EnBrace HR for Depression Treatment and Prevention in Women Trying to Conceive and Early Pregnancy
Phase: NA
Conditions: Depressive Disorder, Pregnancy
Sponsor: Massachusetts General Hospital

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Protocol Title: 
EnBrace HR for Depression Treatment and Prevention in Women Trying to Conceive and Early Pregnancy  
 
Principal Investigator:  
Marlene P. Freeman, MD 
 
Version Date: 
 March 19, 2018 
 
I. BACKGROUND AND SIGNFICANCE 
a. Historical background 
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 
such as MDD. This assumption 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 period. 
The current standard of treatment for recurrent MDD is maintenance antidepressant (AD) therapy(1). 
These guidelines are derived from 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(2). Given these concerns, reproductive age women treated with ADs 
frequently elect to discontinue their medications proximate to pregnancy or immediately after 
becoming pregnant despite the known increased risk for relapse or recurrence. Women who experience 
depressive episodes during pregnancy or while trying to conceive often forgo antidepressant use. 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(3). 
This leaves women 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 treat or prevent depressive episodes in 
women who are pregnant or planning pregnancy.  
However, the potential efficacy of non-psychotropic interventions for the purposes of acute treatment 
and recurrence prevention following AD discontinuation among women who plan to conceive or for 
those who are pregnant has received limited study.  
b. Previous pre-clinical or clinical studies leading up to and supporting the 
research 

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In the following sections we review literature in several critical areas pertaining to the proposed 
investigation: evidence confirming that depression is often a recurrent illness; knowledge of the 
prevalence and outcomes of depression and its treatment across pregnancy; studies examining the 
reproductive safety of AD use during pregnancy, data suggesting that women often discontinue 
maintenance AD use proximate to conception despite an increased risk for relapse and recurrence; and 
investigations specific to the use of methylfolate in the treatment of MDD and for improved pregnancy 
outcomes.   
Depression is a Recurrent Illness 
A growing body of literature indicates that MDD is most often a recurrent illness. The clinical term used 
to describe a depressive episode that reappears within six months of acute response is a relapse while 
symptoms that occur after six months of euthymia are called recurrences(4). Relapses are considered a 
return of the original episode, whereas recurrences represent a new episode. Although these 
distinctions are based on limited data, the phases of treatment to prevent relapse and recurrence have 
been differentiated correspondingly into continuation and maintenance phases, respectively.  
Observational Studies. Data derived from the National Institute of Mental Health Collaborative Program 
on the Psychobiology of Depression (n=380) were examined to investigate the proportion of patients 
experiencing a recurrence of MDD up to 15 years after recovery from the index episode(5). The vast 
majority of patients (85%) experienced a recurrence during this time period, with those remaining well 5 
years after recovery experiencing a rate of recurrence of 58%. Results from the Collaborative Program 
study (n=359) revealed a 20% relapse rate and an overall 88% recurrence rate (within five years of 
recovery)(6). These findings are even more compelling as these patients had received “high levels of 
somatic treatment” during the entire observation period. Other observational studies have confirmed 
high rates of relapse and recurrence in patients with and without optimal psychopharmacologic 
management(7-9).  
Randomized Controlled Trials. Data from randomized controlled trials, typically using a double-blind 
discontinuation method, reveal that long-term treatment with ADs lowers the risk for relapse and 
recurrence when compared with placebo substitution (9-11). However, even while taking ADs for 
prophylaxis, up to 20-80% of patients develop another depressive episode within five years after 
treatment for the initial episode (6, 12-14). One recent meta-analysis pooled data from 31 randomized 
trials and found that maintenance AD therapy (following acute treatment) reduced the odds of relapse 
and recurrence by 70% compared with treatment discontinuation(15). The average rate of relapse on 
placebo was 41% compared with 18% on active treatment. The proportional risk reduction was found to 
be similar in patients with short (6 months) and long (36 months) follow-up periods, which suggests that 
time since response does not affect risk.  
Guidelines for preventing recurrence. The observational studies and randomized controlled trials above 
have informed the development of recognized clinical treatment guidelines, which support the use of 
long term AD treatment to prevent relapse and recurrence, especially for patients described as at high 
risk due to clinical factors(1, 16, 17). These risk factors include a history of three or more depressive 
episodes, two or more depressive episodes within five years, a family history of bipolar disorder or 
recurrent depression, early-onset depression, and previous recurrence within one year of medication 
discontinuation. Additionally, individual risk factors including patient preference, suicide risk, episode 
severity, social support, and life stressors, influence every treatment response. 
 
Course and Treatment of Depression during Attempts to Conceive and During Pregnancy 

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Prevalence of Depression during Pregnancy. MDD is not only a seriously debilitating illness affecting 
many people worldwide, but it is particularly critical in the field of women’s health. MDD is twice as 
prevalent in women as in men, with incidence clusters during the reproductive years, as over 20% of 
women experience an episode of depression during this time(18, 19). Despite a lack of supportive data, 
pregnancy has historically been considered protective against both the emergence and recurrence of 
depressive symptoms. Contrary to this belief, both epidemiological data and a recent naturalistic study 
suggest that, pregnancy may be a time of great risk for recurrence and new onset of depression. The 
limited epidemiological studies conducted in pregnant adults reveal prevalence rates of moderate and 
severe depressive symptoms ranging from 6.9% to 20%(18, 20). The risks of untreated depression during 
pregnancy are significant and include poor nutrition, inadequate weight gain, poor prenatal care, 
inability to care for oneself, the use of cigarettes, alcohol, or other substances, ambivalence or even 
termination of the pregnancy, and an increased risk for postpartum depression(21-23). Postpartum 
depression, a condition only recently understood, is best predicted by the presence of depression during 
pregnancy, thus it is of critical importance to prevent the emergence of depressive symptoms during 
pregnancy(24). 
Depression during pregnancy is a major public health concern, given its prevalence, and the implicit 
treatment dilemma of weighing the unknown effects of fetal AD exposure against the effects of 
untreated depression on 1) maternal well being, 2) obstetrical and neonatal outcomes, and 3) long term 
development of the child. 
Prevalence of AD Use during Pregnancy. As previously demonstrated, based on data derived from health 
insurance and hospital records, investigators found that ADs were prescribed to nearly 8% of all 
pregnant women(2). The investigators found that AD use during pregnancy increased from 2.0% of all 
deliveries in 1996 to 7.6% of all deliveries in 2004 and 2005, with consistently more women dispensed 
an AD during the first trimester of pregnancy than in either the second of the third trimester. Clinicians 
must weigh the morbidity associated with depressive relapse and recurrence in the mother against the 
risk of adverse birth outcomes that may be associated with medication exposure for the fetus.  In order 
to avoid fetal exposure to ADs where attendant risks of in utero exposure is incompletely delineated, 
many women discontinue these medicines regardless of risk for recurrence.   
High Risk of Relapse of Depression during Pregnancy among Women who Discontinue Maintenance AD 
Therapy. Studies conducted over the last decade have demonstrated that prevalence of depression 
during pregnancy is similar to age-matched non-pregnant women, replacing previously held ideas that 
pregnancy was protective against psychiatric illness. Left untreated, depression can negatively impact 
both the mother and the fetus. For women with histories of MDD who discontinue AD medication to 
avoid fetal drug exposure, the risk of depressive relapse is high. In a multi-site NIMH funded 
collaborative study, the rate of depressive relapse among women with a history of MDD who 
discontinued ADs (68%) was significantly higher than the rate (26%) for women who maintained AD 
treatment(3). In this study, continued AD treatment during pregnancy significantly reduced the risk of 
maternal depressive relapse. Data from this large scale, multi-site study also demonstrated that there is 
a broad distribution of AD use early in pregnancy that is not wholly determined by severity of illness as 
defined by number of episodes of MDD.  In fact, there was no association between the decision to 
discontinue medication during pregnancy and duration of illness, number of previous episodes, or 
frequency of co-morbid psychiatric illness. 
Risks Associated With Fetal Exposure to ADs   
The following studies, though conflicting and methodologically limited, raise concern that prenatal AD 
use impacts risk for teratogenic outcomes, perinatal withdrawal symptoms, and obstetrical 
complications and have prompted clinicians and patients to avoid AD exposure during pregnancy. 

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Teratogenicity.  Though recently more data have become available through several large birth defect 
surveillance programs, study limitations including small sample size, variation in outcomes reported, and 
inconsistent conclusions, have made using these sources to inform clinical decisions regarding 
pharmacologic management during pregnancy challenging for both patient and clinician.  For example, 
two large case-control studies published recently questioned the safety of selective serotonin reuptake 
inhibitors (SSRIs) with respect to teratogenic risk using large records from a managed care organization 
and the Swedish Birth registry(25, 26).  Based on their size, these studies might be expected to refine 
the risk estimate for congenital malformations following fetal exposure to SSRIs, but they produced 
divergent results.  
The National Birth Defects Prevention Study compared 9,622 infants with birth defects with 4,092 
control infants born in the United States from 1997 to 2003 and found no overall significant association 
between use of any SSRI in early pregnancy and congenital heart defects or most other birth defects 
analyzed.  The exception was a significantly increased risk, particularly with paroxetine, for anencephaly 
(odds ratio 2.4), craniosynostosis (OR 2.5), and omphalocele (OR 2.8), birth defects that have not been 
associated with in utero exposure to SSRIs in previous studies(25). Yet in the accompanying data from 
the case-control Slone Epidemiology Center Birth Defects Study (9,849 infants with birth defects and 
5,860 infants without), no associations were identified between overall maternal SSRI use in early 
pregnancy and these three anomalies or congenital heart defects(26). There was, however, a significant 
association between paroxetine exposure and right-ventricular outflow tract obstruction defects (odds 
ratio of 3.3), as well as between the use of sertraline specifically and both omphalocele (odds ratio 5.7) 
and septal defects (2.0). It should be noted that the number of actual exposures in these studies to a 
specific SSRI was particularly small (<10).  Thus, despite larger amounts of data which appear to be 
reassuring with respect to fetal exposure to SSRIs and risk for organ malformation, these inconsistent 
conclusions make patients and clinicians vigilant about use of ADs during pregnancy. 
Recently, studies have raised concerns about whether prenatal AD use is associated with an increased 
risk of autism, although studies have been inconsistent in whether there is an increased risk or not 
among children who have been exposed to ADs in utero. 
Perinatal Outcomes. Some(27-31), but not all(22, 32, 33)studies have noted an association between 
fetal exposure to SSRIs and adverse perinatal outcomes, including decreased gestational age, low birth 
weight, and poor neonatal adaptation, leading to increased rates of newborn complications and 
subsequent special care nursery admissions(27, 34-38). Several recent reports have noted an increased 
incidence of neonatal jitteriness, tachypnea, cyanosis, and tremulousness with late pregnancy exposure 
to SSRIs, while other studies have inconsistently reported an increased risk of persistent pulmonary 
hypertension of the newborn (PPHN)(27, 28, 34). While these associations deserve further study, the 
seriousness of the condition has led many women and their health care providers to attempt to 
discontinue AD prior to or during pregnancy. These analyses have led some authors to suggest AD 
discontinuation prior to delivery to presumably minimize the risk of neonatal toxicity.  Additionally, FDA 
mandated labeling across the SSRIs also recommends discontinuation prior to delivery.  While the 
recommendation is intuitive, the data are not conclusive and withdrawing treatment from patients just 
as they are about to enter the postpartum period, a time of heightened risk for affective illness, may 
carry significant clinical risk. 
Although concerning, these studies vary greatly in the method of assessment, have limited blinded 
assessments, and include confounding factors such as other medication use or other psychological 
disorders and retrospective design, limiting their clinical significance. Moreover, research is required 
regarding if these short term symptoms have long-term effects. 
Obstetrical Outcomes. Preterm birth (< 37 weeks gestation) is an obstetrical outcome of significant 

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clinical relevance, as it affects up to 15% of all births in the US and remains a leading cause of perinatal 
morbidity(39). Premature infants are more likely to suffer from cerebral palsy, respiratory difficulties, 
and learning difficulties than infants who are born at term(39, 40). In addition to emotional and social 
burdens to society, preterm birth poses significant financial burdens: in 2003 the March of Dimes 
reported that total hospital costs related to preterm birth were in excess of $18 billion in the US(41).  
While the costs per case decrease with each advancing week of gestation, the number of preterm births 
increases, resulting in comparable total expenses for early and late preterm birth.  Neonatal morbidity is 
most concerning with early preterm births; however recent studies have examined neonatal medical 
problems in premature infants between 35 and 37 weeks, and have found increased cases of 
temperature instability, hypoglycemia, respiratory distress, jaundice, evaluations for sepsis, and 
treatment with intravenous infusions(42). 
Several studies have shown an association between fetal exposure to various medications and preterm 
birth(22, 33, 37, 43-47). Serotonin is a potent vasoconstrictor of the umbilicoplacental circulatory bed 
and circulatory levels of serotonin have been shown to be markedly increased in preeclamplsia(48, 49). 
The net effect of most clinically available ADs is increased serotonin neurotransmission as well as 
alterations in beta-adrenergic receptors.  Though all but one of these negative studies(35) included 
prospectively followed subjects, they were limited by the fact that AD exposure occurred only during 
early pregnancy for the majority of subjects(33, 37, 43-47), by small sample sizes(22, 32, 35, 38, 47, 50), 
and by the lack of a comparison unexposed control group(51).  The exact mechanism by which ADs may 
impact pregnancy duration is not known. 
Treatment Decisions during Pregnancy Are Not Driven by Illness Severity 
In a naturalistic prospective study, investigators found that over 43% of women discontinuing AD 
medications due to pregnancy concerns relapsed, over 50% during the first trimester(3).  It could be 
expected that without random assignment to participation in the study, the participants who elected to 
enroll would be those with the least severe depression histories. This presumes patients with a history 
of multiple episodes would disproportionately choose to continue pharmacologic treatment, as 
compared to women with histories of fewer or more mild illness.  However, data from a large scale, 
multi-site study conducted Cohen, et al. show that there is a broad distribution of AD use early in 
pregnancy in patients that is not wholly confounded with severity of illness as defined by number of 
episodes of major depression. We found no association between the decision to discontinue medication 
during pregnancy and duration of illness, number of previous episodes, or frequency of co-morbid 
psychiatric illness(3). 
Selection of Intervention (EnBrace prenatal supplement) 
The current study will provide evidence regarding the efficacy, tolerability, feasibility and acceptability 
of a selected non-psychotropic treatment alternative to AD use while women are trying to conceive or 
during pregnancy. We hypothesize that rates of MDD relapse coinciding with AD discontinuation 
proximate to pregnancy may be attenuated if there are other effective treatments available to women.  
Candidate Non-psychotropic Treatments for Women Trying to Conceive and During Pregnancy 
Ideally, a candidate treatment for MDD in pregnant women and those trying to conceive would: 1) 
demonstrate efficacy for MDD, 2) have a good safety profile in pregnancy and lactation, and 3) benefit 
the pregnancy beyond its impact upon MDD.  The decision to continue an AD may be appropriate for 
some women who suffer from a history of highly recurrent disease, although most wish to have 
alternatives. Integrative, or Complementary and Alternative Medicine (CAM) treatments, have been 
increasingly used by individuals with MDD, particularly women, making the study of the efficacy of these 
interventions that much more compelling and urgent. Demonstrating the attractiveness of non-

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psychotropic options, a recent report demonstrated that over 40% of the adult population in the U.S. 
used at least one CAM treatment over the past year, with women more likely than men to use CAM(52, 
53). This pattern of utilization highlights the need for more research with integrative treatments for 
depression in women, as they are more likely than men to both suffer from MDD and to use CAM 
treatments(52). MDD is a common indication for nutritional supplement use, particularly among 
women, underscoring the attractiveness of these treatments to patients and the urgent need for 
systematic study of these interventions(54-58).   
L-methylfolate and Other Folate-related Compounds 
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 ADs in pregnancy, but would also confer important benefits 
to pregnancy and child outcomes as well, such as prevention of congenital birth defects and longer term 
neurodevelopmental outomes.  To date, there is an evidence base for AD 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(59-62). 
These reactions, which depend on B12 and homocysteine availability, are postulated to exert an AD 
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 occurrence 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 common in individuals with MDD, methylfolate may be a more effective form of folate 
supplementation to target MDD(63).  Also, methylfolate may be more readily absorbed in the brain 
compared to other folate forms(64). 
Recently, Fava and colleagues demonstrated that adjunct L-methylfolate is significantly superior to 
placebo for the treatment of MDD in patients who had failed to respond to AD therapy alone (65). In 
addition, several other open and blinded studies of methylfolate monotherapy in a variety of depressed 
populations have found that patients experienced significant improvement in depressive symptoms with 
no drug-related adverse events(66-70).  Although more controlled data are needed, initial studies 
indicate that methylfolate may be a safe and effective option for the treatment of MDD, especially in 
populations that are vulnerable to medication-related adverse events, and those who are folate 
deficient or whose folate needs are elevated, such as pregnant women.  
 
Omega-3 Fatty Acids, Depression, and Pregnancy 
Omega-3 Fatty Acids: Omega-3 fatty acids are nutritional compounds with well established benefits for 
human health, and particular benefits for fetal and infant development.   Eicosapentaenoic acid (EPA) 
and docosahexaenoic acid (DHA) are two important omega-3 fatty acids found in fish and most fish oil 
or omega-3 supplements.  The majority of randomized controlled trials demonstrate a significant AD 
benefit of omega-3 fatty acids in mood disorders overall, although they are best studied as an 
augmentation treatment rather than a stand-alone therapy.    
Perinatal Depression Considerations:  The benefits of maternal omega-3 fatty acid intake have been 
established for infant outcomes, although women are often afraid to eat fish during pregnancy since the 
U.S. FDA mercury advisories.  Only a few treatment studies have specifically looked at omega-3 fatty 

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acids as a primary treatment for MDD during pregnancy and postpartum depression, and they have 
been small studies with mixed outcomes. Omega-3 fatty acid supplements have been well tolerated by 
pregnant and postpartum women.  The exact dose still needs to be determined for optimal benefits for 
MDD, but modest doses of EPA and DHA (with a higher ratio of EPA:DHA) have shown the most 
promise, and is a reasonable dose for general health benefits, infant outcome benefits, and as an add-
on treatment for MDD. 
EnBrace HR is a prescription prenatal/postnatal dietary management product that contains vitamins and 
minerals, including folic acid and methylfolate.  It meets the above criteria as a potential ideal candidate 
for the prevention of MDD in pregnancy.  It contains l-methylfolate and other folate derivatives, and is 
optimal for a population with high rates of polymorphisms that affect folic acid metabolism.  It also 
contains omega-3 fatty acids, primarily EPA, which shows promise for the treatment of depression.  
Importantly, these components are crucial for healthy pregnancies.  Folic acid supplementation has 
been associated with the reduced risk of neural tube defects and is recommended for use in women of 
reproductive potential to reduce the risk of birth defects. Given that a substantial proportion of the 
population are poor folic acid metabolizers, methylfolate compounds may provide a more efficient 
delivery of folate-related compounds. Also, folate-related compounds supplemented in utero (folic acid, 
methylfolate) are associated with a lower risk of subsequent autism in children(71, 72). 
Rationale behind research and potential benefits to patients and/or society 
Women who experience depression while trying to conceive and during a pregnancy often seek to 
minimize exposure to psychotropic medications.  Likewise, women in remission from depression who 
are currently taking maintenance AD treatment and who are planning to conceive or are pregnant will 
often discontinue treatment out of concern over known and unknown risks of fetal exposure to these 
medications, regardless of clinical evidence showing that this puts them at a higher risk of relapse. The 
decision to avoid or discontinue maintenance AD treatment during pregnancy is also often made despite 
the risk of recurrence of MDD, which may result in a range of negative outcomes for both the mother 
and her newborn.  
However, few studies have examined folate treatment specifically to assist patients who wish to avoid 
or discontinue ADs, and none have examined this during the time proximate to attempts to conceive, or 
during pregnancy, which is particularly relevant due to safety concerns.  The adaptation of a non-
psychotropic treatment for use in women who are pregnant or planning pregnancy who choose to avoid 
or discontinue maintenance AD treatment would broaden treatment choices available during this 
important time in the female life-cycle. 
 
II. SPECIFIC AIMS 
a. Specify objectives and hypotheses to be tested 
Objective: The overarching goal of this investigation is to assess EnBrace as a treatment for the acute 
treatment and prevention of depression in women with a history of major depressive disorder who 
decide to avoid or discontinue their maintenance AD treatment for pregnancy. After completing this 
protocol, we plan to use the preliminary data for the development of a randomized controlled trial 
protocol.  We will include two groups of women who are interested in minimizing medication exposures 
while trying to conceive or during pregnancy: 1) women who have histories of depression and are not 
depressed, and would like to stop antidepressants for pregnancy, 2) women in depressive episodes who 
are pregnant or trying to conceive (on or off of antidepressant medications).  
Specific Aim 1a: To evaluate the efficacy of EnBrace when used as maintenance treatment for 
MDD in a group of women (N=10) who are trying to conceive or are early in pregnancy and who 

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have decided to stop ADs (Group 1).  Relapse rates for women in this context have been 
demonstrated to be high, with 68% relapse rates in a large multisite NIMH-funded trial. 
Specific Aim 1b: To evaluate the efficacy of EnBrace when used as an acute treatment for MDD in 
a group of women (N=10) who are trying to conceive or are early in pregnancy (Group 2).  Women 
will have major depressive episodes in this group, and may receive EnBrace as monotherapy, or as 
an adjunct to current pharmacotherapy. 
Hypothesis 1a: We hypothesize that relapse rates will be lower for women who receive EnBrace 
compared to historical controls. MDD relapse will be determined by the Mini-International 
Neuropsychiatric Interview (MINI) mood module that will be administered by a study clinician at 
each visit. 
Hypothesis 1b: We hypothesize that the majority of women who receive EnBrace will experience a 
response (50% improvement in depressive symptoms) to EnBrace therapy. 
 
Specific Aim 2: To identify biological markers as potential predictors of response to EnBrace. 
Hypothesis 2: We hypothesize that pre- to post-treatment changes in homocysteine, folate, B12, 
IL-6 and CRP will be associated with response to EnBrace.  We hypothesize specifically that levels 
of folate and B12 will increase and homocysteine will decrease temporally with treatment and be 
predictive of prevention of depressive episodes.  We hypothesize that treatment will lower IL-6 
and CRP levels due to the anti-inflammatory components of EnBrace (i.e., omega-3 fatty acids) 
and that decreased levels of inflammatory markers may predict lower risk of depressive relapse in 
participants who enter the study while not on a depressive episode (Group 1), and will predict 
response to treatment in women who enter the study while in a depressive episode (Group 2). 
 
Specific Aim 3 (Exploratory): To identify factors influencing adherence to and tolerability of 
treatment. This will be achieved by using qualitative methods to explore (a) perceived risks and 
benefits of treatment; (b) perceived side effect profile; (c) treatment convenience; (d) knowledge 
of, attitudes towards, and preferences for depression treatment while attempting to conceive or 
early pregnancy. 
Hypothesis 3: We hypothesize that EnBrace will be perceived by patients as 1) an acceptable and 
attractive treatment with a favorable risk/benefit profile in the context of pregnancy or while 
trying to conceive, 2) well tolerated, 3) convenient and easy to adhere to, 4) will be a treatment 
that women who are trying to conceive or who are pregnant find intuitive and preferable to 
prescription antidepressant medication (or for women on antidepressant treatment in Group 2, 
who prefer the augmentation with EnBrace rather than an increase in antidepressant dose or 
augmentation with a prescription psychotropic medication).  
 
III. SUBJECT SELECTION 
a. Inclusion/Exclusion Criteria 
 
Group 1 
 
 Inclusion Criteria: Subjects will include women 18 years and older who meet the following criteria: 
 

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1. Planning pregnancy or pregnant < 28 weeks gestation 
2. Currently meet criteria for stable remission from MDD, defined as a baseline score of < 10 
on the Montgomery-Åsberg Depression Rating Scale (MADRS)  
3. Current or recent treatment with an AD  
4. Have elected to discontinue AD medication for pregnancy (may have already begun or 
completed taper) 
5. Have a history of a major depressive episode/ Previous Episode of MDD, as verified using 
the MINI Structured Clinical Interview for DSM-5; have MDD as one of their primary 
diagnoses 
6. Has a treating prescribing clinician for the treatment of MDD 
 
Exclusion Criteria: The presence of any of the following criteria will exclude subjects from participation:  
 
1. Current major depressive episode, as diagnosed on the MINI mood portion 
2. Significant risk for self-harm or harm to others 
3. Psychotic symptoms 
4. Meeting criteria for a primary diagnosis of schizophrenia, an active eating disorder, 
dementia, delirium, or other cognitive disorder  
5. Presence of an active substance and/or alcohol abuse disorder within six months prior to 
screening 
6. Pernicious anemia or history of gastric bypass surgery 
7. Seizure disorder and/or on anticonvulsant medications 
8. Allergy to beeswax, soy, fish, nuts, peanuts, egg, wheat, milk, and/or shellfish 
9. Non-English speaking 
 
Group 2 
 
Inclusion Criteria: Subjects will include women 18 years and older who meet the following criteria: 
 
1. Planning pregnancy or pregnant < 28 weeks gestation 
2. Currently experiencing clinically significant depressive symptoms, defined as a baseline 
score of > 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS)  
3. Experiencing a major depressive episode, as verified using the MINI Structured Clinical 
Interview for DSM-5; have MDD as one of their primary diagnoses 
4. Has a treating prescribing clinician for the treatment of MDD 
 
Exclusion Criteria: The presence of any of the following criteria will exclude subjects from participation:  
 
1. Significant risk for self-harm or harm to others 
2. Psychotic symptoms 
3. Meeting criteria for a primary diagnosis of schizophrenia, an active eating disorder, 
dementia, delirium, or other cognitive disorder  
4. Presence of an active substance and/or alcohol abuse disorder within six months prior to 
screening 
5. Pernicious anemia or history of gastric bypass surgery 
6. Seizure disorder and/or on anticonvulsant medications 
7. Allergy to beeswax, soy, fish, nuts, peanuts, egg, wheat, milk, and/or shellfish 

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8. Non-English speaking 
 
b. Recruitment Sources 
 
We plan to enroll 10 women who meet criteria for history of MDD, have decided to stop AD medication 
while trying to conceive or during early pregnancy (< 28 weeks), and are eligible to receive treatment 
with EnBrace prenatal supplement. We also plan to enroll 10 women who meet the criteria for a current 
major depressive episode who are trying to conceive or pregnant (< 28 weeks), and are eligible to 
receive treatment with EnBrace prenatal supplement. 
 
Potential subjects will be enrolled from four major sources: 
1) Women who have had a previous interaction with the MGH Center for Women’s Mental 
Health, either through research or clinically, and have consented to be contacted about 
future studies for which they may be eligible. 
a. These women will be contacted by e-mail, postal mail, and phone, based on how 
each indicated she would prefer to be contacted by our program. 
2) Women who are currently seen in consults who indicate to the MGH Perinatal Psychiatrist 
with whom they have a consult that they would be interested in adjunct or alternative 
medication for pregnancy  
a. These women will be given information about the study at the end of their consult 
with a Perinatal Psychiatrist and asked to schedule a separate appointment for a 
screening interview with a member of the study staff 
3) Women who are seen in the MGH outpatient Obstetrics department 
a. These women will be pre-identified through preliminary screening, and approached 
during their clinic visit by a provider in the Obstetrics department who will introduce 
the study and obtain permission to be contacted by study staff. 
4) Physicians in the community  
 
As a group, clinicians at the MGH Center for Women’s Mental Health (CWMH) have extensive 
experience over the last 25 years providing these consultations to women presenting for the most 
current information regarding both risks of AD exposure during pregnancy and risks of recurrence of 
underlying disorder in the setting of AD discontinuation either while planning to conceive or during 
pregnancy.  This group, under the direction of Dr. Cohen, has a longstanding record of recruiting women 
for federally funded studies of depression before, during and after pregnancy derived from a potential 
subject pool of 900 pregravid women per year who are seen for consultation regarding the risks of 
psychotropic use during pregnancy. Approximately half (450) of these women are euthymic on 
maintenance AD therapy and are referred by their community clinicians for consultation about 
maintaining, changing, or discontinuing their medication for pregnancy.   
During consultations by perinatal psychiatrists, the relative risks of fetal exposure to ADs are explained, 
as are the attendant risks of relapse/recurrence of depression in the setting of AD discontinuation. 
Information about the relative risks of various treatment options is provided to both the patient and the 
referring clinician; referring psychiatrists are contacted both by phone and in writing. Available 
information informing patient decisions about treatment options and the associated risk/benefit 
analysis is also available to patients/potential subjects through a web driven Perinatal Information 
Resource Center (www.womensmentalhealth.org), run by the MGH Perinatal and Reproductive 
Psychiatry Program.  Patients and clinicians are consistently referred to this dynamic website, which is 
constantly updated with the most recent data. 

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As part of MGH IRB approved protocol 2002P001596, patients seen in consultation may consent to be 
contacted over time to monitor their plans and ultimate treatment decisions regarding AD use prior to 
and during pregnancy. Over the course of several years, we have established a very large cohort of 
women with perinatal depression and euthymic women on AD treatment of whom ultimately 50% 
decide to discontinue treatment prior to and during pregnancy.  The pool of study-eligible subjects for 
the current investigation is therefore substantial; given this system, accessioning an adequate number 
of subjects for the pilot is assured. 
At the point of enrollment, potential subjects will have already reviewed risks of perinatal treatment in a 
consultation with a non-study psychiatrist in the CWMH program and in collaboration with the patient’s 
psychiatrist in the community, decided to discontinue AD treatment (Group 1) or begin antidepressant 
monotherapy or supplement current AD treatment (Group 2). 
Consultations presenting to the CWMH are reviewed on a weekly basis by the team of the CWMH 
perinatal psychiatrists to provide consistency in what information is conveyed. No subject will be 
referred to the study for potential inclusion until she has made an informed decision regarding AD 
therapy. 
Potential subjects will also be recruited through outpatient centers of the Department of Obstetrics at 
the Massachusetts General Hospital. Study staff will first identify potentially eligible patients prior to 
their appointments in the clinic and inform their health care provider that they may be eligible. The 
provider who is known to the potential subject and has firsthand knowledge of the patient's medical 
history will initially introduce the study to the patient and obtain the patient's verbal consent to be 
contacted or approached by study staff.  
 
IV. SUBJECT ENROLLMENT 
 
a. Methods of enrollment  
Potential subjects will be recruited from the Massachusetts General Hospital (MGH) Center for Women’s 
Mental Health (CWMH) clinic, outpatient Obstetrics clinic, and from referrals from health care providers 
in the community. Interested potential participants will be referred to study staff for a pre-screening 
phone call. Patients potentially eligible for Group 1 will continue on in the screening process only if the 
patient explicitly states that she has decided to discontinue antidepressant treatment in the context of 
pregnancy (planning or during).  Patients potentially eligible for group 2 will only continue the screening 
process if they state that they do not wish to start therapy with an antidepressant medication. 
 
After a preliminary phone screening, a research coordinator working within the CWMH will schedule the 
patient for a baseline visit. This baseline visit will be conducted by either the principal investigator (PI) or 
another clinician trained in all study assessment procedures, along with trained clinical research 
coordinators. After an explanation of the study procedures, written informed consent will be obtained 
from patients prior to execution of any study assessments or procedures. 
 
b. Informed Consent procedures 
The study coordinator will briefly discuss the main eligibility criteria and study protocol with each 
woman who inquires about the study at the time of a brief phone screen.  At the baseline visit, a study 
coordinator and licensed study physician will review the consent form in its entirety with prospective 
subjects.  Women enrolling in this study must be capable of understanding the nature of this study as 
well as the discomforts and potential benefits.  Any questions or areas of concern regarding the protocol 

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or alternative treatment options will be addressed by one of the study physicians.  If a woman feels 
comfortable with the study procedures, she will sign two copies of the consent form along with the 
study physician.   
Enrolled subjects will be given a copy of the completed consent form before any study procedures are 
completed.  If subjects have reservations about study participation at the first visit, they have the option 
to take the consent form home to review the decision to participate in the study with their family and 
health-care providers, and then return at a later date to discuss the study again with research physicians 
and coordinators before signing the consent form and initiating study procedures.  Subjects may also 
elect to participate in the study remotely by phone for visits 2, 3, 5, and 6, for which verbal consent will 
be recorded in the subject binder. Subjects will be made aware that visits 1, 4, and 7 must be in person 
before signing the consent form. 
 
STUDY PROCEDURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Flow through Study Procedures: 
Phone Screen 
A. Preliminary evaluation of subject eligibility based on inclusion/exclusion criteria 
B. If eligible, a baseline visit is scheduled. 
Baseline Visit with Study Staff and Perinatal Psychiatrist 
A. Review and obtain informed consent 
B. MINI (clinical interview) 
If eligible following clinical interview: 
C. Subject completes self-report study instruments (Q-LES-Q-SF, QIDS-SR) 
D. Subject meets with physician to plan tapering schedule if still on AD  
E. Blood draw and buccal swab for laboratory tests  
F. Patient will receive the study intervention to start, which includes daily intake of EnBrace and a 
standard prenatal vitamin (PNV) 
Acute Treatment Phase – 12 weeks 
A. Bi-weekly study visits for clinician rated scales  
B. Bi-weekly assessments of mood and patient well-being 
C. Repeated blood draw labs at 6 and 12 weeks 
D. A Qualitative Interview will be conducted at completion in order for us to obtain feedback about 
the intervention after the acute phase of treatment  
**If recurrence occurs between visits, a “recurrence determination visit” is scheduled with a study 
perinatal psychiatrist.  At any time throughout the study, patients can ask to meet with the 
psychiatrist or study staff. 
Continuation Treatment Phase –6 months (optional) 
A. Monthly telephone assessments  
B. Optional clinical interviews with study psychiatrists offered at each monthly booster  
**If recurrence occurs between visits, a “recurrence determination visit” is scheduled with a study 
perinatal psychiatrist. 

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Procedures/Data Collection  
 
For the acute treatment phase, visits will include a baseline visit (2-3 hours), and every other week 
assessments (thirty minutes to one hour each). Please note that the schedule of independent outcome 
assessments and in-person visits may vary depending on patient scheduling issues. Furthermore, 
research personnel will attempt to schedule all assessments as in-person visits, however to 
accommodate subjects, assessments may be done over the phone.  
Participants may elect to participate in visits 2, 3, 5, and 6 via phone interview rather than in-
person visits. All participants must participate in visits 1, 4, and 7 in person. Study physicians 
will perform clinician-administered questionnaires by telephone for participants who elect to 
participate remotely for visits 2, 3, 5, and 6. Verbal consent will be obtained from the subject to 
conduct visits by phone and will be recorded in the subject’s research file. Those subjects who 
choose to participate in visits 2, 3, 5, and 6 will receive the study drug by mail using first-class 
shipping to ensure appropriate dispensing and supply of the study drug over the course of the 
study. 
 
Additionally, patients may request a physician meeting at any visit. Please see table below for listing of 
assessments at each visit.  
Schedule of Assessments: Acute Phase (12 weeks)  
 
Visit # 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
Week # 
0 
2 
4 
6 
8 
10 
12 
MINI: full MINI at V1; depression 
module at follow-ups 
X 
X 
X 
X 
X 
X 
X 
Demographics, medical & 
psychiatric history 
X 
 
 
 
 
 
 
Labs: genetic sample 
X 
 
 
 
 
 
 
Labs: folate, homocysteine, B12, 
IL-6, CRP 
X 
 
 
X 
 
 
X 
Vital Signs: Height only at V1, 
weight, blood pressure 
X 
X 
X 
X 
X 
X 
X 
MADRS 
X 
X 
X 
X 
X 
X 
X 
CGI-Clinician 
X 
X 
X 
X 
X 
X 
X 
EPDS 
X 
X 
X 
X 
X 
X 
X 
QIDS-SR 
X 
X 
X 
X 
X 
X 
X 
Q-LES-Q-SF 
X 
 
 
X 
 
 
X 
 
A Qualitative interview will be conducted by study staff after completion of the acute treatment phase 
in order to obtain feedback on the intervention.  
 
Instrument Descriptions:  
 

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Mini-International Neuropsychiatric Interview (MINI): The MINI is a widely used clinician-administered, 
structured interview used to diagnose psychiatric patients.  It was designed to rapidly and accurately 
assess psychiatric illness, and has been found to be reliable and valid in making a diagnosis of MDD and 
other psychiatric diagnoses(73-75). The MINI can be administered by non-clinicians who are trained to 
administer it and the MDD section takes up to 10 minutes to complete.   
Montgomery-Åsberg Depression Rating Scale (MADRS): The MADRS is a widely used 10-item clinician-
rated scale that describes the severity of depressive symptoms (range >60, higher score indicates more 
depression symptoms)(76). The MADRS has good internal consistency (Cronbach’s α = 0.82), test-retest 
reliability (correlation 0.90), and validity and is highly sensitive to changes with treatment(76-78). 
Remission of depression in clinical trials has been defined loosely as a final MADRS score <10 or, more 
strictly, as a score <5(79).  
Clinical Global Impressions Scale (CGI): The CGI contains 7-point global severity and change 
(improvement) scales and will be used as an overall outcome measure(80).   
Quick Inventory of Depressive Symptoms (QIDS-SR): The QIDS-SR is a 16-item self report rating scale for 
depressive symptoms. This instrument was used in the STARD effectiveness trial, in which >4000 
depressed patients were enrolled. In a recent paper, Trivedi and colleagues reported on the 
psychometric properties of the QIDS-SR, including documentation of high concurrent validity and 
internal consistency(81).  
Edinburgh Postnatal Depression Scale (EPDS): This measure is a 10-item self-report used to measure 
postpartum depressive symptoms and takes <5 minutes to complete(82).  This scale will be one of our 
outcome measures for depressive symptoms. It has been validated in community and obstetrical 
samples.  A score of >10 is suggestive of perinatal depression.  Because it measures symptoms and is not 
diagnostic of a relapse, we will use the MINI to assess the recurrence of a major depressive episode.  
The EPDS is widely utilized in multidisciplinary settings and de-emphasizes somatic symptoms that are 
common in pregnancy and postpartum. The EPDS is validated for use in pregnancy as well as 
postpartum with good specificity and sensitivity(83).  
Quality of Life Satisfaction Questionnaire Short Form (Q-LES-Q-SF): The Q-LES-Q asks questions in 8 
modules of 6-16 questions each, about physical health/activities, general feelings of well being and 
relaxation, function at work, household duties, school or course work, leisure activities, social relations, 
and general activities over the past week(84). The “short form” includes only the General Activities 
section. Patients are asked to rate the answers on a scale of 1-5, from “not at all or never” to “frequently 
or all the time.” Answers in the “frequently” range indicate greater satisfaction with life. A total score 
for the “short form” is calculated by simply totaling answers to all 16 items of the General Activities 
section.   
 
Laboratory Measures 
 
Blood samples will be collected for laboratory analyses that may serve as biomarkers of treatment 
response.  These include levels of biologic measures that are associated with folate metabolism and 
inflammatory markers that may be associated with omega-3 fatty acid intake (known to be anti-
inflammatory). The following will be assessed at baseline, 6 weeks, and 12 weeks:  folate, B12, and 
homocysteine levels; IL-6 and CRP, inflammatory markers.  Cheek swab samples for genetic testing will 
be collected at baseline for polymorphisms associated with folate metabolism (i.e., genes encoding for 
MTHFR, methylene tetra-hydro folate reductase). 
 
Drop criteria:  

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1. Participant experiences severe worsening of depression symptoms, as indicated by a CGI-I of 6 or 7 
on 2 consecutive visits determined by a licensed study psychiatrist. Subjects with a CGI-I of 6 or 7 on 
2 consecutive visits will be terminated from the study and referred for additional clinical treatment 
as needed. 
2. A Group 1 participant who is not experiencing depression symptoms decides to restart 
antidepressant treatment while they are well 
3. A Group 2 participant who enrolled during a current depressive episode has either started a new 
antidepressant or increased the dose of an antidepressant they were already taking 
4. Emergence of suicidal ideation, homicidal ideation, or psychotic symptoms. The anchors for 
suicidality will include the QIDS-SR, Question 12 (with an answer of 2 or 3) and the MADRS, Question 
10 (with an answer of 4, 5, or 6). Acute suicidality, based on these measures and the licensed 
psychiatrist’s clinical assessment, will result in termination of participation in the study and swift 
triage to the Acute Psychiatry Service at Massachusetts General Hospital. 
5. Evidence of abuse or misuse of study medication 
6. Evidence of current alcohol and/or drug abuse 
7. Any severe or unstable medical illness that includes concern regarding safety of continued use of 
study medication   
8. Intolerance to study medication as determined by research clinician 
9. Significant hypersensitivity reaction 
10. Inability or unwillingness to complete the study procedures 
 
V. BIOSTATISTICAL ANALYSIS 
 
We will compare the rates of depressive relapse and duration of time out of a depressive episode for 
Group 1 participants, and compare these data to historical controls that were also assessed 
prospectively.  For Group 2, we will compare depressive response rates (response defined as 50% 
reduction in depressive symptoms on the MADRS, our primary outcome) to response rates in studies of 
SSRIs for the treatment of depression. 
In addition, we will monitor depressive symptom burden with continuous variables across the treatment 
study for both groups.   
To control for prenatal vitamin (PNV) use, we will supply a standard PNV to each participant to take daily 
in combination with EnBrace.  The Sponsor has offered to supply the PNV, such that each participant will 
take the same PNV; this will lower the risk of inconsistencies between participants.  In the statistical 
analysis, the data collected in this preliminary study will be compared to historical controls with a 
history of MDD who discontinued AD maintenance therapy during pregnancy, most of which were 
taking standard PNVs, but not EnBrace.  This reference will allow us to estimate the relative efficacy of 
EnBrace in relapse prevention of women who discontinue maintenance ADs for pregnancy. 
Exploratory Analyses  
We will also explore the collected laboratory tests as potential biomarkers.  
 
VI. RISKS AND DISCOMFORTS 
 

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Subject burden for participation includes the time spent participating in study visits.  Visits will include a 
baseline visit (2-3 hours), follow up visits (30 min to one hour each), and three blood draws over the 
course of the study. The total time burden for subjects is similar to our previous investigations involving 
very similar populations. Risks of this study include potential psychological distress that may occur 
during treatment and assessment visits, during which history, current symptoms and life stressors are 
discussed.  Participation in this study does not directly affect risk for recurrence or worsening of 
depression. To be eligible, subjects must have already made an informed decision regarding 
antidepressant treatment in the context of pregnancy.  Study assessment and treatment visits may 
increase recognition of symptom worsening and ensure that appropriate treatment is provided.  
Patients who experience worsening of depressive symptoms will be presented with options for 
treatment, including antidepressant medications. 
According to the NIH National Library of Medicine, adverse reactions to EnBrace that have been 
reported include: allergic sensitization associated with folic acid; paresthesia, somnolence, nausea, and 
headaches associated with pyridoxine; and mild transient diarrhea, polycythemia vera, itching, 
transitory exanthema and the feeling of swelling of the entire body associated with cobalamin. Finally, 
EnBrace may cause allergic reaction. If patients have any side effects, they will be instructed to report 
them immediately to the study doctor.  If any subject develops an adverse event, the adverse event will 
be reported to the MGH IRB consistent with Human Research Committee (HRC) guidelines. EnBrace 
carries no known risks to an embryo, fetus, or breastfeeding infant. 
This research study poses the potential risk of subjects consuming higher than recommended doses of B 
vitamins, iron, and folate when taking EnBrace in combination with a standard prenatal vitamin.  The 1.5 
milligrams of iron contained in EnBrace is very minimal such that when combined with iron in the typical 
PNV, there would be little to no risk of exposure to higher than recommended levels of iron.  This is also 
the case for certain B vitamins, which are present in minimal level in EnBrace. Finally, there is potential 
risk for consumption of higher than recommended doses of folic acid, which can mask vitamin B12 
deficiency.  To minimize this risk, we will exclude patients with known pernicious anemia or who have 
had gastric bypass, which may lead to a vulnerability to vitamin B12 deficiency. 
As with any clinical research study, there is a potential risk for loss of confidentiality. We will make every 
effort to keep personal health information confidential. 
 
Risks of Blood Draws 
Phlebotomy can cause pain, bleeding or bruising at the site where the needle enters the vein. Some 
subjects may feel dizzy or light-headed during a blood draw. There is a very small risk of infection at the 
site from which we take the blood. A suspected infection would be treated with antibiotics and the 
subject would be encouraged to follow up with their primary care physician.  
 
Adequacy of Protection against Risks 
Salient safety issues that we address in this section include: 1) ensuring that patients do not feel 
obligated to enroll in the study, but elect to participate by their own volition 2) caring for patients who 
may experience a recurrence of their depression during the course of the study 3) maintaining the 
confidentiality of the study subjects, and 4) ensuring that staff are sensitive to issues of beneficence, 
justice, race, ethnicity, and gender.  The following elements of our proposal are designed to reduce risk 
for human subjects. 
 
Recruitment and Informed Consent 

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Subjects will be recruited through the MGH Center for Women’s Mental Health and clinician referrals, 
under the direction of Dr. Marlene Freeman and Dr. Lee Cohen.  At the outset of the proposed 
investigation, staff psychiatrists and research assistants of the MGH Center for Women’s Mental Health 
will participate in a one-hour meeting with the study PI and co-PI for the purpose of reviewing the aims, 
design and selection criteria for the proposed investigation.   
This clinical and research group sees 900 women annually who are seeking consultation for expert 
guidance in evaluating the risks and benefits of discontinuing psychotropic medication proximate to 
pregnancy.  Over the last five years, half of these women have suffered from recurrent major depression 
and have presented on maintenance AD therapy.   
We have spent the last decade recruiting a sample of women for perinatal depression (e.g. Prospective 
Pregnancy Study, n=201, Postpartum Study, n= 129).  Under a separate MGH IRB approved protocol we 
have permission for ongoing dynamic contact with these patients as they proceed through their 
reproductive life cycles.  Through this system, we have recruited participants for two large scale 
research studies involving pregnancy.   
Also, for an NIMH R-21 funded study to assess depressive relapse risk in women undergoing infertility 
treatment, we successfully recruited 49 participants.   We also recruited N=12 women for a CBT study in 
pregnancy, designed to utilize CBT to reduce the risk of depressive relapse in women trying to conceive 
and discontinuing ADs. 
The Clinical Research Department has a seamless relationship with the Clinical Center. At the Clinical 
Center, psychiatrists see over 600 women a year for consults regarding treatment recommendations for 
psychotropic medication during pregnancy.   
Every woman who comes to either the Research Program to participate in a clinical trial or for a consult 
with one of the psychiatrists in our program has the opportunity to fill out a form allowing us to enter 
her information into our tracking system.  This is also complemented by our internet resource center 
(www.womensmentalhealth.org) as well as a seasonal e-newsletter with nearly 4,000 subscribers.  
These critical recruitment tools generate a constant flow of patients that may be eligible and interested 
in participating in the current study.  If a potential Group 1 patient indicates that she is undecided on 
whether she wants to discontinue her antidepressant treatment or elects to stay on antidepressant 
treatment, she will not be informed about the current study. 
Informed consent will be obtained by one of the research psychiatrists from patients at the start of the 
baseline visit, prior to conducting any study assessments or procedures.  The PI or another member of 
the study team (MD or PhD-level clinician) who is trained in all study assessment procedures will review 
the consent form with all patients.  Subjects in this study must be capable of understanding the nature 
of this study as well as the discomforts and potential benefits.  These will be explained in full by the 
HRC-approved research staff.  All subjects will then be asked to read, understand, and sign the informed 
consent prior to participation. 
 
Protection Against Risk  
As discussed above, in order to (1) prevent patients from feeling obligated to participate in the study, 
subjects eligible for Group 1 will only be enrolled if they decide to discontinue AD treatment.  Subjects 
eligible for Group 2 will only be included if they have decided not to accept treatment with an 
antidepressant medication (if not currently on an antidepressant) or opt not to increase the dose or add 
an adjunctive antidepressant medication (if presenting on an antidepressant).  The risks and benefits of 

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discontinuing maintenance AD treatment will be described to the patient in detail.  Additionally, the 
research clinician will inform the patient that they can choose, at any point, to reinitiate AD treatment.  
For (2) prompt identification of patients who experience a depressive recurrence or worsening of acute 
depression during the study, it is likely that over the course of the investigation some women may have 
significant psychiatric symptoms requiring acute intervention and/or evaluation and referral. The 
investigators have the clinical expertise and resources available to provide acute evaluations and, if 
needed, referral. The Acute Psychiatry Service of the MGH is staffed and available 24 hours/day to 
handle psychiatric emergencies.  Because subjects are assessed for mood symptoms at each study 
assessment visit, the likelihood that symptom worsening will be identified in a timely manner is 
increased.  
As in all clinical research studies, it will be critical to (3) maintain the confidentiality of the women with 
psychiatric illnesses and/or treatment.  Data collected in the study will be used for research purposes 
only. All members of the research team will treat all data with strict confidentiality. All members of the 
research team, prior to working on a research protocol, are required to complete a designated course in 
the ethics and regulations governing research with human subjects.  Documentation of completion of 
this course will be required for all study personnel at the beginning of the investigation.  Subject 
confidentiality will be assured by use of identification numbers on pre-coded data collection sheets. 
Only one master log with identifying information linking the patient name and the identification number 
will be maintained and kept in a secure location separate from the remainder of the study data. Signed 
informed consent forms will be kept in a locked room for documentation purposes.  Any paper data 
obtained during the investigation, which includes interview, symptom rating scale, and lab result forms, 
will be kept in a separate secure filing cabinet with access limited to the research team.  After 
recruitment and analysis of data are complete (at the end of the funding period), all subjects’ identifying 
information will be destroyed and will not be included as part of long-term storage of data sets.  No data 
will be reported on an individual basis; all findings will be presented in aggregate. 
Additional steps will be taken to protect confidentiality of genetic data as outlined: 
1.  All study staff are trained to make confidentiality of genetic data a priority.  
2.  No genetic research data (or any other data related to the study) will be entered into the medical 
record. 
3.  The results of the genetic analyses will only be shared with participants who elect to receive them 
through secure email, postal mail, or in person at study visits using an approved letter. This 
information will not be shared with their family members or unauthorized third parties. All 
questions regarding genetic results will be deferred to participants’ treating providers. 
4.  Genetic data are encoded using coded identifiers. These codes, rather than personal identifiers, are 
used in any analytic datasets. The code key linking coded identifiers to personal identifiers are kept in 
an access-restricted, password protected electronic file and are not shared with the genetics 
laboratories.    
5.  Samples and genetic data stored in the laboratory will be identified only by the code numbers and 
laboratory personnel will not have access to personal identifiers. 
6.  The most serious risk would be identification of individuals in the publicly shared database.  To 
prevent this, computerized data files provided to other investigators will not include any of the 
HIPPA-defined personal identifiers.  
In order to assure that the (4) subject’s personal contribution to this research study is acknowledged, all 
study staff will receive training in human subject research, which includes emphasis on issues of 
confidentiality, respect, beneficence, justice, race, ethnicity and gender. 
 

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VII. POTENTIAL BENEFITS 
 
There are many benefits that may result from participation in the proposed investigation.  Subjects 
enrolled in the study will contribute to the base of scientific knowledge concerning effective methods to 
1) discontinue AD treatment proximate to conception, 2) prevent recurrence of depression during a 
high-risk period, and 3) treat acute depression with alternative or adjunct pharmacotherapy.  If a safety 
issue or mental health problem is identified during a study assessment, the subject will benefit from 
having the study team member facilitate management of her symptoms. If subjects do experience a 
depressive recurrence or other clinical deterioration during study participation, the study team will 
facilitate referral for coordination of care.  Since contact with the study team will occur at multiple time 
points, subjects will have the opportunity to easily access experts in the area of depression and 
pregnancy.  Subjects who request the results of the MTHFR genetics analysis may benefit from useful 
information regarding folate use in the context of pregnancy-related decision-making with their 
providers. Lastly, subjects will be compensated $50 at three time points for a total of $150 for their 
participation in the study. Parking validation will be provided to cover costs of parking fees during study 
visits. The study may additionally compensate for travel expenses for MBTA public transportation if 
requested. 
 
 
VIII. MONITORING AND QUALITY ASSURANCE 
 
During the course of the protocol, study and non-study related events such as hospitalization or 
recurrence of depression may occur, therefore risk management protocols are in place to address these 
events as they occur.  All professional and technical staff are fully trained and available to manage 
adverse events.  Physicians are available by phone and pager to be informed of serious adverse events. 
These events will be promptly reported to the MGH IRB, according to the Code of Federal Regulations, 
and the subject’s primary care and mental health providers will also be informed.  
At each visit, study physicians will prompt the participant to report any occurrences of health problems 
beyond the subject’s depression.  Any serious or non-serious adverse event will be recorded in the 
participant’s study binder at each examination.  Serious and non-serious adverse events will also be 
reported to the Human Research Committee in accordance with Human Research Committee reporting 
guidelines, following the timeframes specified by the Partners Investigator’s Guidelines.  In case of a 
serious adverse event, appropriate diagnostic and therapeutic measures will be taken, as determined by 
the investigator.  All adverse event reports will be reviewed by the principal investigator and reported to 
the FDA in accordance with the guidelines outlined in the Investigational New Drug application.   
 
 
 
IX. REFERENCES 
 
1. 
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antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines. J 
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Andrade SE, Raebel MA, Brown J, Lane K, Livingston J, Boudreau D, et al. Use of antidepressant 
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4. 
Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW, et al. Conceptualization and 
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Mueller TI, Leon AC, Keller MB, Solomon DA, Endicott J, Coryell W, et al. Recurrence after 
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Lavori PW, Dawson R, Mueller TB. Causal estimation of time-varying treatment effects in 
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Montgomery SA, Dufour H, Brion S. The prophylactic efficacy of fluoxetine in unipolar 
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Frank E, Kupfer DJ, Perel JM. Three-year outcomes for maintenance therapies in recurrent 
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Kupfer DJ, Frank E, Perel JM, Cornes C, Mallinger AG, Thase ME, et al. Five-year outcome for 
maintenance therapies in recurrent depression. Arch Gen Psychiatry. 1992;49(10):769-73. 
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Entsuah AR, Rudolph RL, Hackett D, Miska S. Efficacy of venlafaxine and placebo during long-
term treatment of depression: a pooled analysis of relapse rates. Int Clin Psychopharmacol. 
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Hirschfeld RM. Clinical importance of long-term antidepressant treatment. Br J Psychiatry Suppl. 
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Quitkin FM, Stewart JW, McGrath PJ, Nunes E, Ocepek-Welikson K, Tricamo E, et al. Further 
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