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1.4.8.6 Antiepileptics, antipsychotics, and lithium
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1. Medications
1.4. Medications by organ system
1.4.8. Drugs of the nervous system
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Antiepileptics, antipsychotics, and lithium

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Antiepileptics

Antiepileptics are drugs used to prevent and treat seizures by reducing abnormal electrical activity in the brain. You may also see them called anticonvulsants or AEDs.

Epilepsy is a chronic disorder marked by recurring seizures. A seizure happens when electrical activity in the brain becomes dysregulated. This abnormal activity can be:

  • Localized (focal)
  • Generalized

AEDs help regulate and stop disorderly electrical activity by acting on ion channels, including:

  • Sodium channels
  • GABA-mediated chloride channels
  • Calcium channels

Some AEDs also block glutamate-mediated electrical currents. Most AEDs affect more than one target.

Several AEDs are strong sodium channel blockers, including:

  • Phenytoin
  • Topiramate
  • Zonisamide
  • Valproic acid
  • Lamotrigine
  • Carbamazepine

Some benzodiazepines (for example, clonazepam) have strong GABA-related activity. Ethosuximide primarily blocks calcium channels.

Some antiepileptics (such as gabapentin, pregabalin, and carbamazepine) are also used to treat neuropathic pain.

Commonly prescribed antiepileptics and their brand names are listed below:

  • Carbamazepine - Tegetrol, Epitol
  • Levetiracetam - Keppra, Roweepra
  • Lamotrigine - Lamictal
  • Ethosuximide - Zarontin
  • Phenytoin - Dilantin, Phenytek
  • Fosphenytoin - Cerebyx
  • Phenobarbital - Solfoton, Luminal
  • Felbamate - Felbatol
  • Topiramate - Topamax, Topiragen
  • Valproate or valproic acid or divalproex sodium - Epilim, Depakote, Depakene, Stavzor, Depacon
  • Gabapentin - Gralise, Horizant, Neurontin
  • Pregabalin - Lyrica
  • Vigabatrin - Sabril
  • Tiagabine - Gabitril
  • Clonazepam - Klonopin, Ceberclon
  • Oxcarbazepine - Trileptal
  • Zonisamide - Zonegran
  • Primidone - Mysoline
  • Lacosamide - Vimpat

Antiepileptics are frequently associated with adverse effects, which can make long-term adherence difficult. Common adverse effects include:

  • Drowsiness
  • Rash
  • Diarrhea
  • Disruption of menstrual cycles
  • Infertility
  • Sexual dysfunction
  • Teratogenicity
  • Cognitive issues
  • Restlessness

Weight effects vary by drug:

  • Weight gain: valproic acid, gabapentin, carbamazepine, pregabalin
  • Weight loss: topiramate, zonisamide, felbamate

Other important risks include increased suicidal tendencies, changes in blood counts, and severe allergic reactions.

Notable drug-specific adverse effects include:

  • Phenytoin: gum hyperplasia (overgrowth) and hirsutism
  • Valproate: highest risk of congenital defects in newborn children
  • Vigabatrin: vision problems
  • Carbamazepine, phenytoin, and barbiturates: metabolic disturbances such as Vitamin D deficiency and dyslipidemias
  • Felbamate and valproate: liver dysfunction

Lithium

Sold under the brand names Lithobid, Carbolith, and Eskalith, lithium is used to treat bipolar disorder and some cases of schizophrenia.

Bipolar disorder is a mood disorder characterized by episodes of mania followed by episodes of depression. Lithium is a mood stabilizer that can help control manic symptoms.

Lithium’s effects include:

  • Balancing neurotransmitters such as GABA and dopamine
  • Reducing oxidative stress
  • Inhibiting the enzyme glycogen synthase kinase
  • Producing a neuroprotective effect

Adverse effects include restlessness, tremors, bloating, weight changes, rash, and hair loss.

Lithium excess can cause toxicity. Early toxicity may include:

  • Nausea and vomiting
  • Abdominal pain
  • Mental status changes (for example, delirium)
  • Imbalance
  • Slurred speech
  • Seizures
  • Coma

Chronic toxicity may cause kidney damage called nephrogenic diabetes insipidus, which can lead to excessive urination, thirst, and dehydration. Lithium may also cause thyroid dysfunction.

Lithium has a narrow therapeutic index, so blood levels must be monitored regularly.

Antipsychotics

Drugs used in the treatment of psychotic disorders: Antipsychotics are medications used to treat psychosis, which can occur in disorders such as schizophrenia, PTSD, and drug-induced psychosis.

Based on their activity at neurotransmitter receptors, antipsychotics are classified as:

  • Typical (first-generation)
  • Atypical (second-generation)

Atypical antipsychotics generally have greater overall efficacy and a lower risk of movement disorders, but they carry a higher risk of metabolic syndrome.

Typical or conventional or first-generation antipsychotics: These drugs act primarily by blocking D2 dopamine receptors. They include chlorpromazine, thioridazine (Mellaril), trifluoperazine, haloperidol (Haldol), fluphenazine, loxapine (Adasuve), prochlorperazine (Compro), molindone, perphenazine, thiothixene and pimozide (Orap).

Long-acting intramuscular formulations are available for haloperidol, perphenazine, fluphenazine, and chlorpromazine. Long-acting forms are especially useful when compliance is a problem.

Typical antipsychotics can control positive symptoms of schizophrenia but are not useful for treating negative symptoms.

  • Positive symptoms: hallucinations, delusions, paranoia, etc.
  • Negative symptoms: lack of emotions, decreased speech, decreased drive, etc.

Adverse effects of typical antipsychotics include sedation, dry mouth, constipation, low blood pressure, cognitive defects, dystonia, muscle stiffness, tremors, galactorrhea and elevated prolactin levels, seizures, movement disorders, and metabolic syndrome (less likely).

Some drugs have notable eye-related effects:

  • Thioridazine may cause retinal deposits
  • Chlorpromazine may cause corneal deposits

Movement disorders can be incapacitating and may lead to drug non-compliance. These include acute dystonia, akinesia, bradykinesia, akathisia, and tardive dyskinesia.

Atypical or second-generation antipsychotics: These drugs are more selective D2 blockers than typical antipsychotics, and they also block serotonin 5HT2A receptors. They are effective in treating both positive and negative symptoms of schizophrenia.

They include clozapine (Clozaril, Versacloz), olanzapine (Zyprexa, Symbyax, Lybalvi), aripiprazole (Abilify, Aristada), asenapine (Saphris, Secuado), brexpiprazole (Rexulti), cariprazine (Vraylar), ziprasidone (Geodon), risperidone (Perseris, Risperdal), lurasidone (Latuda), quetiapine (Seroquel) etc.

Second-generation drugs are preferred because they have a low risk of extrapyramidal effects (movement disorders). However, they are associated with higher mortality in older patients with dementia.

Key points about specific agents:

  • Clozapine is notable for high efficacy.
  • Aripiprazole, olanzapine, and risperidone are available in long-acting injectable formulations.

Adverse effects of clozapine include sedation, hypotension, tachycardia, weight gain, metabolic syndrome, glucose intolerance, and rare but potentially fatal agranulocytosis. WBC count must be monitored regularly during clozapine therapy.

Major adverse effects of second-generation drugs include metabolic syndrome, weight gain, and dyslipidemias. Blood glucose and lipid levels should be monitored.

Next-generation antipsychotics: Xanomeline and trospium combination sold as COBENFY were FDA-approved in 2024. They work by modulating parasympathetic M or muscarinic receptors in the brain.

Adverse effects include urinary retention, liver dysfunction, jaundice, glaucoma, angioedema, fast heart rate, constipation, nausea, dizziness, and hypertension.

Antipsychotics that may prolong QTc: They include thioridazine, haloperidol, olanzapine, risperidone, and ziprasidone. That may precipitate cardiac arrest and arrhythmias.

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