https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)60456-6.pdf

Epilepsy: new advances

Objectives: To provide guidance for the management of mood disorders, based on scientific evidence supplemented by expert clinical consensus and formulate recommendations to maximise clinical salience and utility. Methods: Articles and information sourced from search engines including PubMed and EMBASE, MEDLINE, PsycINFO and Google Scholar were supplemented by literature known to the mood disorders committee (MDC) (e.g., books, book chapters and government reports) and from published depression and bipolar disorder guidelines. Information was reviewed and discussed by members of the MDC and findings were then formulated into consensus-based recommendations and clinical guidance. The guidelines were subjected to rigorous successive consultation and external review involving: expert and clinical advisors, the public, key stakeholders, professional bodies and specialist groups with interest in mood disorders. Results: The Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders (Mood Disorders CPG) provide up-to-date guidance and advice regarding the management of mood disorders that is informed by evidence and clinical experience. The Mood Disorders CPG is intended for clinical use by psychiatrists, psychologists, physicians and others with an interest in mental health care.

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Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders

More than 150 years after bromide was introduced as the first antiepileptic drug, adverse effects remain a leading cause of treatment failure and a major determinant of impaired health-related quality of life in people with epilepsy. Adverse effects can develop acutely or many years after starting treatment and can affect any organ or structure. In the past two decades, many efforts have been made to reduce the burden of antiepileptic drug toxicity. Several methods to screen and quantify adverse effects have been developed. Patient profiles associated with increased risk of specific adverse effects have been uncovered through advances in the areas of epidemiology and pharmacogenomics. Several new-generation antiepileptic drugs with improved tolerability profiles and reduced potential for drug interaction have been added to the therapeutic armamentarium. Overall, these advances have expanded the opportunities to tailor treatment with antiepileptic drugs, to enhance effectiveness and minimise the risk of toxic effects.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(12)70153-9.pdf

Adverse effects of antiepileptic drugs

Summary Background Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. Methods We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Findings Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p Interpretation Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study. Funding Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.

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Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry

The management of psychiatric disorders during the perinatal period can be difficult; psychiatric decompensation during pregnancy can affect not only the mother but also the fetus and neonate. It is imperative that psychiatric providers proactively discuss pregnancy planning, and be able to thoughtfully weigh the risks of untreated psychiatric illness and psychotropic medications in pregnancy and breast-feeding. With the exception of valproate and carbamazepine, several mood stabilizers and antipsychotics can be utilized during pregnancy with minimal risk to the fetus and neonate in terms of major malformations; there is a growing body of evidence regarding the risk profile of use of these medications in pregnancy. Key Points Preconception planning is very helpful when it can be done; consider discussion and documentation of risks at time of administration of psychotropic medications for any reproductive-aged women, regardless of plans for conception. Continued psychiatric stability through the perinatal period is imperative; the risks of an untreated psychiatric disorder are just as important, if not more so important, than the risks of psychotropic medication exposure. Exposure to one psychotropic medication is safer than exposure to multiple medications. Utilize lowest effective dose of medication; most risks are not dose dependent, therefore would typically prefer higher dose of medication, rather than emergence of psychiatric symptoms, in order to avoid exposure of the fetus to both psychotropic medications and psychiatric symptoms. General recommendations are to avoid valproate and carbamazepine in reproductive-aged women. With close monitoring, lithium can be safely utilized in pregnancy. Preliminary data regarding use of atypical antipsychotics is reassuring in regards to major malformations; however, larger numbers of participants are needed to provide more complete reproductive safety data with this class. Clearly document risks of an untreated psychiatric illness as well as risks of psychotropic medication management to the mother and developing fetus/neonate.

Managing Your Own Mood Lability: Use of Mood Stabilizers and Antipsychotics in Pregnancy

Objective: To assess the safety of the newer antiepileptic drugs (AEDs) during pregnancy. Methods: The study population was pregnant women who enrolled in the North American AED Pregnancy Registry between 1997 and 2011. Data on AED use and maternal characteristics were collected through phone interviews at enrollment, at 7 months9 gestation, and postpartum. Malformations were confirmed by medical records. The risk of major malformations was calculated among infants exposed to specific AEDs in monotherapy during the first trimester of pregnancy and among an unexposed group. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated with logistic regression. Results: The risk of major malformations was 9.3% (30 of 323) for valproate, 5.5% (11 of 199) for phenobarbital, 4.2% (15 of 359) for topiramate, 3.0% (31 of 1.033) for carbamazepine, 2.9% (12 of 416) for phenytoin, 2.4% (11 of 450) for levetiracetam, and 2.0% (31 of 1,562) for lamotrigine. Compared with lamotrigine, the RR was 5.1 (95% CI 3.0–8.5) for valproate, 2.9 (1.4–5.8) for phenobarbital, and 2.2 (1.2–4.0) for topiramate. The proportion of women with epilepsy who had seizures during pregnancy ranged from 23% for valproate to 31% for lamotrigine. Valproate was associated with a higher risk of neural tube defects, hypospadias, cardiac defects, and oral clefts and phenobarbital with a higher risk of cardiac defects and oral clefts; 5 infants exposed to topiramate (1.4%) had a cleft lip. Conclusions: AEDs such as valproate and phenobarbital were associated with a higher risk of major malformations than newer AEDs such as lamotrigine and levetiracetam. Topiramate was associated with an increased risk of cleft lip compared with that of a reference population.

W.A. Hauser

Papers

Comparative safety of antiepileptic drugs during pregnancy