Antiepileptics for psychiatric illness: Find the right match
Selecting the optimal agent requires knowing each drug’s efficacy and safety profile
Other effects. Valproate-induced pancreatitis is a rare, life-threatening adverse effect that generally occurs in the first 12 months of treatment and with dose increases.8 Amylase levels are not strong predictors of valproate-induced pancreatitis because elevations occur in asymptomatic users and normal levels have been reported in affected patients. Valproate also is linked to polycystic ovaries; evidence of this association is stronger in women with seizures than in those with mood disorders.19
Secondary to developing metabolic acidosis, both topiramate and zonisamide elevate the risk of developing calcium phosphate kidney stones with long-term use (>1 year).12,20 The risk appears higher in patients who are male, elderly, or have a personal or family history of kidney stones. Encourage patients taking topiramate or zonisamide to increase their fluid intake because this significantly reduces kidney stone risk.
Rare but potentially fatal angioedema has been reported with oxcarbazepine and pregabalin.12 History of angioedema or concurrent use of medications associated with angioedema (eg, angiotensin-converting enzyme inhibitors) may confer additional risk.12
Pregnancy and lactation. Carbamazepine and valproate have been associated with neural tube, craniofacial, and cardiac defects in the developing fetus.21 If possible, these agents should be avoided during pregnancy.21 Despite being teratogenic, carbamaze-pine and valproate are thought to be safe for women who are breast-feeding.8 Lamotrigine is associated with mid-facial clefts with first trimester exposure, but is still believed to be a relatively safe option during pregnancy.2 Because lamotrigine clearance increases as pregnancy progresses, the dosage may need to be increased during pregnancy and decreased after delivery to maintain therapeutic levels. Data are inadequate to assess the safety of gabapentin, levetiracetam, oxcarbaze-pine, tiagabine, topiramate, and zonisamide use during pregnancy and lactation.8,21
Table 422 provides additional clinical pearls regarding AED adverse effects.
Table 3
Comparison of antiepileptics’ effects on cognition
| Medication | Comparative effect on cognition | Compared with |
|---|---|---|
| Carbamazepine | ↑ | Topiramate |
| ↔ | Oxcarbazepine, tiagabine, valproate | |
| ↓ | Gabapentin, lamotrigine, levetiracetam, oxcarbazepine | |
| Lamotrigine | ↑ | Carbamazepine, topiramate |
| ↔ | Gabapentin | |
| Valproate | ↑ | Topiramate |
| ↔ | Carbamazepine, oxcarbazepine | |
| Gabapentin | ↑ | Carbamazepine, topiramate |
| ↔ | Lamotrigine | |
| Levetiracetam | ↑ | Carbamazepine, pregabalin, topiramate |
| Oxcarbazepine | ↔ | Carbamazepine, valproate |
| Pregabalin | ↓ | Levetiracetam |
| Tiagabine | ↑ | Topiramate |
| ↔ | Carbamazepine | |
| Topiramate | ↓ | Carbamazepine, gabapentin, lamotrigine, levetiracetam, tiagabine, valproate |
| ↑: positive profile; ↔: similar profile; ↓: negative profile Source: Reference 10 | ||
Table 4
Managing adverse effects of antiepileptics
| Medication | Comment(s) |
|---|---|
| Carbamazepine | Patients screening positive for the variant HLA-B1502 allele are at an elevated risk of developing Stevens-Johnson syndrome or toxic epidermal necrolysis. All patients of Asian descent should be screened22 |
| Gabapentin | Associated with weight gain, edema, and sedation; no reported effects on liver function tests |
| Lamotrigine | If therapy has been interrupted for ≥5 to 7 days (≥5 half-lives), restart according to initial dosing recommendations to significantly reduce the risk of rash |
| Levetiracetam | Appears to have the highest risk of psychiatric adverse effects |
| Oxcarbazepine | Higher risk of hyponatremia than carbamazepine |
| Pregabalin | Cases of angioedema have been reported (rare); may cause PR prolongation |
| Tiagabine | Elevated risk of seizures and status epilepticus when used in non-seizure patients |
| Topiramate | Increased fluid intake reduces the risk of developing kidney stones |
| Valproate | Tremor, thrombocytopenia, alopecia, and elevated liver enzymes have been associated with higher valproate doses/serum concentrations |
| Zonisamide | Avoid use in patients with severe sulfonamide allergy |
Therapeutic monitoring
Therapeutic serum drug concentration monitoring can help evaluate toxicity, medication adherence, and effects of potential drug-drug interactions. Individual variances in drug metabolism and distribution may affect the correlation between serum concentrations and clinical benefit or toxicity. Therapeutic monitoring can help establish target drug concentrations specific to your patient. The best time to obtain a drug concentration is when your patient is stable or free of most symptoms; this concentration may serve as the patient’s “therapeutic” concentration. Although laboratories have set therapeutic concentration ranges for each medication, treatment should focus on addressing your patient’s clinical presentation, rather than achieving the laboratory-suggested range.
Carbamazepine and valproate require therapeutic monitoring to prevent adverse effects from supratherapeutic concentrations (see this article at CurrentPsychiatry.com for a Table listing suggested ranges). The foundation for the therapeutic concentrations of these agents stems from neurology; however, these concentration ranges have been applicable in psychiatry.23
Carbamazepine generally requires more frequent monitoring because it has a narrow therapeutic index and relatively high potential for drug-drug interactions. Compared with lower doses, carbamazepine dosing associated with levels >12 μg/mL is more likely to induce toxicity.23 Carbamazepine autoinduction begins approximately 3 to 5 days after initiation and peaks between 3 to 4 weeks. Therefore, a drop in carbamazepine level from week 1 to week 4 of treatment likely is a pharmacokinetic indicator rather than a sign of nonadherence.
Some acute mania and maintenance bipolar studies have shown a correlation between clinical efficacy and valproate levels.24 A range of 50 to 125 μg/mL is well-accepted in clinical practice.24 For some patients, however, symptoms might not resolve until they are above the therapeutic range, but adverse effects are more likely at higher levels.24
