Pregnancy

• Risk Category C [some animal studies show adverse effects; no controlled studies in humans]

• Use in women of childbearing potential requires weighing potential benefits to the mother against the risks to the fetus

• Pregnancy registry data show increased risk of isolated cleft palate or cleft lip deformity with first trimester exposure

✽ If treatment with lamotrigine is continued, plasma concentrations of lamotrigine may be reduced during pregnancy, possibly requiring increased doses with dose reduction following delivery

• Pregnancy exposure registry for lamotrigine: (800) 336–2176

• Taper drug if discontinuing

• Seizures, even mild seizures, may cause harm to the embryo/fetus

• Recurrent bipolar illness during pregnancy can be quite disruptive

✽ For bipolar patients, lamotrigine should generally be discontinued before anticipated pregnancies

✽ For bipolar patients in whom treatment is discontinued, given the risk of relapse in the postpartum period, lamotrigine should generally be restarted immediately after delivery

✽ Atypical antipsychotics may be preferable to lithium or anticonvulsants such as lamotrigine if treatment of bipolar disorder is required during pregnancy, but lamotrigine may be preferable to other anticonvulsants such as valproate if anticonvulsant treatment is required during pregnancy

• Bipolar symptoms may recur or worsen during pregnancy and some form of treatment may be necessary

Breast Feeding

• Some drug is found in mother’s breast milk

✽ Generally recommended either to discontinue drug or bottle feed

• If drug is continued while breast feeding, infant should be monitored for possible adverse effects

• If infant shows signs of irritability or sedation, drug may need to be discontinued

✽ Bipolar disorder may recur during the postpartum period, particularly if there is a history of prior postpartum episodes of either depression or psychosis

✽ Relapse rates may be lower in women who receive prophylactic treatment for postpartum episodes of bipolar disorder

• Atypical antipsychotics and anticonvulsants such as valproate may be preferable to lithium or lamotrigine during the postpartum period when breast feeding

LAMOTRIGINE: THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages

• Depressive stages of bipolar disorder (bipolar depression)

• To prevent recurrences of both depression and mania in bipolar disorder

Potential Disadvantages

• May not be as effective in the manic stage of bipolar disorder

Primary Target Symptoms

• Incidence of seizures

• Unstable mood, especially depression, in bipolar disorder

• Pain

Pearls

✽ Lamotrigine is a first-line treatment option that may be best for patients with bipolar depression

✽ Seems to be more effective in treating depressive episodes than manic episodes in bipolar disorder (treats from below better than it treats from above)

✽ Seems to be effective in preventing both manic relapses as well as depressive relapses (stabilizes both from above and from below) although it may be even better for preventing depressive relapses than for preventing manic relapses

✽ Despite convincing evidence of efficacy in bipolar disorder, is often used less frequently than anticonvulsants without convincing evidence of efficacy in bipolar disorder (e.g., gabapentin or topiramate)

✽ Low levels of use may be based upon exaggerated fears of skin rashes or lack of knowledge about how to manage skin rashes if they occur

✽ May actually be one of the best tolerated mood stabilizers with little weight gain or sedation

• Actual risk of serious skin rash may be comparable to agents erroneously considered “safer” including carbamazepine, phenytoin, phenobarbital, and zonisamide

• Rashes are common even in placebo-treated patients in clinical trials of bipolar patients (5–10%) due to non-drug related causes including eczema, irritant, and allergic contact dermatitis, such as poison ivy and insect bite reactions

✽ To manage rashes in bipolar patients receiving lamotrigine, realize that rashes that occur within the first 5 days or after 8–12 weeks of treatment are rarely drug-related, and learn the clinical distinctions between a benign rash and a serious rash (see What to Do About Side Effects above)

• Rash, including serious rash, appears riskiest in younger children, in those who are receiving concomitant valproate, and/or in those receiving rapid lamotrigine titration and/or high dosing

• Risk of serious rash is less than 1% and has been declining since slower titration, lower dosing, adjustments to use of concomitant valproate administration, and limitations on use in children under 12 have been implemented

• Incidence of serious rash is very low (approaching zero) in recent studies of bipolar patients

• Benign rashes related to lamotrigine may affect up to 10% of patients and resolve rapidly with drug discontinuation

✽ Given the limited treatment options for bipolar depression, patients with benign rashes can even be rechallenged with lamotrigine 5–12 mg/day with very slow titration after risk/benefit analysis if they are informed, reliable, closely monitored, and warned to stop lamotrigine and contact their physician if signs of hypersensitivity occur

• Only a third of bipolar patients experience adequate relief with a monotherapy, so most patients need multiple medications for best control

• Lamotrigine is useful in combination with atypical antipsychotics and/or lithium for acute mania

• Usefulness for bipolar disorder in combination with anticonvulsants other than valproate is not well demonstrated; such combinations can be expensive and are possibly ineffective or even irrational

• May be useful as an adjunct to atypical antipsychotics for rapid onset of action in schizophrenia

• May be useful as an adjunct to antidepressants in major depressive disorder

• Early studies suggest possible utility for patients with neuropathic pain such as diabetic peripheral neuropathy, HIV-associated neuropathy, and other pain conditions including migraine

Suggested Reading

Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psych 1999;60:79–88.

Calabrese JR, Sullivan JR, Bowden CL, Suppes T, Goldberg JF, Sachs GS, Shelton MD, Goodwin FK, Frye MA, Kusumakar V. Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management. J Clin Psychiatry 2002;63:1012–19.

Culy CR, Goa KL. Lamotrigine. A review of its use in childhood epilepsy. Paediatr Drugs 2000;2:299–330.

Cunningham M, Tennis P, and the International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology 2005;64:955–60.

Goodwin GM, Bowden CL, Calabrese JR, et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance treatment in bipolar I disorder. J Clin Psychiatry 2004;65:432–41.

Green B. Lamotrigine in mood disorders. Curr Med Res Opin 2003;19:272–7.

LEVETIRACETAM

LEVETIRACETAM: THERAPEUTICS

Brands

• Keppra

• Keppra XR

see index for additional brand names

Generic?

Yes

Class

• Anticonvulsant, synaptic vesicle protein SV2A modulator

Commonly Prescribed for

(bold for FDA approved)

• Adjunct therapy for partial seizures in patients with epilepsy (≥16 years of age for extended-release, ≥4 years of age for immediate-release)

• Adjunct therapy for myoclonic seizures in juvenile myoclonic epilepsy (ages 12 and older)

• Adjunct therapy for primary generalized tonic-clonic seizures in idiopathic generalized epilepsy (ages 6 and older)

• Neuropathic pain/chronic pain

• Mania