Anti-manic drugs: Lithium and others

Introduction

Mania is a hallmark feature of bipolar disorder and is characterized by heightened mood, increased energy, decreased need for sleep, racing thoughts, grandiosity, and, often, impulsive or reckless behaviors. During manic episodes, individuals experience profound alterations in mood and neurophysiological processes, sometimes leading to severe psychosocial impairments. Treating mania demands a nuanced blend of pharmacologic intervention, psychotherapeutic support, and close monitoring, especially where risks of psychosis, self-harm, or harm to others may be significant.

Over recent decades, significant progress has been made in recognizing and differentiating several mood-stabilizing drug classes that provide relief from manic symptoms and reduce relapse frequency. From lithium—the prototypical mood stabilizer—to anticonvulsants such as valproate and carbamazepine, to more recent expansions in atypical antipsychotics, clinicians now have multiple effective pharmacotherapies at their disposal.

This article provides an in-depth exploration of the pharmacotherapy of mania, addressing the pathophysiological underpinnings of mania, the primary drug classes, their mechanisms of action, clinical usage, side effects, and emerging trends. References are derived from “Goodman & Gilman’s The Pharmacological Basis of Therapeutics” (13th Edition), “Katzung BG, Basic & Clinical Pharmacology” (15th Edition), and “Rang & Dale’s Pharmacology” (8th Edition).

Understanding Mania and Pathophysiology

The exact pathophysiological mechanisms fueling mania remain incompletely understood; however, current hypotheses center on:

1. Monoamine Dysregulation: Elevated levels or synaptic activity of dopamine, norepinephrine, and/or related neurotransmitters promote euphoria, hyperactivity, and reduced impulse control.
2. Signal Transduction Abnormalities: Dysbalanced intracellular signaling (e.g., second messengers such as cAMP) and irregularities in neurotrophic factors (e.g., BDNF) can disrupt normal mood regulation.
3. Glutamate and GABA Imbalance: Excessive excitatory transmission or insufficient inhibitory modulation may contribute to manic activation.
4. Genetic Vulnerability: Shared genetic factors often predispose individuals to bipolar disorder, in which mania represents one end of a mood-spectrum continuum.

Pharmacotherapies generally aim to stabilize or modulate these neurochemical circuits, toning down overactivity and forestalling manic relapses.

Goals of Pharmacotherapy in Mania

1. Rapid Symptom Control: Quelling dangerous or disruptive behaviors, agitation, or possible psychosis.
2. Mood Stabilization: Maintaining consistency in mood and preventing further manic or depressive swings.
3. Prevention of Relapse: Long-term prophylaxis to reduce the frequency and severity of mood episodes.
4. Functional Restoration: Facilitating return to normal social, occupational, and interpersonal function.
5. Safety and Tolerability: Minimizing adverse effects, drug interactions, and ensuring adherence.

Clinical decisions often require balancing efficacy against tolerability and adjusting regimens based on the patient’s comorbid conditions, medication history, and acute symptom severity.

Lithium

Mechanism of Action

Lithium is the cornerstone treatment in bipolar mania, although its exact mechanism remains complex. Proposed actions include:

• Modulation of Intracellular Signaling: Lithium affects phosphoinositide and cAMP pathways. By inhibiting inositol monophosphatase and GSK-3 (glycogen synthase kinase-3), it stabilizes neuronal excitability and gene transcription.
• Neuroprotective Influence: Lithium may enhance neurotrophic factors, preserving neuronal viability and connectivity.
• Ionic Shifts: Lithium replaces sodium in certain cell transport mechanisms, affecting neuronal excitability.

Clinical Effectiveness and Role

• Acute Manic Episodes: Lithium is effective in controlling mania symptoms (e.g., euphoria, psychomotor agitation) and can be combined with an antipsychotic or benzodiazepine for more rapid sedation.
• Maintenance Therapy: Lithium significantly reduces relapse rates and stabilizes mood fluctuations over the long term.
• Antisuicidal Properties: Notably, lithium has documented protective effects against suicidality in bipolar disorder.

Pharmacokinetics and Dosing

• Absorption: Nearly complete after oral intake, peak levels within 1–2 hours for standard formulations.
• Elimination: Primarily renal excretion; half-life of ~24 hours in adults.
• Therapeutic Levels: Typically, 0.6–1.2 mEq/L. Levels above 1.5 mEq/L can cause toxicity.
• Monitoring: Regular serum lithium measurement is essential. Dosage adjustments consider fluid balance, renal function, and drug interactions.

Adverse Effects and Toxicity

• Common Side Effects: Tremor, polyuria/polydipsia, mild GI upset, weight gain, potential edema.
• Long-Term Risks: Hypothyroidism, nephrogenic diabetes insipidus, possible hypercalcemia or cardiac arrhythmias.
• Toxicity: Neurological disturbances (confusion, ataxia, seizures), severe GI upset, cardiovascular compromise. Vigilance in maintaining stable sodium levels (e.g., avoiding diuretics without caution) is crucial.

Place in Therapy

Despite challenges with side effects and narrow therapeutic index, lithium remains a first-line agent for acute mania and maintenance—particularly in patients with classic euphoric mania and minimal comorbidities.

Valproate (Valproic Acid / Divalproex Sodium)

Mechanism of Action

Valproate raises brain gamma-aminobutyric acid (GABA) levels and inhibits sodium channels at higher neuron firing rates:

• Enhanced GABAergic Tone: Augmentation of GABA synthesis or blockade of GABA catabolism can dampen excitatory circuits.
• Sodium/Calcium Channel Inhibition: Stabilizes hyperactive neurons, reducing mania’s excitatory drive.
• Histone Deacetylase (HDAC) Inhibition: May underlie epigenetic changes aiding mood stabilization.

Efficacy and Clinical Role

• Acute Mania: Valproate often surpasses lithium in mixed episodes or rapid cycling bipolar disorder. It can be administered in loading doses for quicker therapeutic effect.
• Maintenance: Good prophylactic efficacy, especially in comorbid substance use or impulsive aggression.
• Combination Therapy: Frequently paired with antipsychotics for severe mania or partial responders.

Dosing and Monitoring

• Therapeutic Range: 50–125 µg/mL for mania management.
• Loading Strategy: Up to 20–30 mg/kg/day initial dose can expedite symptom control.
• Levels and Liver Function: Routine valproate serum checks, plus hepatic panels and CBC for early detection of hepatotoxicity or thrombocytopenia.

Adverse Effects

• GI Distress: Nausea, vomiting, particularly on initiation.
• Tremor, Hair Thinning, Weight Gain are frequent.
• Teratogenicity: High risk for neural tube defects; stringent contraception in women of childbearing potential.
• Hepatic Injury, Pancreatitis: Rare but severe. Requiring close monitoring for abdominal pain or abrupt hepatic enzymes change.

Summary

Valproate stands as a first-line option for acute mania, especially in mixed or rapid-cycling presentations or where lithium is contraindicated. Clinician vigilance in monitoring hepatic function, weight changes, and blood counts is paramount.

Carbamazepine and Oxcarbazepine

Mechanism of Action

Carbamazepine is an anticonvulsant with proven mood-stabilizing effect:

• Voltage-Gated Sodium Channel Blockade: Maintains neurons in a hyperpolarized state during high-frequency firing.
• GABA-ergic Enhancement: Indirect through uncertain pathways.
• Anti-Kindling Effect: Reduces the progressive intensification of neuronal discharges often implicated in mood episodes.

Oxcarbazepine, a related derivative, has fewer drug interactions due to less hepatic enzyme induction.

Indications and Efficacy

• Acute Mania: Carbamazepine is effective in mania control, especially in those poorly responsive to lithium or valproate.
• Maintenance: Used adjunctively or monotherapeutically in preventing mania recurrences, though evidence ranks lower than lithium or valproate.
• Mixed States, Rapid Cycling: Carbamazepine may offer particular utility here.

Pharmacokinetics and Drug Interactions

• Metabolism: Hepatic cytochrome P450 induction leads to potential interactions (e.g., with oral contraceptives, warfarin, or other psychotropics).
• Therapeutic Concentrations: Typically aimed at 4–12 µg/mL for mania.
• Autoinduction: Over time, carbamazepine upregulates its own metabolism, requiring dose escalation.

Adverse Effects

• CNS: Dizziness, diplopia, sedation, ataxia.
• Hyponatremia (SIADH): Particularly in older patients or with concurrent diuretic use.
• Blood Dyscrasias: Rarely aplastic anemia or agranulocytosis.
• Dermatologic Reactions: Stevens-Johnson syndrome (SJS) in genetically susceptible populations (e.g., HLA-B*1502 in Asians).

Oxcarbazepine Distinctions

• Comparable efficacy to carbamazepine for mania, with fewer hepatic enzyme inductions.
• Hyponatremia remains a risk.
• Favored when drug interactions are a major concern.

Lamotrigine

Mechanism of Action

Lamotrigine blocks presynaptic voltage-sensitive sodium channels, diminishing excitatory neurotransmitter release (e.g., glutamate). It also stabilizes neuronal membranes:

• Glutamate Dampening may be especially beneficial in bipolar disorder’s depressive side.

Clinical Role in Mania

• Bipolar Depression: Lamotrigine excels at preventing depressive episodes rather than controlling acute mania.
• Maintenance: Effective prophylaxis in bipolar I, particularly for preventing bipolar depression relapses.
• Limited Use in Acute Mania: Not usually a first choice if mania is prominent or severe, due to slow titration requirements to avoid rash.

Dosing and Safety

• Slow Titration: Minimizes SJS/TEN risk. If therapy is interrupted >5 days, re-titration is mandatory.
• Drug Interactions: Valproate can double lamotrigine levels, necessitating halved lamotrigine dosing.
• Side Effects: Apart from dermatologic concerns, lamotrigine is generally well tolerated (headache, dizziness).

Summary

While not the principal option for acute mania, lamotrigine holds a key position in comprehensive bipolar treatment, particularly for prophylaxis against depressive relapses. Its synergy with lithium or valproate is valuable in some patients.

Atypical Antipsychotics

Mechanism of Action in Mania

Atypical antipsychotics (e.g., Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone, Paliperidone, Lurasidone, Asenapine, etc.) block dopamine D₂ receptors and modulate serotonin pathways, particularly 5-HT₂A antagonism. These actions quell manic agitation, euphoria, and potential psychotic features:

• Rapid Control of mania, often within days.
• Mood Stabilization through downstream changes in cortical-limbic circuits.

Indications and Clinical Efficacy

• Acute Manic Episodes: Monotherapy or in combination with mood stabilizers, especially in severe mania or psychosis.
• Maintenance: Olanzapine, quetiapine, risperidone LAI, and others are FDA-approved for preventing relapse.

Adverse Effects

• Metabolic Syndrome: Weight gain, dyslipidemia, hyperglycemia (particularly with olanzapine, clozapine).
• Extrapyramidal Symptoms (EPS): More likely with risperidone or higher doses.
• Sedation: Common with lower potency or more antihistaminic profiles (e.g., quetiapine).
• Cardiac Effects: QT-prolongation possible with ziprasidone.
• Prolactin Elevation: Particularly with risperidone, leading to galactorrhea or sexual dysfunction.

Role in Therapy

For acute mania, atypical antipsychotics frequently yield rapid improvements, especially relevant if psychosis or hostility is present. They’re also valuable for longer-term prophylaxis, often co-administered with lithium or valproate.

Typical Antipsychotics

Usage in Mania

Older typical antipsychotics (e.g., Haloperidol, Chlorpromazine) can effectively subdue manic agitation:

• D₂ Receptor Blockade lowers excessive dopaminergic drive in mania.
• Rapid sedation helps in severe mania or aggression.

Shortcomings

• High Risk of EPS: Acute dystonia, akathisia, parkinsonism, tardive dyskinesia with prolonged use.
• Less Favored: Replaced largely by atypical antipsychotics for mania, though haloperidol remains an important fallback in acute agitation if modern agents are unavailable or contraindicated.

Benzodiazepines

Adjunctive Role

Benzodiazepines (e.g., Lorazepam, Clonazepam) address insomnia, agitation, and anxiety in mania:

• Short-Term Sedation: Useful while waiting for mood stabilizers (e.g., lithium, valproate) to take effect.
• Skeletal Muscle Relaxant: Eases tension.

Therapeutic Considerations

• Dependence and tolerance risk limit long-term use.
• Potential synergy with antipsychotics or mood stabilizers to calm severe mania should be balanced with sedation and respiratory depression concerns.

Combination Therapy in Mania

Necessity of Multidrug Strategies

Severe mania or partial responders often warrant combination therapy:

1. Mood Stabilizer + Atypical Antipsychotic: Common gold standard for acute mania. Examples: Lithium + Quetiapine or Valproate + Olanzapine.
2. Mood Stabilizer + Mood Stabilizer: e.g., Valproate + Carbamazepine or Lithium + Valproate in complex or treatment-resistant mania.
3. Adjunctive Benzodiazepines: For acute agitation or insomnia.

Advantages and Cautions

• Rapid Response: Overlapping modes of action can yield quicker mania resolution.
• Reduced Dosages: Combining agents may allow lower individual drug doses, mitigating side effects.
• Higher Side Effect Burden: Summation of adverse effects, drug interactions. Monitoring remains paramount (e.g., metabolic panel, CBC, EKG, serum levels).

Monitoring and Safety Considerations

Laboratory Tests

• Lithium or Valproate Levels**: Ensuring therapeutic but non-toxic plasma concentrations.
• CBC and LFTs: For valproate, carbamazepine, and some antipsychotics to detect leukopenia, hepatic injury.
• Thyroid Function: Lithium can induce hypothyroidism, requiring TSH checks.
• Metabolic Profile: Atypical antipsychotics can cause hyperlipidemia, hyperglycemia, significant weight gain.

Tolerability and Compliance

• Education about side effects (e.g., sedation, weight gain, tremor) fosters realistic expectations and can preempt abrupt discontinuation.
• Simplifying regimens (once or twice daily) encourages adherence, especially in patients struggling with the insight/impulsivity of mania.

Risk-Benefit Analysis

• Teratogenicity: Valproate is especially risky in pregnancy (neural tube defects). Lithium carries risk of Ebstein anomaly, though absolute risk remains small.
• Renal vs. Hepatic Function: Mindful adjustment of dosages to patients’ organ function.
• Drug Interactions: e.g., SSRIs can elevate lithium levels or provoke mania in susceptible individuals, while carbamazepine can reduce effectiveness of certain other medications.

Treatment-Resistant Mania

Definitions

Treatment-resistance arises when patients fail to respond adequately to two or more conventional mood stabilizers and/or antipsychotics at therapeutic doses.

Management Approaches

1. Combination or Polypharmacy: e.g., Lithium + Valproate + Antipsychotic, guided by side-effect acceptance.
2. Clozapine: Has utility in refractory bipolar mania, though side effects (agranulocytosis) limit usage.
3. Electroconvulsive Therapy (ECT): Particularly for acute mania with psychosis, catatonia, or risk to self.
4. Emerging Agents: Off-label usage of Gabapentin or Topiramate, though evidence is less robust.

Clinical Pearls

• Evaluate underlying secondary factors (e.g., substance abuse, poor adherence, undiagnosed comorbidities) before labeling mania as treatment-resistant.
• TDM (therapeutic drug monitoring) and patient psychoeducation remain critical.

Special Populations

Geriatric Patients

• More prone to side effects from sedation, orthostatic hypotension, renal/hepatic impairment.
• Lower starting doses, slower titration, periodic re-evaluation of cognition and gait.
• Atypical antipsychotics carry black box warnings for mortality risk in dementia-related psychosis.

Pediatric and Adolescent Patients

• Lithium, valproate, and some atypical antipsychotics are approved for youth mania, but careful monitoring is required for growth, hormonal changes, and metabolic parameters.
• Psychosocial interventions form an integral part of therapy for younger populations.

Pregnancy and Lactation

• Valproate: High teratogenic risk (category D or X in many guidelines).
• Lithium: Congenital cardiac anomalies risk; weigh maternal stability vs. fetal risk.
• Atypical Antipsychotics: Some can be used with caution, but data on long-term effects remain limited.

Emerging Treatments and Research

Novel Anticonvulsants and Modulators

Agents like zonisamide, levetiracetam, or topiramate have been explored, with inconsistent or limited evidence in mania. Researchers continue investigating glutamate modulators or neuropeptide-targeting interventions.

Ketamine and NMDA Antagonists

Ketamine infusions revolutionized treatment-resistant depression, though mania-focused data are minimal. Risk of switching from depression to mania requires caution.

Anti-inflammatory Therapies

Given some evidence linking mania pathogenesis to immune dysregulation, trials of anti-inflammatory agents or cytokine modulators remain an area of interest.

Biomarkers and Personalized Medicine

Distinct biotypes of bipolar mania might respond differently to lithium vs. valproate or antipsychotics. Future directions include pharmacogenomic profiling, advanced neuroimaging, and machine learning approaches to refine medication selection.

Practical Guidelines and Treatment Algorithm

Step 1: Evaluation and Acute Intervention

• Safety Assessment: Evaluate risk to self/others, need for hospitalization, possible comorbid substance use.
• Initiate Mood Stabilizer or Atypical Antipsychotic: E.g., Valproate loading or Lithium + Antipsychotic if severe mania with psychosis.
• Short-Term Adjunct: Add benzodiazepines for agitation/insomnia if required.

Step 2: Early Response Monitoring

• Check blood levels (if using lithium/valproate) after ~5 days.
• Titrate dosage to mid-therapeutic range, watch for sedation, EPS, GI intolerance.
• Reinforce psychoeducation, assess substance use cessation, ensure psychosocial support.

Step 3: Lack of Response or Partial Response

• Optimize monotherapy dose.
• Consider switching to or adding a second agent (e.g., combining Valproate + Atypical Antipsychotic).
• Evaluate medication interactions, comorbidities, or poor adherence.

Step 4: Maintenance and Long-Term Prophylaxis

• Once mania stabilizes, continue medication 6–12 months for a first episode. In recurrent mania, indefinite maintenance is advisable.
• Refine regimen for minimal side effect burden, incorporate necessary labs every 3–6 months.
• Provide therapy to address triggers, lifestyle factors, repeated psychoeducation for sustained adherence.

Conclusion

Pharmacological management of mania demands a careful balance between prompt control of acute symptoms and prudent long-term prophylaxis against recurrent episodes. Lithium, valproate, carbamazepine, and atypical antipsychotics remain the pillars of first-line therapy, supported by robust evidence from clinical trials and decades of frontline practice. Agents such as lamotrigine broaden prophylactic options, especially for bipolar depression. In more severe or treatment-resistant mania, combination regimens or advanced interventions (e.g., ECT) may be essential.

In practice, individualized therapy hinges on evaluating each patient’s unique clinical presentation, comorbidities, side effect tolerances, and real-world challenges (e.g., medication adherence, availability of supportive mental health resources). While mania can be profoundly disruptive, timely and appropriately tailored pharmacotherapy—augmented by psychosocial strategies—significantly improves outcomes, decreases relapse risk, and helps restore functional stability.

Book Citations

1. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition.
2. Katzung BG, Basic & Clinical Pharmacology, 15th Edition.
3. Rang HP, Dale MM, Rang & Dale’s Pharmacology, 8th Edition.