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Tuesday, August 19, 2025

Antimanic agents


Introduction

Mania is a cardinal feature of bipolar disorder, characterized by abnormally elevated or irritable mood, increased activity or energy, impulsivity, reduced need for sleep, and impaired judgment. Left untreated, mania can result in severe functional impairment, hospitalization, or self-destructive behavior. Pharmacological treatment is essential in both acute mania and long-term stabilization to prevent relapse into depressive or manic episodes.

Antimanic agents refer to a group of medications used to control acute manic symptoms and stabilize mood over time. These include:

  • Mood stabilizers (e.g., lithium, valproate, carbamazepine, lamotrigine)

  • Atypical (second-generation) antipsychotics (e.g., olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, lurasidone)

  • Typical (first-generation) antipsychotics (less commonly, e.g., haloperidol, chlorpromazine)

  • Adjunctive agents (benzodiazepines for agitation, antidepressants used cautiously)

This article examines antimanic agents in detail, focusing on their pharmacology, mechanisms, therapeutic use, and clinical considerations.

1. Classification of Antimanic Agents

  1. Lithium salts

    • Lithium carbonate

    • Lithium citrate

  2. Anticonvulsants with mood-stabilizing properties

    • Valproate (sodium valproate, divalproex sodium)

    • Carbamazepine

    • Oxcarbazepine

    • Lamotrigine (more effective for bipolar depression but sometimes adjunctive in mania)

    • Topiramate (limited evidence, sometimes adjunctive)

  3. Atypical antipsychotics (SGAs)

    • Olanzapine

    • Risperidone

    • Quetiapine

    • Aripiprazole

    • Ziprasidone

    • Lurasidone (more bipolar depression, adjunctive in mania)

    • Asenapine

    • Cariprazine

  4. Typical antipsychotics (FGAs)

    • Haloperidol

    • Chlorpromazine

    • Loxapine (occasionally used in acute mania)

  5. Adjunctive medications

    • Benzodiazepines (lorazepam, clonazepam) for acute agitation

    • Antidepressants (SSRIs, cautiously in bipolar depression, as they can precipitate mania)

2. Mechanisms of Action

Lithium

  • Precise mechanism remains incompletely understood.

  • Modulates intracellular signaling pathways, including inositol monophosphatase inhibition, leading to reduced second messenger signaling.

  • Affects glycogen synthase kinase-3β (GSK-3β), enhancing neuroplasticity.

  • Stabilizes neuronal firing by influencing ion channels (Na⁺, K⁺, Ca²⁺).

Valproate

  • Increases GABAergic transmission by inhibiting GABA breakdown and enhancing its synthesis.

  • Blocks voltage-gated sodium channels and T-type calcium channels.

  • Reduces neuronal hyperexcitability in mania.

Carbamazepine & Oxcarbazepine

  • Block voltage-gated sodium channels, reducing repetitive neuronal firing.

  • Also modulate glutamate release and may affect calcium signaling.

Lamotrigine

  • Stabilizes neuronal membranes by blocking voltage-gated sodium channels.

  • Reduces glutamate release.

  • Stronger effect in preventing bipolar depression than mania.

Atypical Antipsychotics

  • Block dopamine D2 receptors (antimanic effect).

  • Block serotonin 5-HT2A receptors (improves tolerability, reduces extrapyramidal symptoms).

  • Some also act on 5-HT1A, 5-HT2C, H1 histamine, and α-adrenergic receptors, contributing to efficacy and side effect profile.

Typical Antipsychotics

  • Potent dopamine D2 receptor antagonists, rapidly controlling acute mania.

  • Higher risk of extrapyramidal side effects (EPS) and tardive dyskinesia.

3. Clinical Uses of Antimanic Agents

  1. Acute Mania

    • Rapid control of psychotic features, agitation, and impulsivity.

    • Common agents: lithium, valproate, atypical antipsychotics (olanzapine, risperidone, quetiapine, aripiprazole).

    • Severe agitation: may require combination therapy (e.g., antipsychotic + benzodiazepine).

  2. Maintenance Therapy (Mood Stabilization)

    • Prevents recurrence of manic or depressive episodes.

    • Lithium remains the gold standard.

    • Valproate and lamotrigine also used for long-term stabilization.

    • Antipsychotics may be continued for maintenance if well tolerated.

  3. Bipolar Depression (Adjunctive Role)

    • Lamotrigine, quetiapine, lurasidone, and cariprazine have evidence for bipolar depression.

    • Antidepressants used with caution, always with a mood stabilizer.

  4. Rapid Cycling Bipolar Disorder

    • Valproate is particularly effective.

  5. Mixed States (simultaneous mania + depression)

    • Antipsychotics and valproate often used.

4. Generic Names and Typical Dosing

Lithium

  • Lithium carbonate: 300 mg two to three times daily, titrated to therapeutic serum levels (0.6–1.2 mEq/L for maintenance, up to 1.5 mEq/L in acute mania).

  • Lithium citrate: used in liquid formulations.

Valproate

  • Sodium valproate/divalproex sodium: 750–1500 mg/day in divided doses.

  • Therapeutic serum concentration: 50–125 µg/mL.

Carbamazepine

  • 400–1200 mg/day in divided doses.

  • Therapeutic range: 4–12 µg/mL.

Oxcarbazepine

  • 600–2400 mg/day.

Lamotrigine

  • Initiated at 25 mg/day, slowly titrated (to reduce rash risk) up to 100–200 mg/day.

Atypical Antipsychotics

  • Olanzapine: 10–20 mg/day.

  • Risperidone: 2–6 mg/day.

  • Quetiapine: 400–800 mg/day.

  • Aripiprazole: 10–30 mg/day.

  • Ziprasidone: 40–80 mg twice daily.

  • Asenapine: 5–10 mg sublingual twice daily.

  • Cariprazine: 1.5–6 mg/day.

Typical Antipsychotics

  • Haloperidol: 2–20 mg/day (oral or IM).

  • Chlorpromazine: 100–800 mg/day.

Benzodiazepines (Adjuncts)

  • Lorazepam: 1–2 mg every 6–8 hours PRN.

  • Clonazepam: 0.5–2 mg two to three times daily.

5. Contraindications

Lithium

  • Severe renal impairment

  • Hyponatremia

  • Dehydration

  • Pregnancy (risk of Ebstein’s anomaly)

  • Untreated hypothyroidism

Valproate

  • Hepatic disease

  • Urea cycle disorders

  • Pregnancy (teratogenic: neural tube defects)

Carbamazepine

  • History of bone marrow suppression

  • Hypersensitivity to tricyclic compounds

  • Hepatic failure

Antipsychotics

  • Prolonged QT interval (especially ziprasidone)

  • Severe CNS depression

  • Parkinson’s disease (dopamine blockade worsens symptoms)

6. Side Effects

Lithium

  • Tremor, polyuria, polydipsia, hypothyroidism, weight gain.

  • Toxicity: nausea, vomiting, ataxia, seizures, coma.

Valproate

  • GI upset, weight gain, tremor, hepatotoxicity, pancreatitis, alopecia.

Carbamazepine

  • Drowsiness, dizziness, hyponatremia, agranulocytosis, aplastic anemia.

Lamotrigine

  • Rash (risk of Stevens-Johnson syndrome).

Atypical Antipsychotics

  • Weight gain, metabolic syndrome (especially olanzapine, quetiapine).

  • Extrapyramidal symptoms (less than FGAs but possible with risperidone).

  • Sedation, orthostatic hypotension.

Typical Antipsychotics

  • High EPS risk, tardive dyskinesia, hyperprolactinemia.

7. Precautions

  • Lithium: monitor renal and thyroid function, maintain adequate hydration and sodium intake.

  • Valproate: monitor liver function tests, platelets.

  • Carbamazepine: monitor CBC and liver enzymes.

  • Antipsychotics: monitor weight, glucose, lipid profile, ECG (QT prolongation).

8. Drug Interactions

  • Lithium: interaction with diuretics (thiazides increase lithium levels), NSAIDs (increase levels), ACE inhibitors/ARBs (increase levels).

  • Valproate: increases lamotrigine levels (risk of toxicity).

  • Carbamazepine: strong CYP450 inducer, reduces efficacy of oral contraceptives, warfarin, other antipsychotics.

  • Antipsychotics: additive sedation with alcohol or benzodiazepines; QT prolongation risk with other agents (macrolides, antiarrhythmics).

9. Comparative Overview

  • Lithium: most effective for classic euphoric mania and long-term prevention, with anti-suicidal properties.

  • Valproate: better for rapid cycling, mixed states, and when lithium is not tolerated.

  • Carbamazepine: useful alternative in lithium/valproate non-responders.

  • Atypical antipsychotics: rapid onset in acute mania, often used in combination.

  • Typical antipsychotics: still used for rapid tranquilization but less favored long-term.

  • Lamotrigine: more preventive for bipolar depression, not acute mania.

10. Future Directions in Antimanic Therapy

  • Novel glutamatergic agents (ketamine, memantine) under investigation.

  • Targeting intracellular signaling pathways (e.g., GSK-3 inhibitors).

  • Long-acting injectable antipsychotics increasingly used for adherence.

  • Personalized psychiatry approaches using pharmacogenomics to predict response.




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