EnBrace HR for Depression Treatment and Prevention in Women Trying to Conceive and Early Pregnancy

Major depressive disorder (MDD) occurs twice as often in women as in men, with an age of onset that coincides with the childbearing years. As over 20% of reproductive-age women experience an episode of depression, identifying safe and effective treatments for depression before, during and after pregnancy has become a critical public health issue. Historically, pregnancy has been viewed as a protective time with respect to risk for psychiatric illnesses, which has resulted in a lack of prospective systematic investigations on the subject of acute treatment and prevention of MDD while women are planning to conceive and during pregnancy. Contrary to previous assumptions, recent large-scale studies demonstrate that new onset and recurrence of depressive episodes occur commonly during pregnancy and the postpartum periods. The current standard of treatment for recurrent major depression is maintenance antidepressant (AD) therapy, due to the high risk of recurrence among patients who discontinue maintenance AD therapy.

Although ADs are frequently used during pregnancy, concerns remain regarding a spectrum of adverse outcomes associated with fetal exposure to these medications including: increased risk for teratogenicity compromised obstetrical outcomes and a variety of negative neonatal clinical syndromes. Given these concerns, reproductive age women treated with AD frequently elect to discontinue their medications proximate to pregnancy or immediately after becoming pregnant despite the known increased risk for relapse or recurrence. With the exception of observational data that demonstrate that women who discontinue medication around the time of conception are at high risk of recurrence, no previous studies are available to inform clinical treatment regarding medication discontinuation for a planned pregnancy.

This leaves women who are successfully treated with ADs and want to become pregnant caught in the difficult clinical dilemma of weighing the risks of fetal exposure to medication against the potential impact of untreated maternal depression during pregnancy. Clinical decisions are made even more complex by the fact that most studies are far from definitive in terms of comparing the risks of in utero exposure to ADs to the risks of untreated antenatal mood disorder. Given this level of uncertainty, many women and their health care providers would welcome evidence-based non-psychotropic interventions as an alternative to ADs in order to prevent recurrence in euthymic women with histories of MDD as they plan pregnancy. However, the potential efficacy of non-psychotropic interventions for this population has not been systematically investigated.

There is consistent and growing evidence of a role for various folate forms in the prevention and treatment of depression. In fact, there is compelling evidence that treatment with a methylfolate agent would not only avoid the potential risks of antidepressants in pregnancy, but would also confer important benefits to pregnancy and child outcomes as well, such as prevention of major birth defects and longer term neurodevelopmental outcomes. To date, there is an evidence base for antidepressant effects for folic acid, folinic acid, and methylfolate, and similar findings may be attributable to the fact that these folate forms share an interconversion potential in the complex set of pathways that comprise the one-carbon cycle. These reactions, which in turn depend on B12 and homocysteine availability, are postulated to exert an antidepressant effect by impacting the synthesis of neurotransmitters such as norepinephrine, dopamine, and serotonin.

Some but not all studies suggest efficacy of folate monotherapy for MDD, but this intervention may be limited by the common occurence of polymorphisms in the general population that make folate a less efficient one-carbon cycle constituent than L-methylfolate. Since certain polymorphisms that impair methylation processes and the conversion of folate into its active form, methylfolate, have been found to be overrepresented in individuals with depression, methylfolate may be a more effective form of folate supplementation to target MDD. Also, methylfolate may be more readily absorbed in the brain compared to other folate forms.