Marlene Freeman

Harvard Medical School | HMS · Department of Psychiatry

Background: Women with psychiatric disorders are vulnerable to relapse in pregnancy, and the COVID-19 pandemic has presented an additional stressor. Methods: Data came from a supplemental study offered to women enrolled in the Massachusetts General Hospital Center for Women's Mental Health National Pregnancy Registry for Psychiatric Medications....

Purpose/background: The prevalence of attention-deficit/hyperactivity disorder in adult females is 3% to 4%. Attention-deficit/hyperactivity disorder is highly comorbid with other psychiatric disorders such as mood, anxiety, and substance use disorders. For reproductive-aged women, the treatment of attention-deficit/hyperactivity disorder with sti...

Objective: Clinical studies of depression have historically excluded participants with suicidal ideation. Research participant safety protocols are critical to allow for the much-needed study of suicide risk. This report summarizes participant feedback about the safety protocol used in a national, remote study of perinatal women with suicidal ideat...

This Editorial is a response to the Canadian Task Force on Preventive Health Care's recent recommendation "against instrument-based depression screening using a questionnaire with cut-off score to distinguish 'screen positive' and 'screen negative' administered to all individuals during pregnancy and the postpartum period (up to 1 year after childb...

Purpose/background: Since its US Food and Drug Administration approval in 1996, olanzapine has been one of the most commonly prescribed atypical antipsychotics, making a better understanding of its reproductive safety profile critical. The goal of the current analysis was to determine the risk of major malformations among infants exposed to olanza...

Objective: Postpartum psychosis (PP) is a severe psychiatric disorder, with incomplete consensus on definition and diagnostic criteria. The Massachusetts General Hospital Postpartum Psychosis Project (MGHP3) was established to better ascertain the phenomenology of PP in a large cohort of diverse women spanning a wide geographical range (primarily...

Background: Second-generation antipsychotics (SGAs), also called atypical antipsychotics, are common therapies for women with a spectrum of psychiatric disorders. No systematically ascertained human reproductive safety data are available for lurasidone, and prospective data for quetiapine are limited, making decisions regarding use of these medicat...

Objective: While poor neonatal adaptation syndrome (PNAS) has been particularly well described among infants exposed to antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), this is not the case for second-generation antipsychotics (SGAs). In 2011, the US Food and Dru...

Objective: Ketamine is a novel and rapidly acting treatment for major depressive disorder (MDD). Benzodiazepines are commonly coprescribed with antidepressants in MDD. This study sought to examine data from a randomized clinical trial that compared a single infusion of intravenous (IV) ketamine to midazolam placebo in treatment-resistant depression...

The normal physical changes associated with pregnancy may increase the risk of body dissatisfaction, which is associated with negative mental health outcomes including depression and disordered eating. The purpose of this study was to explore body image and eating concerns among a sample of participants in pregnancy and postpartum and to assess int...

Background: Systematic data regarding long-term neurobehavioral effects of maternal antidepressant use during pregnancy are sparse. The aim of this study was to evaluate the impact of gestational exposure to antidepressants on later neurodevelopmental function. Methods: This study describes a cohort of mother-child dyads (44 mothers, 54 children...

Background Perinatal anxiety affects 20% of women, and untreated maternal mental illness can cause deleterious effects for women and their children. Benzodiazepines are commonly used to treat anxiety disorders. The reported risk of congenital malformations after in utero benzodiazepine exposure has been inconsistent. Methods The Massachusetts Gene...

Buspirone is commonly used to treat anxiety disorders among reproductive-aged women. To date, the reproductive safety of buspirone in humans has been particularly sparse. We sought to provide preliminary data from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications (NPRPM) on the risk of major malformations af...

Objectives: The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) an...

Objective We sought to examine the impact of the COVID-19 pandemic on the pregnancy, delivery and postpartum experiences of women with histories of psychiatric disorders. Method Women already enrolled in a United States registry which prospectively studies the relationship between the use of psychiatric medications during pregnancy and major conge...

This corrects the article DOI: 10.4088/JCP.21lcx14254.

Women may experience new-onset or worsening depressive disorders during pregnancy and the postpartum. If untreated, there may be detrimental consequences to the health and wellbeing of the woman and to her baby. There is a need for improved tools and approaches that can be easily and broadly implemented to effectively detect depression during the p...

Objective: Second-generation antipsychotics (SGAs) are prescribed for a wide range of indications in women of reproductive age. The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was established to determine the risk of major malformations among infants exposed to these medications during the first trimester relative to a compariso...

Aripiprazole has become one of the most commonly prescribed psychotropics, making a more comprehensive understanding of its reproductive safety profile a priority. The goal of the current analysis was to determine the risk of major malformations in infants exposed during the first trimester of pregnancy to aripiprazole compared to infants whose mot...

A correction to this paper has been published: https://doi.org/10.1007/s00737-021-01133-4

This study aimed to assess the effect of a single infusion of intravenous (IV) ketamine on suicidal ideation in patients with treatment-resistant depression (TRD). Patients with TRD were randomized in a double-blind fashion to a single infusion of IV ketamine or IV midazolam placebo. Suicidal ideation was measured using the Montgomery-Asberg Depres...

The purpose of this study is to examine initiation rates of breastfeeding and other breastfeeding outcomes among women taking second generation antipsychotics (SGAs). Participants were enrolled in the National Pregnancy Registry for Atypical Antipsychotics; an ongoing prospective cohort study enrolling women age 18–45 years who are exposed and unex...

Objective The aim of this study was to characterize the course of ADHD during pregnancy. Method Women ages 18 to 45 were followed prospectively at <20 weeks, 24 weeks, and 36 weeks pregnant. Three groups emerged: women who discontinued, maintained, or adjusted their ADHD medications. ADHD symptoms were recorded using the AISRS. Anxiety, depression...

Objective: This was an analysis of the effect of pimavanserin, a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist, on dysregulated sleep in patients with major depressive disorder (MDD) by DSM-5 criteria and an inadequate antidepressant response. Methods: For this analysis of CLARITY, a phase 2 study of adjunctive pimavanserin (N =...

Background: Kappa-opioid antagonism may possess antidepressant properties. We assessed, in a proof-of-concept pilot trial among patients with major depressive disorder with inadequate response to antidepressants, the efficacy of adjunctive CERC-501 (formerly LY2456302), a kappaselective opioid receptor antagonist. Methods: In a Sequential Parall...

In a post hoc analysis, the effect of pimavanserin on anxious depression was determined from CLARITY, a randomized, double-blind, placebo-controlled study in patients with major depression and an inadequate response to previous therapy. Patients were randomized in a 3:1 ratio to placebo or pimavanserin 34 mg daily added to ongoing antidepressant th...

Background : Up to 15% of patients with major depressive disorder (MDD) attempt suicide and up to 2% complete suicide. This was a post-hoc analysis aimed to evaluate the risk of suicide ideation and behavior associated with adjunctive pimavanserin treatment in adults with MDD. Methods : CLARITY was a randomized, double-blind, placebo-controlled st...

Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active plac...

Supplementary Figure 1 and Supplementary Tables 1–4 have been re-uploaded so as to reflect the versions supplied during proofs stage. The publisher apologizes for the error in versioning. The HTML version of the paper has been updated.

Purpose/background: Major depressive disorder (MDD) and obesity commonly co-occur. We sought to assess the impact of body mass index (BMI) on the acute antidepressant effects of ketamine in patients with treatment-resistant depression. Methods/procedures: Post hoc analyses were conducted from a multisite, randomized, double-blind, placebo-contro...

Background Sexual dysfunction is common among patients with major depressive disorder (MDD). In the CLARITY study, the safety and efficacy of adjunctive pimavanserin, an inverse agonist at 5‐HT2A receptors, were demonstrated when added to existing treatment for MDD. This analysis provides a detailed assessment of the effects of pimavanserin on sexu...

Study Objectives Sexual dysfunction occurs in 40%-60% of patients with major depressive disorder (MDD), due to either the illness itself and/or the effects of antidepressant treatment. The phase-2 CLARITY trial recently demonstrated the efficacy of adjunctive pimavanserin (PIM) for MDD when added to ongoing selective serotonin or serotonin–norepine...

Study Objectives Depression is the leading cause of disability worldwide, with fewer than 50% of treated patients achieving full remission. This study (“CLARITY,” ACP-103-042: NCT03018340) examined the 5-HT2A inverse agonist pimavanserin (PIM) as a potential adjunctive treatment for major depressive disorder (MDD). Method Adult female and male sub...

Introduction: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are recommended as an integrative treatment for major depressive disorder (MDD). In 2019, the International Society for Nutritional Psychiatry Research (ISNPR) developed the first practice guidelines for n-3 PUFA treatment of MDD. To strengthen these guidelines and enhance their clinica...

Objective To determine whether estradiol variability, ovulatory levels of progesterone, and VMS burden are independently associated with perimenopausal depressive symptomatology. Design and Intervention Depressive symptoms, serum levels of estradiol and progesterone, and VMS frequency were assessed weekly in an 8-week observational study. Associat...

Objective: Pimavanserin is a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist. This phase 2 study examined the efficacy and safety of pimavanserin as adjunctive therapy in patients with major depressive disorder (MDD). Methods: This was a multicenter, randomized, double-blind, placebo-controlled study in patients with DSM-5-defined...

Objective: To examine the rate and time to relapse for remitters and responders to ketamine in treatment-resistant depression (TRD). Methods: Subjects with TRD were randomized to a single infusion of one of several doses of intravenous ketamine, or midazolam. Using Kaplan-Meier survival function, the current report examines the rate and time to rel...

Major depressive disorder (MDD) is a complex mental illness with unmet therapeutic needs. The antidepressant effects of ω-3 polyunsaturated fatty acids (n-3 PUFAs) have been widely reported. The subcommittee of the International Society for Nutritional Psychiatry Research organized an expert panel and conducted a literature review and a Delphi proc...

Objective: Obesity is associated with an increased risk of adverse pregnancy outcomes. As individuals with psychiatric disorders are at a higher risk of obesity than the general population, we aimed to examine the effect of obesity on neonatal and maternal outcomes in this population. Methods: Pregnant women with psychiatric disorders were enrol...

Background: While ketamine has been increasingly studied for treatment resistant depression (TRD), the impact of sex differences on treatment outcomes has not been well studied. The objective was to ascertain whether there were differences in response to a single administration of ketamine for TRD between men and women, and between pre- and post-m...

Objective To examine the effect of high baseline anxiety on response to ketamine versus midazolam (active placebo) in treatment‐resistant depression (TRD). Methods In a multisite, double‐blind, placebo‐controlled trial, 99 subjects with TRD were randomized to one of five arms: a single dose of intravenous ketamine 0.1, 0.2, 0.5, 1.0 mg/kg, or mida...

Background: Patients with major depressive disorder (MDD) often experience a re-emergence or worsening of symptoms despite ongoing treatment with previously effective antidepressant pharmacotherapy. This lost or reduced antidepressant response during maintenance, referred to as tachyphylaxis, negatively impacts treatment outcomes and quality of lif...

1 Background Maternal major depressive disorder (MDD) has an adverse effect on child development and increases risk for child psychopathology. It is paramount to understand the course of maternal depression during the childhood years particularly before, during, and after pregnancy. 2 Objective To follow the course of MDD in women with prior histo...

Objective: Second-generation antipsychotics are commonly prescribed to reproductive-age women for the treatment of a spectrum of psychiatric disorders. Quetiapine is the most commonly prescribed medication in this class, and therefore a better understanding of its reproductive safety profile is critical. The goal of this study was to determine the...

Background: Despite high prevalence rates among women of mood disorders and of infertility, there is a paucity of systematic data to inform the treatment of women at risk for psychiatric morbidity in the context of assisted reproductive technologies (ART). The objective was to delineate predictors of depressive relapse in women with histories of m...

Pregnancy labeling of prescription medications in the US is in the midst of a major transformation. The FDA's previous system, which used letter ratings to convey drug safety, was simple but led to misunderstandings-both faulty assurances and undue concerns. The new system, established under the Pregnancy and Lactation Labeling Rule, aims for more...

Objective: The goal of this analysis was to examine the effect of benzodiazepine use during pregnancy on maternal and neonatal outcomes in a cohort of women with psychiatric disorders. Methods: 794 evaluable women from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications were followed across pregnancy (N = 1...

Background: In a preliminary trial, we assessed the efficacy of vortioxetine for major depressive disorder (MDD) during the menopausal transition. Secondary outcomes included hot flashes (HFs), anxiety, and cognitive complaints. Methods: Perimenopausal and early postmenopausal women with MDD (N = 27) received 8 weeks of open-label, flexible-dose...

Background: Obesity during pregnancy is the most common high-risk obstetric condition, resulting in increased rates of adverse maternal and neonatal outcomes. Individuals with psychiatric disorders have a higher risk of obesity than the general population, but data regarding implications of obesity in women with psychiatric disorders are sparse....

Background: Low-Field Magnetic Stimulation (LFMS) is a novel, non-invasive, sub-threshold neuromodulation technique, shown in preliminary studies to have immediate mood elevating effects in both unipolar and bipolar depressed patients. Objective: We aimed to assess the antidepressant augmentation effects at 48 h of LFMS administered on two conse...

Purpose/background: Two-thirds of women with depressive disorders report reemergence of depression premenstrually, or premenstrual exacerbation (PME), despite effective treatment of the underlying mood disorder during the remainder of the cycle. There is a paucity of studies that rigorously assess treatments targeting PME. Open-label data suggest...

Background: Second generation antipsychotic medications (SGAs) are widely used by reproductive-age women to treat a number of psychiatric illnesses. Some SGAs have been associated with an increased risk of developing diabetes, although information regarding their diabetogenic effect in pregnant women is scarce. Objective: To evaluate the risk of...

Background: Failed treatment trials are common in major depressive disorder and treatment-resistant depression, and remotely performed multifaceted, centralized structured interviews can potentially enhance signal detection by ensuring that enrolled patients meet eligibility criteria. Methods: We assessed the use of a specific remote structured...

Background: In treated patients with major depressive disorder (MDD), residual symptoms are common and challenging to disentangle from possible antidepressant side effects. Our objective was to prospectively differentiate between rates of residual symptoms and treatment-emergent side effects. Methods: Participants in an episode of MDD were enrol...

Context: Women are at increased risk for mood disturbance during the menopause transition. Hot flashes (HFs), sleep disruption, and fluctuating estradiol levels correlate with menopause-associated depression but co-occur, making cause and effect relationships difficult to disentangle. Objective: Using a GnRH agonist (GnRHa) experimental model, w...

Women of reproductive age commonly use integrative treatments. However, the reproductive safety for most complementary products lacks systematic study. We aimed to study the use of supplements by women in a prospective pregnancy registry. The Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics was established to e...

Management of bipolar disorder during pregnancy often involves medications with potential adverse effects, including risks to the mother and fetus. Although some specifics are known, many medications continue to have incompletely characterized reproductive safety profiles. Women with bipolar disorder who are planning pregnancy face challenging deci...

Background: Given the growing policy and public health interest in the identification and treatment of depression in pregnancy, an understanding of the feasibility, challenges, and implications for resource utilization of the implementation of a universal screening program is crucial. Objective: The purpose of this study was to assess the feasib...

Unplanned pregnancies account for approximately 50% of pregnancies in the United States and 40% globally. Therefore, it is good clinical practice to treat women of reproductive potential with the idea in mind that they may become pregnant during the course of treatment, regardless of their stated intentions. In psychiatry, most of the disorders we...

The aim of this study was to evaluate the effects of levomilnacipran extended-release (ER) on depression-related fatigue in adults with major depressive disorder. Post-hoc analyses of five phase III trials were carried out, with evaluation of fatigue symptoms based on score changes in four items: Montgomery-Åsberg Depression Rating Scale (MADRS) it...

Objective: Second-generation antipsychotics are used to treat a spectrum of psychiatric illnesses in reproductive-age women. The National Pregnancy Registry for Atypical Antipsychotics was established to determine the risk of major malformations among infants exposed to second-generation antipsychotics during pregnancy relative to a comparison gro...

Major depressive disorder is often accompanied by elevated levels of anger, hostility, and irritability, which may contribute to worse outcomes. The present study is a secondary analysis examining the role of anger/hostility in the treatment response to low-dose aripiprazole added to antidepressant therapy in 225 patients with major depressive diso...

The objective of this open-label, preliminary study was to assess the efficacy of omega-3 fatty acids for treating dyslipidemia associated with use of atypical antipsychotics. Participants treated with atypical antipsychotics who had hypertriglyceridemia (>200 mg/dL) and/or hypercholesterolemia (>250 mg/dL) were enrolled in an open trial and receiv...

In this issue of JCP, Cohen et al present the methodology of the National Pregnancy Registry for Atypical Antipsychotics (NPRAA). In full disclosure, the investigators are my colleagues, and I have great interest in the topic of pregnancy registries, including this particular registry, as a perinatal psychiatrist and from a scientific perspective....

Optimal successive treatment decisions are not well established after an initial medication nonresponse in major depressive disorder or bipolar disorder. While practice guidelines offer consensus-based expert treatment recommendations, little is known about "real world" pharmacology decision making by practicing psychopharmacologists. We surveyed v...

This study aims to obtain preliminary data on the efficacy of armodafinil for improving menopause-related fatigue and quality of life. Women (aged 40-65 y) experiencing menopause-related fatigue received open-label armodafinil therapy (up to 150 mg/d) for 4 weeks. Changes from baseline in Brief Fatigue Inventory score and Menopause-Specific Quality...

The start of a new year is traditionally a time we make resolutions. It is also a good moment to reflect, count our blessings, and give thanks. Those of us privileged to be physicians know first-hand the burden of illness. And every year of health-for ourselves and those we love-is a blessing. © Copyright 2015 Physicians Postgraduate Press, Inc.

Psychiatry is at an important juncture, with the current pharmacologically focused model having achieved modest benefi ts in addressing the burden of poor mental health worldwide. Although the determinants of mental health are complex, the emerging and compelling evidence for nutrition as a crucial factor in the high prevalence and incidence of men...

An integrated approach addressing maternal depression and associated mother-infant relationship dysfunction may improve outcomes. This study tested Perinatal Dyadic Psychotherapy (PDP), a dual-focused mother-infant intervention to prevent/decrease maternal postpartum depression and improve aspects of the mother-infant relationship related to child...

Objective: To systematically evaluate the literature on anxiety disorders during pregnancy. Data sources: MEDLINE, PsycINFO, and CINAHL were searched through October 2013 for original research studies published in English using combinations of the terms pregnancy, prenatal, or pregnancy outcomes; anxiety disorder; and generalized anxiety. Refere...

Healthy Start programs have made tremendous contributions toward improving the health of mothers and infants through the screening and early detection of perinatal depression. In a collaborative partnership with the Dallas Healthy Start (DHS) program, this pilot study investigated rates of follow-up to systematic referrals for the treatment of peri...