American College of Neuropsychopharmacology (ACNP): Annual Meeting Press Phone Briefing

Children exposed to maternal depression throughout their first year of life are more likely than nonexposed children to develop mental disorders by age 6 years, particularly if their oxytocin system functioning is disordered, according to findings from a longitudinal study of 155 mother-child pairs.

Of the children in the study who were exposed to depression throughout their first year, 60% exhibited mental disorders by age 6 years, compared with only 15% of those born to mothers with no depression or other mental disorders, Ruth Feldman, Ph.D., reported at the annual meeting of the American College of Neuropsychopharmacology.

Anxiety disorders and conduct disorders were the most common conditions exhibited by the exposed children, although depression is likely to show more prominently at the next assessment when the children are aged 9 or 10 years, noted Dr. Feldman of Bar-llan University in Ramat Gan, Israel.

The exposed children also demonstrated lower social engagement with their mothers, lower playfulness and creativity, and diminished social involvement, compared with non-exposed children, and also were less verbal and expressed less empathy to the pain, suffering, and embarrassment of strangers, she said at a press briefing held in conjunction with the meeting.

Like their mothers, who had an increased likelihood of having disordered oxytocin functioning and who produced less peripheral oxytocin in their saliva, the children were found to have disordered functioning of the oxytocin system and lower salivary oxytocin levels.

The depressed mothers, as well as their children, had a threefold greater prevalence of a risky variant (a variant with two "G" alleles) of the oxytocin receptor gene.

Of note, the 40% of exposed children who did not develop a mental disorder by age 6 years demonstrated more normal functioning of the oxytocin system, and they had better social engagements and higher levels of empathy, Dr. Feldman said.

Furthermore, these children were born to women who had less disruption of the oxytocin system and a less risky variant (the "A" allele variant) of the oxytocin receptor gene, as well as typical levels of oxytocin in their saliva.

These women, despite their depression, had better emotional skills and an improved capacity for providing adequate care, Dr. Feldman said.

It appears that a properly functioning oxytocin system offers protection against the effects of chronic maternal depression in some children, she added.

Study participants were recruited from a larger sample of nearly 2,000 mothers who participated in a mental health survey when they delivered, and again at 6 and 9 months after delivery. The oxytocin measures and in-home observations between parents and children were conducted in those who participated in this portion of the study. In addition to the 20% of participants who had depression throughout the first postpartum year, 4% were diagnosed with subclinical depression and 4% with subclinical anxiety, and 62% had no signs of mental disorders or symptoms during the first year.

The findings are of interest because the oxytocin system is an open system with cross-generation effects, Dr. Feldman said, explaining that if the system is known to be disrupted – in cases of postpartum depression, for example – oxytocin-related interventions could be provided. Mothers could be instructed to increase maternal touch and gaze, or intranasal oxytocin could be administered, for example.

Such interventions could provide a protective barrier against some of the psychopathologies associated with maternal depression. Indeed, intranasal oxytocin administration to both infants and fathers (whose oxytocin levels also were shown in this study to be lower in the setting of maternal depression), was shown to improve vagal tone, duration of social engagement behavior, and to markedly increase salivary oxytocin, Dr. Feldman concluded.

She reported no disclosures.

Children exposed to maternal depression throughout their first year of life are more likely than nonexposed children to develop mental disorders by age 6 years, particularly if their oxytocin system functioning is disordered, according to findings from a longitudinal study of 155 mother-child pairs.

Of the children in the study who were exposed to depression throughout their first year, 60% exhibited mental disorders by age 6 years, compared with only 15% of those born to mothers with no depression or other mental disorders, Ruth Feldman, Ph.D., reported at the annual meeting of the American College of Neuropsychopharmacology.

Anxiety disorders and conduct disorders were the most common conditions exhibited by the exposed children, although depression is likely to show more prominently at the next assessment when the children are aged 9 or 10 years, noted Dr. Feldman of Bar-llan University in Ramat Gan, Israel.

The exposed children also demonstrated lower social engagement with their mothers, lower playfulness and creativity, and diminished social involvement, compared with non-exposed children, and also were less verbal and expressed less empathy to the pain, suffering, and embarrassment of strangers, she said at a press briefing held in conjunction with the meeting.

Like their mothers, who had an increased likelihood of having disordered oxytocin functioning and who produced less peripheral oxytocin in their saliva, the children were found to have disordered functioning of the oxytocin system and lower salivary oxytocin levels.

The depressed mothers, as well as their children, had a threefold greater prevalence of a risky variant (a variant with two "G" alleles) of the oxytocin receptor gene.

Of note, the 40% of exposed children who did not develop a mental disorder by age 6 years demonstrated more normal functioning of the oxytocin system, and they had better social engagements and higher levels of empathy, Dr. Feldman said.

Furthermore, these children were born to women who had less disruption of the oxytocin system and a less risky variant (the "A" allele variant) of the oxytocin receptor gene, as well as typical levels of oxytocin in their saliva.

These women, despite their depression, had better emotional skills and an improved capacity for providing adequate care, Dr. Feldman said.

It appears that a properly functioning oxytocin system offers protection against the effects of chronic maternal depression in some children, she added.

Study participants were recruited from a larger sample of nearly 2,000 mothers who participated in a mental health survey when they delivered, and again at 6 and 9 months after delivery. The oxytocin measures and in-home observations between parents and children were conducted in those who participated in this portion of the study. In addition to the 20% of participants who had depression throughout the first postpartum year, 4% were diagnosed with subclinical depression and 4% with subclinical anxiety, and 62% had no signs of mental disorders or symptoms during the first year.

The findings are of interest because the oxytocin system is an open system with cross-generation effects, Dr. Feldman said, explaining that if the system is known to be disrupted – in cases of postpartum depression, for example – oxytocin-related interventions could be provided. Mothers could be instructed to increase maternal touch and gaze, or intranasal oxytocin could be administered, for example.

Such interventions could provide a protective barrier against some of the psychopathologies associated with maternal depression. Indeed, intranasal oxytocin administration to both infants and fathers (whose oxytocin levels also were shown in this study to be lower in the setting of maternal depression), was shown to improve vagal tone, duration of social engagement behavior, and to markedly increase salivary oxytocin, Dr. Feldman concluded.

She reported no disclosures.

Children exposed to maternal depression throughout their first year of life are more likely than nonexposed children to develop mental disorders by age 6 years, particularly if their oxytocin system functioning is disordered, according to findings from a longitudinal study of 155 mother-child pairs.

Of the children in the study who were exposed to depression throughout their first year, 60% exhibited mental disorders by age 6 years, compared with only 15% of those born to mothers with no depression or other mental disorders, Ruth Feldman, Ph.D., reported at the annual meeting of the American College of Neuropsychopharmacology.

Anxiety disorders and conduct disorders were the most common conditions exhibited by the exposed children, although depression is likely to show more prominently at the next assessment when the children are aged 9 or 10 years, noted Dr. Feldman of Bar-llan University in Ramat Gan, Israel.

The exposed children also demonstrated lower social engagement with their mothers, lower playfulness and creativity, and diminished social involvement, compared with non-exposed children, and also were less verbal and expressed less empathy to the pain, suffering, and embarrassment of strangers, she said at a press briefing held in conjunction with the meeting.

Like their mothers, who had an increased likelihood of having disordered oxytocin functioning and who produced less peripheral oxytocin in their saliva, the children were found to have disordered functioning of the oxytocin system and lower salivary oxytocin levels.

The depressed mothers, as well as their children, had a threefold greater prevalence of a risky variant (a variant with two "G" alleles) of the oxytocin receptor gene.

Of note, the 40% of exposed children who did not develop a mental disorder by age 6 years demonstrated more normal functioning of the oxytocin system, and they had better social engagements and higher levels of empathy, Dr. Feldman said.

Furthermore, these children were born to women who had less disruption of the oxytocin system and a less risky variant (the "A" allele variant) of the oxytocin receptor gene, as well as typical levels of oxytocin in their saliva.

These women, despite their depression, had better emotional skills and an improved capacity for providing adequate care, Dr. Feldman said.

It appears that a properly functioning oxytocin system offers protection against the effects of chronic maternal depression in some children, she added.

Study participants were recruited from a larger sample of nearly 2,000 mothers who participated in a mental health survey when they delivered, and again at 6 and 9 months after delivery. The oxytocin measures and in-home observations between parents and children were conducted in those who participated in this portion of the study. In addition to the 20% of participants who had depression throughout the first postpartum year, 4% were diagnosed with subclinical depression and 4% with subclinical anxiety, and 62% had no signs of mental disorders or symptoms during the first year.

The findings are of interest because the oxytocin system is an open system with cross-generation effects, Dr. Feldman said, explaining that if the system is known to be disrupted – in cases of postpartum depression, for example – oxytocin-related interventions could be provided. Mothers could be instructed to increase maternal touch and gaze, or intranasal oxytocin could be administered, for example.

Such interventions could provide a protective barrier against some of the psychopathologies associated with maternal depression. Indeed, intranasal oxytocin administration to both infants and fathers (whose oxytocin levels also were shown in this study to be lower in the setting of maternal depression), was shown to improve vagal tone, duration of social engagement behavior, and to markedly increase salivary oxytocin, Dr. Feldman concluded.

She reported no disclosures.

Evidence increasingly supports the notion of an autoimmune version of autism, and a new study involving specific autoantibodies that are directed at fetal brain tissue and that are found in a modest proportion of mothers with an autistic child, bolsters this theory.

In an earlier study, researchers at the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute at the University of California, Davis, demonstrated that 12% of women with an autistic child had "unusual" antibodies not present in mothers of typically developing children or in mothers of children with other intellectual developmental disorders. Since this raised the hypothesis that the antibodies, which were immunoglobulin G and thus cross the placenta, might be interacting with the fetal brain, leading to disregulation of development (and ultimately to autism), the researchers expanded their study by testing the effects of the antibodies in pregnant Rhesus monkeys.

They found that the offspring of monkeys injected with the IgG showed distinctive autistic characteristics, David G. Amaral, Ph.D., research director at the MIND Institute, reported at the annual meeting of the American College of Neuropsychopharmacology.

Specifically, pregnant monkeys were injected over a 6-week period with either purified autoantibodies to fetal brain proteins from the blood of the mothers of children with autism, or with autoantibodies from mothers with typically developing children. The offspring of the monkeys injected with autoantibodies from mothers with an autistic child – but not those injected with samples from mothers of typically developing children, demonstrated social impairment and stereotypic behaviors across several behavioral testing paradigms, Dr. Amaral said during a press briefing held in conjunction with the meeting.

The social impairment as detected by blinded investigators was subtle and did not reach the level of social impairment consistent with autism, but the stereotypy was profound.

"Given that (stereotypy) is one of the clinical signs of autism, we thought this was intriguing," he said, adding: "The ability to reproduce this effect in an animal model was strong evidence that these antibodies may have a disease-causing effect."

Dr. Amaral and his colleagues have replicated these findings in two independent studies, and are currently extending their analysis to a magnetic resonance imaging study of brain development in the treated monkeys. In other prior research by the MIND Institute investigators, a substantial proportion of boys with autism have been shown to have precocious brain growth during early childhood, and the MRI studies are designed to determine if similar patterns of brain development occur in the treated Rhesus monkeys.

If confirmed, the findings of this study could lead to screening tests for pregnant mothers, and perhaps to preventive measures for certain types of autism.

For example, if the researchers successfully segment an autoimmune version of autism as a uniform, homogenous version, unique preventive measures and treatment options could be developed, Dr. Amaral explained.

Currently an estimated 1% of children in the United States have an autism-spectrum disorder, and the probability of a mother with an autistic child having a subsequent child with autism is 25% if the subsequent child is a boy, and 9% if the child is a girl. The ability to test for antibodies against fetal brain tissue in pregnant mothers who already have a child with autism could lead to earlier recognition of the disorder in the second child, and to interventions that prevent or reduce the effects of the harmful antibodies, he said.

"What’s intriguing about this line of work is that in the majority of autism we don’t have a lot of targets for intervention or prevention, whereas if this were to be replicated and pan out, these antibodies are quite easy to identify," he added.

Dr. Amaral said he had no disclosures.

Evidence increasingly supports the notion of an autoimmune version of autism, and a new study involving specific autoantibodies that are directed at fetal brain tissue and that are found in a modest proportion of mothers with an autistic child, bolsters this theory.

In an earlier study, researchers at the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute at the University of California, Davis, demonstrated that 12% of women with an autistic child had "unusual" antibodies not present in mothers of typically developing children or in mothers of children with other intellectual developmental disorders. Since this raised the hypothesis that the antibodies, which were immunoglobulin G and thus cross the placenta, might be interacting with the fetal brain, leading to disregulation of development (and ultimately to autism), the researchers expanded their study by testing the effects of the antibodies in pregnant Rhesus monkeys.

They found that the offspring of monkeys injected with the IgG showed distinctive autistic characteristics, David G. Amaral, Ph.D., research director at the MIND Institute, reported at the annual meeting of the American College of Neuropsychopharmacology.

Specifically, pregnant monkeys were injected over a 6-week period with either purified autoantibodies to fetal brain proteins from the blood of the mothers of children with autism, or with autoantibodies from mothers with typically developing children. The offspring of the monkeys injected with autoantibodies from mothers with an autistic child – but not those injected with samples from mothers of typically developing children, demonstrated social impairment and stereotypic behaviors across several behavioral testing paradigms, Dr. Amaral said during a press briefing held in conjunction with the meeting.

The social impairment as detected by blinded investigators was subtle and did not reach the level of social impairment consistent with autism, but the stereotypy was profound.

"Given that (stereotypy) is one of the clinical signs of autism, we thought this was intriguing," he said, adding: "The ability to reproduce this effect in an animal model was strong evidence that these antibodies may have a disease-causing effect."

Dr. Amaral and his colleagues have replicated these findings in two independent studies, and are currently extending their analysis to a magnetic resonance imaging study of brain development in the treated monkeys. In other prior research by the MIND Institute investigators, a substantial proportion of boys with autism have been shown to have precocious brain growth during early childhood, and the MRI studies are designed to determine if similar patterns of brain development occur in the treated Rhesus monkeys.

If confirmed, the findings of this study could lead to screening tests for pregnant mothers, and perhaps to preventive measures for certain types of autism.

For example, if the researchers successfully segment an autoimmune version of autism as a uniform, homogenous version, unique preventive measures and treatment options could be developed, Dr. Amaral explained.

Currently an estimated 1% of children in the United States have an autism-spectrum disorder, and the probability of a mother with an autistic child having a subsequent child with autism is 25% if the subsequent child is a boy, and 9% if the child is a girl. The ability to test for antibodies against fetal brain tissue in pregnant mothers who already have a child with autism could lead to earlier recognition of the disorder in the second child, and to interventions that prevent or reduce the effects of the harmful antibodies, he said.

"What’s intriguing about this line of work is that in the majority of autism we don’t have a lot of targets for intervention or prevention, whereas if this were to be replicated and pan out, these antibodies are quite easy to identify," he added.

Dr. Amaral said he had no disclosures.

Evidence increasingly supports the notion of an autoimmune version of autism, and a new study involving specific autoantibodies that are directed at fetal brain tissue and that are found in a modest proportion of mothers with an autistic child, bolsters this theory.

In an earlier study, researchers at the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute at the University of California, Davis, demonstrated that 12% of women with an autistic child had "unusual" antibodies not present in mothers of typically developing children or in mothers of children with other intellectual developmental disorders. Since this raised the hypothesis that the antibodies, which were immunoglobulin G and thus cross the placenta, might be interacting with the fetal brain, leading to disregulation of development (and ultimately to autism), the researchers expanded their study by testing the effects of the antibodies in pregnant Rhesus monkeys.

They found that the offspring of monkeys injected with the IgG showed distinctive autistic characteristics, David G. Amaral, Ph.D., research director at the MIND Institute, reported at the annual meeting of the American College of Neuropsychopharmacology.

Specifically, pregnant monkeys were injected over a 6-week period with either purified autoantibodies to fetal brain proteins from the blood of the mothers of children with autism, or with autoantibodies from mothers with typically developing children. The offspring of the monkeys injected with autoantibodies from mothers with an autistic child – but not those injected with samples from mothers of typically developing children, demonstrated social impairment and stereotypic behaviors across several behavioral testing paradigms, Dr. Amaral said during a press briefing held in conjunction with the meeting.

The social impairment as detected by blinded investigators was subtle and did not reach the level of social impairment consistent with autism, but the stereotypy was profound.

"Given that (stereotypy) is one of the clinical signs of autism, we thought this was intriguing," he said, adding: "The ability to reproduce this effect in an animal model was strong evidence that these antibodies may have a disease-causing effect."

Dr. Amaral and his colleagues have replicated these findings in two independent studies, and are currently extending their analysis to a magnetic resonance imaging study of brain development in the treated monkeys. In other prior research by the MIND Institute investigators, a substantial proportion of boys with autism have been shown to have precocious brain growth during early childhood, and the MRI studies are designed to determine if similar patterns of brain development occur in the treated Rhesus monkeys.

If confirmed, the findings of this study could lead to screening tests for pregnant mothers, and perhaps to preventive measures for certain types of autism.

For example, if the researchers successfully segment an autoimmune version of autism as a uniform, homogenous version, unique preventive measures and treatment options could be developed, Dr. Amaral explained.

Currently an estimated 1% of children in the United States have an autism-spectrum disorder, and the probability of a mother with an autistic child having a subsequent child with autism is 25% if the subsequent child is a boy, and 9% if the child is a girl. The ability to test for antibodies against fetal brain tissue in pregnant mothers who already have a child with autism could lead to earlier recognition of the disorder in the second child, and to interventions that prevent or reduce the effects of the harmful antibodies, he said.

"What’s intriguing about this line of work is that in the majority of autism we don’t have a lot of targets for intervention or prevention, whereas if this were to be replicated and pan out, these antibodies are quite easy to identify," he added.

Dr. Amaral said he had no disclosures.

Sex differences in the risk of developing co-occurring depression and cardiovascular disease in adulthood may result from disruptions during the development of the stress response circuitry in the fetal brain, according to findings from a longitudinal cohort study.

Specifically, fetal exposure to maternal immune activation resulting from preeclampsia or conditions that restricted fetal growth was shown in the 40-year study to be significantly associated the co-occurrence of major depressive disorder and cardiovascular diseases in adult women, Jill M. Goldstein, Ph.D., said during a press briefing held in conjunction with the annual meeting of the American College of Neuropsychopharmacology.

The findings have implications for the development of early interventions in adults who may be predisposed to this common co-occurrence, said Dr. Goldstein, professor of psychiatry and medicine at Harvard Medical School, Boston.

This is particularly important because co-occurring depression and cardiovascular disease, with a prevalence of about 20%, is predicted to be the leading cause of disability worldwide by 2020, she noted.

"Women are at greater risk than men, and we don’t understand why," said Dr. Goldstein, also director of research at the Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital, Boston.

However, given that stress response circuitry involves a "perfect storm" of brain regions with some of the most striking sex differences, which both develop and function differently in men and women, and which regulate mood and cardiac function, Dr. Goldstein and her colleagues hypothesized that disruptions in this circuitry during fetal development might result in the sex-specific vulnerabilities to co-occurring depression and cardiovascular disease later in life.

Indeed, functional magnetic resonance imaging studies in 60 of the 295 adults with fetal exposure to maternal immune activation and their nonexposed siblings in the study cohort showed that fetal exposure was significantly associated with later sex-specific deficits on several measures of stress response brain activity, endocrine function, and autonomic nervous system function.

"Women are at greater risk than men, and we don’t understand why."

For example, the functional MRI scans, conducted in 30 exposed and 30 nonexposed subjects who viewed images with negative valence/high arousal vs. neutral valence/low arousal stimuli to assess stress response, indicated that exposure was significantly associated with low high-frequency R-R interval variability (HF-RRV) in response to stress 40 years later.

The association was threefold greater in those with major depressive disorder than in those without major depressive disorder, and exposed women had a significantly higher risk of comorbidity of major depressive disorder and HF-RRV, compared with men (relative risk 1.38). This comorbidity was significantly associated with tumor necrosis factor–alpha levels in the maternal sera of exposed women, compared with nonexposed women.

Also, significantly greater blood oxygen level-dependent (BOLD) signal changes in the hippocampus, anterior hypothalamus, and anterior cingulate cortex, and hypoactivity in the orbitofrontal cortex occurred in response to stress in fetal-exposed women. Only hypoactivity in the orbitofrontal cortex was significantly increased in exposed men.

Fetal-exposed women with major depressive disorder had the greatest hyperactivity in the anterior hypothalamus, and the greatest hypoactivity in the anterior cingulate cortex, the orbitofrontal cortex, and the hippocampus. This suggests hyperarousal, and lack of cortical and hippocampus control in fetal-exposed women who have major depressive disorder, Dr. Goldstein explained.

Significant associations also were seen between important stress response brain regions and loss of parasympathetic cardiac regulation, she noted.

Higher levels of TNF-alpha/interleukin-10 and interleukin-6 were significantly associated with lower BOLD changes in the hippocampus and anterior cingulate cortex, and these co-occurred with disruption in the hormones that were collected during the MRI scans (and timed to the stress response), including dehydroepiandrosterone or DHEAS, testosterone, estradiol or E2 (which were lowered), and progesterone, and cortisol (which increased) in response to stress.

This study was an expansion of a National Institutes of Health study initiated in the 1950s. Mothers were followed through pregnancy, their sera were stored at the NIH, and offspring were followed for 7 years. For this part of the study, Dr. Goldstein and her colleagues rerecruited exposed offspring and their nonexposed siblings, and followed them for 20 years, into their late 40s.

The findings suggest shared fetal risk factors for the co-occurrence of major depressive disorder and cardiovascular disease risk in women, and they suggest that fetal programming of the stress response circuitry might help explain sex-specific vulnerability to major depressive disorder and cardiovascular disease risk, Dr. Goldstein said.

Understanding the early signals and pathways could lead to early interventions that could lessen disability and perhaps even prevent the illnesses, she concluded.

This study was funded by the National Institute of Mental Health and the NIH Office of Research on Women’s Health. Dr. Goldstein reported no disclosures.

Sex differences in the risk of developing co-occurring depression and cardiovascular disease in adulthood may result from disruptions during the development of the stress response circuitry in the fetal brain, according to findings from a longitudinal cohort study.

Specifically, fetal exposure to maternal immune activation resulting from preeclampsia or conditions that restricted fetal growth was shown in the 40-year study to be significantly associated the co-occurrence of major depressive disorder and cardiovascular diseases in adult women, Jill M. Goldstein, Ph.D., said during a press briefing held in conjunction with the annual meeting of the American College of Neuropsychopharmacology.

The findings have implications for the development of early interventions in adults who may be predisposed to this common co-occurrence, said Dr. Goldstein, professor of psychiatry and medicine at Harvard Medical School, Boston.

This is particularly important because co-occurring depression and cardiovascular disease, with a prevalence of about 20%, is predicted to be the leading cause of disability worldwide by 2020, she noted.

"Women are at greater risk than men, and we don’t understand why," said Dr. Goldstein, also director of research at the Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital, Boston.

However, given that stress response circuitry involves a "perfect storm" of brain regions with some of the most striking sex differences, which both develop and function differently in men and women, and which regulate mood and cardiac function, Dr. Goldstein and her colleagues hypothesized that disruptions in this circuitry during fetal development might result in the sex-specific vulnerabilities to co-occurring depression and cardiovascular disease later in life.

Indeed, functional magnetic resonance imaging studies in 60 of the 295 adults with fetal exposure to maternal immune activation and their nonexposed siblings in the study cohort showed that fetal exposure was significantly associated with later sex-specific deficits on several measures of stress response brain activity, endocrine function, and autonomic nervous system function.

"Women are at greater risk than men, and we don’t understand why."

For example, the functional MRI scans, conducted in 30 exposed and 30 nonexposed subjects who viewed images with negative valence/high arousal vs. neutral valence/low arousal stimuli to assess stress response, indicated that exposure was significantly associated with low high-frequency R-R interval variability (HF-RRV) in response to stress 40 years later.

The association was threefold greater in those with major depressive disorder than in those without major depressive disorder, and exposed women had a significantly higher risk of comorbidity of major depressive disorder and HF-RRV, compared with men (relative risk 1.38). This comorbidity was significantly associated with tumor necrosis factor–alpha levels in the maternal sera of exposed women, compared with nonexposed women.

Also, significantly greater blood oxygen level-dependent (BOLD) signal changes in the hippocampus, anterior hypothalamus, and anterior cingulate cortex, and hypoactivity in the orbitofrontal cortex occurred in response to stress in fetal-exposed women. Only hypoactivity in the orbitofrontal cortex was significantly increased in exposed men.

Fetal-exposed women with major depressive disorder had the greatest hyperactivity in the anterior hypothalamus, and the greatest hypoactivity in the anterior cingulate cortex, the orbitofrontal cortex, and the hippocampus. This suggests hyperarousal, and lack of cortical and hippocampus control in fetal-exposed women who have major depressive disorder, Dr. Goldstein explained.

Significant associations also were seen between important stress response brain regions and loss of parasympathetic cardiac regulation, she noted.

Higher levels of TNF-alpha/interleukin-10 and interleukin-6 were significantly associated with lower BOLD changes in the hippocampus and anterior cingulate cortex, and these co-occurred with disruption in the hormones that were collected during the MRI scans (and timed to the stress response), including dehydroepiandrosterone or DHEAS, testosterone, estradiol or E2 (which were lowered), and progesterone, and cortisol (which increased) in response to stress.

This study was an expansion of a National Institutes of Health study initiated in the 1950s. Mothers were followed through pregnancy, their sera were stored at the NIH, and offspring were followed for 7 years. For this part of the study, Dr. Goldstein and her colleagues rerecruited exposed offspring and their nonexposed siblings, and followed them for 20 years, into their late 40s.

The findings suggest shared fetal risk factors for the co-occurrence of major depressive disorder and cardiovascular disease risk in women, and they suggest that fetal programming of the stress response circuitry might help explain sex-specific vulnerability to major depressive disorder and cardiovascular disease risk, Dr. Goldstein said.

Understanding the early signals and pathways could lead to early interventions that could lessen disability and perhaps even prevent the illnesses, she concluded.

This study was funded by the National Institute of Mental Health and the NIH Office of Research on Women’s Health. Dr. Goldstein reported no disclosures.

Sex differences in the risk of developing co-occurring depression and cardiovascular disease in adulthood may result from disruptions during the development of the stress response circuitry in the fetal brain, according to findings from a longitudinal cohort study.

Specifically, fetal exposure to maternal immune activation resulting from preeclampsia or conditions that restricted fetal growth was shown in the 40-year study to be significantly associated the co-occurrence of major depressive disorder and cardiovascular diseases in adult women, Jill M. Goldstein, Ph.D., said during a press briefing held in conjunction with the annual meeting of the American College of Neuropsychopharmacology.

The findings have implications for the development of early interventions in adults who may be predisposed to this common co-occurrence, said Dr. Goldstein, professor of psychiatry and medicine at Harvard Medical School, Boston.

This is particularly important because co-occurring depression and cardiovascular disease, with a prevalence of about 20%, is predicted to be the leading cause of disability worldwide by 2020, she noted.

"Women are at greater risk than men, and we don’t understand why," said Dr. Goldstein, also director of research at the Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital, Boston.

However, given that stress response circuitry involves a "perfect storm" of brain regions with some of the most striking sex differences, which both develop and function differently in men and women, and which regulate mood and cardiac function, Dr. Goldstein and her colleagues hypothesized that disruptions in this circuitry during fetal development might result in the sex-specific vulnerabilities to co-occurring depression and cardiovascular disease later in life.

Indeed, functional magnetic resonance imaging studies in 60 of the 295 adults with fetal exposure to maternal immune activation and their nonexposed siblings in the study cohort showed that fetal exposure was significantly associated with later sex-specific deficits on several measures of stress response brain activity, endocrine function, and autonomic nervous system function.

"Women are at greater risk than men, and we don’t understand why."

For example, the functional MRI scans, conducted in 30 exposed and 30 nonexposed subjects who viewed images with negative valence/high arousal vs. neutral valence/low arousal stimuli to assess stress response, indicated that exposure was significantly associated with low high-frequency R-R interval variability (HF-RRV) in response to stress 40 years later.

The association was threefold greater in those with major depressive disorder than in those without major depressive disorder, and exposed women had a significantly higher risk of comorbidity of major depressive disorder and HF-RRV, compared with men (relative risk 1.38). This comorbidity was significantly associated with tumor necrosis factor–alpha levels in the maternal sera of exposed women, compared with nonexposed women.

Also, significantly greater blood oxygen level-dependent (BOLD) signal changes in the hippocampus, anterior hypothalamus, and anterior cingulate cortex, and hypoactivity in the orbitofrontal cortex occurred in response to stress in fetal-exposed women. Only hypoactivity in the orbitofrontal cortex was significantly increased in exposed men.

Fetal-exposed women with major depressive disorder had the greatest hyperactivity in the anterior hypothalamus, and the greatest hypoactivity in the anterior cingulate cortex, the orbitofrontal cortex, and the hippocampus. This suggests hyperarousal, and lack of cortical and hippocampus control in fetal-exposed women who have major depressive disorder, Dr. Goldstein explained.

Significant associations also were seen between important stress response brain regions and loss of parasympathetic cardiac regulation, she noted.

Higher levels of TNF-alpha/interleukin-10 and interleukin-6 were significantly associated with lower BOLD changes in the hippocampus and anterior cingulate cortex, and these co-occurred with disruption in the hormones that were collected during the MRI scans (and timed to the stress response), including dehydroepiandrosterone or DHEAS, testosterone, estradiol or E2 (which were lowered), and progesterone, and cortisol (which increased) in response to stress.

This study was an expansion of a National Institutes of Health study initiated in the 1950s. Mothers were followed through pregnancy, their sera were stored at the NIH, and offspring were followed for 7 years. For this part of the study, Dr. Goldstein and her colleagues rerecruited exposed offspring and their nonexposed siblings, and followed them for 20 years, into their late 40s.

The findings suggest shared fetal risk factors for the co-occurrence of major depressive disorder and cardiovascular disease risk in women, and they suggest that fetal programming of the stress response circuitry might help explain sex-specific vulnerability to major depressive disorder and cardiovascular disease risk, Dr. Goldstein said.

Understanding the early signals and pathways could lead to early interventions that could lessen disability and perhaps even prevent the illnesses, she concluded.

This study was funded by the National Institute of Mental Health and the NIH Office of Research on Women’s Health. Dr. Goldstein reported no disclosures.