major Categories

1. Classical Mood Stabilizer:
   • Lithium
2. Anticonvulsant Mood Stabilizers:
   • Valproic acid and Divalproex sodium
   • Carbamazepine
   • Oxcarbazepine
   • Lamotrigine
   • Others: Gabapentin, topiramate
3. Atypical Antipsychotics with Mood-Stabilizing Properties:
   • Quetiapine, olanzapine, aripiprazole, risperidone, ziprasidone, lurasidone, asenapine

Table: Principal Mood Stabilizer Drugs

Drug	Mechanism	Indications	Key Adverse Effects
Lithium	Inhibits inositol cascade, modulates GSK-3β, ↓ excitatory NTs, alters intracellular Ca²⁺	Bipolar disorder (acute, prophylaxis), unipolar depression augmentation, suicidality	Tremor, renal/thyroid dysfunction, GI upset, weight gain, toxicity
Valproic acid/Divalproex	↑ GABA, blocks Na⁺ channels, modulates HDACs	Mania, mixed episodes, prevention, seizures	Hepatotoxicity, teratogenicity, weight gain, GI
Carbamazepine	Inhibits Na⁺ channels, reduces neurotransmission	Mania, prophylaxis (esp. rapid cyclers), seizures, trigeminal neuralgia	Hyponatremia, rash, aplastic anemia, hepatic
Lamotrigine	Blocks Na⁺ channels, ↓ glutamate/aspartate release	Depression prevention (bipolar II), epilepsy	Rash (SJS), diplopia, headache
Oxcarbazepine	Blocks Na⁺ channels	Mania (adjunct), seizures	Hyponatremia (≥ CBZ), headache
Quetiapine (atypical antipsychotic)	D2, 5-HT2A, partial 5-HT1A antagonist; actions complex	Acute mania, bipolar depression, maintenance	Weight gain, sedation, metabolic syndrome

*NTs = neurotransmitters; SJS = Stevens-Johnson syndrome; HDAC = histone deacetylase.

Lithium: The Prototypical Mood Stabilizer

Mechanism of Action

While the precise mechanism remains incompletely understood, lithium acts on multiple neural signaling pathways:

• Inhibition of Inositol Monophosphatase: Reduces the recycling of inositol required for phosphatidylinositol signaling, altering second messenger cascades believed to underlie manic and depressive switching.
• Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibition: Modulates gene transcription, neuroprotection, and circadian regulation.
• Modulation of Glutamate and Dopamine Transmission: Dampens excitatory neurotransmission.
• Neuroprotective and Neurotrophic Effects: Promotes neurogenesis, reduces oxidative stress.

Indications and Clinical Use

• Acute Mania: Lithium is a classic first-line agent, though the full antimanic response is typically delayed 7–14 days. For severely agitated or psychotic mania, it’s often combined with antipsychotics or benzodiazepines.
• Maintenance Prophylaxis: Reduces recurrence of mania and depression, particularly effective in “classic” euphoric mania.
• Anti-suicidal Effect: Unique evidence supports lithium’s reduction in suicide risk in mood disorders.
• Adjunct in Treatment-Resistant Depression.

Dosage and Monitoring

• Therapeutic serum level: 0.6–1.0 mEq/L (acute: up to 1.2 mEq/L). Maintenance: typically 0.5–0.8 mEq/L.
• Monitoring: Baseline renal and thyroid function, serum calcium; follow-up levels every 3–6 months and as clinically indicated.
• Pharmacokinetics:
  • 100% oral bioavailability, not protein-bound, not metabolized.
  • Renal excretion—handled like sodium; dehydration, sodium loss, or concurrent diuretic/NSAID use increases toxicity risk.

Adverse Effects

• Common: Fine tremor, GI upset, polyuria/polydipsia (nephrogenic diabetes insipidus), mild cognitive blunting, weight gain.
• Serious/Long-term: Hypothyroidism, goiter, hyperparathyroidism, chronic kidney disease, arrhythmias.
• Toxicity: >1.5 mEq/L. Presents as coarse tremor, ataxia, dysarthria, confusion; >2.5 mEq/L: seizures, coma, death.
• Pregnancy/Special Populations: Avoid in pregnancy (teratogenic: Ebstein’s anomaly); use with caution in elderly or renal impairment.

Drug Interactions

• ↑ Risk of toxicity with thiazide diuretics, ACE inhibitors, NSAIDs, low-salt diet.
• Contraindications: Severe renal/cardiovascular disease, states predisposing to sodium depletion.

Anticonvulsant Mood Stabilizers

Valproic Acid (Valproate, Divalproex Sodium)

Mechanism

• Increases brain GABA via inhibition of GABA transaminase, blocks voltage-gated sodium/calcium channels, modulates gene expression via HDAC inhibition.
• Broader spectrum, faster onset in acute mania (especially with mixed episodes or rapid cycling); also used in epilepsy and migraine prophylaxis.

Clinical Use

• Acute Mania: Recommended first-line for mania/mixed states; titration to effect often faster than lithium.
• Maintenance: Can be combined with atypical antipsychotics or lithium for more refractory cases.

Dosage and Monitoring

• Typical dose: 750–3000 mg daily (adjust for weight/side effects).
• Serum level target: 50–100 μg/mL.
• Labs: Baseline/periodic LFTs, CBC; monitor ammonia (if confusion/encephalopathy suspected).

Adverse Effects

• Common: GI upset, tremor, weight gain, hair loss.
• Serious: Hepatotoxicity (rare but severe, esp. in children <2), pancreatitis, thrombocytopenia, encephalopathy.
• Teratogenicity: Neural tube defects (spina bifida); avoid in women of childbearing age.

Interactions/Warnings

• CYP450 inhibitor; can increase levels of other antiepileptics.
• Provides rapid stabilization in acute mania—preferred in liver function–tolerant adults without pregnancy potential.

Carbamazepine

Mechanism

• Stabilizes hyperexcitable neuronal membranes via blockade of voltage-dependent sodium channels.
• Also enhances ADH action (risk of hyponatremia).
• Induces hepatic enzymes (CYP3A4, CYP2C9).

Clinical Use

• Mania (esp. rapid cycling or those intolerant of lithium/valproate).
• Epilepsy, trigeminal neuralgia.

Dosage and Monitoring

• Start 200–400 mg/day; maintenance 600–1200 mg/day.
• Monitor serum levels (4–12 μg/mL), LFTs, CBC, electrolytes (Na+), and periodic renal/thyroid tests.

Adverse Effects

• Rash (SJS risk, esp. HLA-B*1502 in Asians), dizziness, sedation, diplopia.
• Hyponatremia (SIADH), leukopenia, agranulocytosis, hepatotoxicity.
• Teratogenic (neural tube defects, craniofacial anomalies).

Drug Interactions

• Induces own metabolism (“autoinduction”), other mood stabilizers/metabolized drugs.
• Avoid with MAOIs, caution with other enzyme inducers/inhibitors.

Lamotrigine

Mechanism

• Blocks voltage-gated sodium channels, reduces glutamate release.
• Excellent efficacy for prevention of depressive episodes; less robust in mania.

Use

• Bipolar depression maintenance: Best data for BD II.
• Adjunctive therapy: May be combined with other mood stabilizers.

Dosage/Monitoring

• Start at 25 mg/day, increase slowly to avoid rash; maintenance usually up to 200 mg/day.
• If combined with valproate: halve dose.

Adverse Effects

• Rash (5–10%; Stevens-Johnson—rare but potentially fatal); headache, dizziness, ataxia, mild GI.
• Avoid in severe liver dysfunction.

Oxcarbazepine

• Mechanistically similar to carbamazepine; fewer drug interactions (does not induce own metabolism).
• More hyponatremia. Used in bipolar disorder—less robust main evidence.

Topiramate, Gabapentin

• Occasionally used adjunctively; weaker evidence for efficacy. Topiramate: can cause weight loss, cognitive impairment.

Atypical Antipsychotics as Mood Stabilizers

A large body of modern evidence supports the use of atypical (second-generation) antipsychotics for bipolar mania, depression, and maintenance.

Mechanism

• D2 receptor antagonism (or partial agonism, e.g., aripiprazole)
• 5-HT2A antagonism (improves negative symptoms, mood regulation).

Drugs and Indications

Drug	Mania	Maintenance	Bipolar Depression
Quetiapine	Yes	Yes	Yes
Olanzapine	Yes	Yes	Yes (not primary)
Risperidone	Yes	Yes	No
Aripiprazole	Yes	Yes	Some benefit
Lurasidone	No	Yes	Yes
Ziprasidone	Yes	Yes	No
Asenapine	Yes	Yes	No

Combination therapy (e.g., lithium/valproate + atypical antipsychotic) is especially valuable for acute mania or in treatment-resistant maintenance.

Adverse Effects and Monitoring

• Extrapyramidal symptoms (rare, esp. with risperidone)
• Sedation, weight gain (notably olanzapine, quetiapine)
• Metabolic syndrome (hyperglycemia, hyperlipidemia)
• Increased risk for tardive dyskinesia, neuroleptic malignant syndrome
• Regular monitoring: weight, glucose, lipids, prolactin (if symptomatic)

Principles of Therapy: Guidelines and Evidence

Acute Mania

• First-line: Lithium OR valproate OR atypical antipsychotic (monotherapy)
• Combination therapy: For severe/psychotic mania lithium or valproate + antipsychotic
• Benzodiazepines: Short-term adjunct for agitation/insomnia

Acute Bipolar Depression

• Lamotrigine, quetiapine, lurasidone, cariprazine, or combination therapies.
• Avoid antidepressant monotherapy (may induce mania/hypomania).

Maintenance Therapy

• Continue the agent effective in acute episode (lithium, valproate, second-generation antipsychotic, or lamotrigine).
• Polytherapy for refractory cases, frequent relapses, rapid cycling.

Rapid Cycling/Comorbidity

• Valproate/carbamazepine have better evidence than lithium.
• Address medical contributors: hypothyroidism, substance use, medication triggers.

Special Populations

• Pregnancy: High teratogenicity risk with valproate, carbamazepine, (AVOID). Relative safety: lamotrigine (caution), antipsychotics (varies, consult guidelines), lithium (Ebstein anomaly).
• Children/Adolescents: Limited data; atypical antipsychotics commonly used.
• Elderly: Lower doses, slower titration, frequent monitoring.

Lithium Toxicity: Clinical Features and Management

Clinical Presentation

• Acute Intoxication: GI—nausea, vomiting, diarrhea; early tremor, lethargy.
• Progression: Coarse tremor, confusion, ataxia, dysarthria, seizures, coma.
• Cardiac: Arrhythmias, hypotension, T-wave changes on ECG.

Risk Factors

• Dehydration, salt depletion, renal impairment, drug interactions (NSAIDs, ACE inhibitors, thiazide diuretics).

Management

• Discontinue lithium, supportive care, correct fluid/electrolyte disturbances.
• Hemodialysis: Indicated for severe toxicity (Li >4 mEq/L acute, >2.5 in chronic, severe symptoms).
• No specific antidote.

Comparative Table: Mood Stabilizers

Drug	Onset of Action	Manic Control	Depression Control	Maintenance	Major Toxicities	Teratogenicity
Lithium	Slow (7–14 days)	Good	Modest	Good	Renal, thyroid	Ebstein anomaly
Valproic Acid/Divalproex	Rapid (few days)	Good	Poor	Good	Hepatic, weight, GI	Spina bifida
Carbamazepine	Intermediate	Good	Poor	Good	Hepatic, rash, SIADH	Spina bifida
Lamotrigine	Slow (weeks)	Poor	Good	Good	Rash (SJS/TEN)	Cleft palate?
Quetiapine/atypicals	Rapid	Good	Good (some)	Good	Metabolic, sedation	Varies by agent

Key Clinical Pearls

• Baseline Assessment: Screen for renal/hepatic/thyroid status, pregnancy, drug interactions.
• Monitor regularly: Renal/liver/thyroid, serum level (lithium/valproate), weight/metabolic syndrome (atypicals).
• Start low, go slow: Particularly elderly, hepatic/renal dysfunction.
• Combine for acute mania: Lithium or valproate plus an atypical antipsychotic.
• Switching/Cross-titration: Gradual overlap or substitution often needed to reduce relapse risk or manage side effects.

References

1. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition
2. Katzung BG, Trevor AJ. Basic & Clinical Pharmacology, 15th Edition
3. Stahl SM. Essential Psychopharmacology, 5th Edition
4. American Psychiatric Association. Practice Guidelines for the Treatment of Patients with Bipolar Disorder (2023)
5. NICE Clinical Guidelines: Bipolar Disorder (2021)
6. Muench J, Hamer AM. Adverse effects of antipsychotic medications. American Family Physician