European Medicines Agency (EMA) strengthens measures to avoid use of valproate medicines in pregnancy
In March 2018 the EMA announced stronger measures aimed at avoiding the exposure of babies to valproate medicines in the womb. Under the new restrictions, valproate medicines are contraindicated in bipolar disorder during pregnancy due to the high risk of congenital malformations and developmental problems in the child.
Valproate medicines must not be used in female patients of childbearing potential unless there is a pregnancy prevention program in place and certain conditions are met. These include:
An assessment of the patient's potential for becoming pregnant
Pregnancy tests before starting and during treatment as needed
Counseling about the risks of valproate treatment and the need for effective contraception throughout treatment
A review of ongoing treatment by a specialist at least annually
A risk acknowledgment form that patients and prescribers will go through at each such annual review to confirm that appropriate advice has been given and understood.
The EMA said the new measures were put in place because of evidence suggesting that information on the risks of valproate use in pregnancy was still not getting through to women despite earlier steps aimed at ensuring this.
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The adult criteria describe a disorder of fluctuating mood cycles, consisting of episodes of elevated mood and increased goal-directed activity or energy (mania) lasting at least 1 week, and episodes of lowered mood and activity (depression); an episode of mania is necessary for a diagnosis to be made.
An uncommon condition in children that becomes more frequent in teens, approaching the rate seen in adults.
A serious illness with recurrent episodes, leading to considerable impairment and an increased risk of suicide.
Diagnosis can be controversial, as criteria overlap with other childhood conditions such as ADHD and comorbid oppositional defiant disorder.
First-line treatment for manic episodes is antipsychotic therapy; the evidence base in children and adolescents is small, and comes mostly from industry-supported trials.
Medications have potentially serious adverse effects, so the risks and possible benefits need to be carefully assessed.
Bipolar disorder in children encompasses bipolar I disorder (manic episodes with or without depressive episodes) and bipolar II disorder (depressive episodes with periods of milder, briefer, and less impairing mania, called hypomania).
Bipolar I disorder, which has been most specifically studied in youth, is a chronic disorder of fluctuating mood, consisting of episodes of elevated mood and increased goal-directed activity or energy (mania) lasting at least 1 week, and episodes of lowered mood and activity (depression). Other symptoms of mania include distractibility, grandiosity, disinhibition, flight of ideas, hyperactivity, reduced sleep, and talkativeness. Varying diagnostic approaches have been proposed in children, but the implications of these approaches for treatment and prognosis remain unclear. Many children exhibiting chronic nonepisodic irritability and severe temper outbursts have been diagnosed with bipolar disorder in the US, despite the lack of distinct mood episodes. Disruptive mood dysregulation disorder, a new diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), aims to address this over-diagnosis and treatment of bipolar disorder in children; however, the inclusion of this new diagnostic entity has also raised concerns regarding inappropriate diagnosis and over-treatment of irritability with a category that remains poorly validated. Despite concerns regarding over-diagnosis, there is also evidence that diagnoses of bipolar disorder can be significantly delayed and under-treated.
Bipolar I disorder is discussed here.
History and exam
- history of major depressive episode(s)
- ≥7 days of elated, expansive, or irritable mood and increased goal-directed activity/energy different from patient's usual self (mania)
- inflated self-esteem or grandiosity
- decreased need for sleep
- pressure of speech
- subjective experience that thoughts are racing
- excessive involvement in pleasurable activities that have a high potential for painful consequences
- impairment in functioning
- family history of bipolar disorder
- history of depression
- physical and/or sexual abuse
- poor sleep
- neurodevelopmental abnormalities
- lack of maternal warmth/expressed emotion (duration)
- life events
- increased sociability and verbal functioning
- persistent affective symptoms (transition to bipolar disorder)
- male gender (when ADHD is comorbid)
- high intellectual performance
- family conflict
- symptoms of inattention
Professor of Psychiatry
Ohio State Wexner Medical Center
Nationwide Children's Hospital
Division of Pulmonary Medicine
RAK is on the data safety monitoring committee for Forrest and Pfizer, and is compensated for his time for this effort. He is also an author of a number of references cited in the this topic.
Dr Robert A. Kowatch would like to gratefully acknowledge Dr Bernadka Dubicka and Dr Gabrielle A. Carlson, previous contributors to this topic. BD is a member of the UK National Institute of Health Research Health Technology Assessment (HTA) panel, and has previously received HTA funding. She is a clinical advisor to NHS England and an occasional advisor to the National Institute for Health and Care Excellence. BD serves as Vice Chair of the Royal College of Psychiatrists child and adolescent faculty, and as Editor on the journal Child and Adolescent Mental Health. BD is an author of a number of references cited in this topic. GAC is an author of a number of references cited in this topic.
Division of Child & Adolescent Psychiatry
Department of Psychiatry & Behavioral Sciences
University of Washington
JM is an author of a number of references cited in this topic.
Child and Adolescent Psychiatrist
Emeritus Professor of Psychiatry
The Werry Centre for Child and Adolescent Mental Health
Department of Psychological Medicine
University of Auckland
JW is an author of a number of references cited in this topic.
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