Dannah Hirsch, MD, MPH

Kate, age 14, is referred for follow-up treatment of depression after she impulsively swallowed a bottle of acetaminophen. She says she is in academic trouble and has no friends. Kate describes her childhood as mostly happy except for her parents’ arguments. Her medical history indicates she began developing breasts at age 10 and had her first menstrual period at age 12.

Her father is largely absent, traveling and working long hours. Her mother developed postpartum depression and stopped working after Kate’s younger brother was born.

Girls and boys show similar depression risks during childhood, but girls are twice as likely as boys to become clinically depressed after puberty. The key to treating depression in teen girls is to recognize that brain development and fluctuating hormones can influence behavior in ways that confuse them and the people around them. Successfully treating teen girls’ depression may require a gender-specific approach.

3 stages of brain development

Fetal differentiation. All brains start out with female-type brain circuits. At 8 weeks of fetal life, however, tiny testicles in the male begin to produce large amounts of testosterone, which changes the brain and body to male. Thus, sex-specific genes and hormones guide aspects of the first phase of brain development.¹

Table 1

Female hormonal development: Gestation to puberty

Infantile puberty and the second phase of brain development begin in early childhood, as the ovaries and testicles start to produce large amounts of estrogen and testosterone soon after birth.

Puberty launches the final brain development phase. Up to 2 years before menstruation begins, pulsatile gonadotropin-releasing hormone cells in the hypothalamus wake up and start stimulating the ovaries to produce estrogen, thrusting the girl brain into puberty (Figure). The teen girl brain begins to experience not only estrogen surges from the ovary but progesterone and testosterone surges as well.

Although brain size and basic circuitry are mostly set by age 5, puberty stimulates new brain cells and increases myelin production.² Faster myelinated connections between emotionally impulsive limbic brain areas such as the amygdala and sensible, cognitive areas such as the prefrontal cortex are not finished until the early 20s.³

Hormonal changes at puberty

The female brain is remodeled during puberty, leading to sexually dimorphic brain activation and development that further differentiates it from the male brain.⁴

Estrogen surges are associated with increased production of neurohormones and neurochemicals, such as:

• oxytocin, which reinforces social bonding and intimacy
• dopamine, which stimulates motivation and pleasure circuits in the brain.

Hormonal changes and brain development alter gene expression and affect neurodevelopment. These events may trigger a first depression in pubertal girls with a family history of mood disorder (Table 1).^4,5 Although menarche has begun at an average age of 12 in the United States for decades, the most recent National Health and Examination Survey (NHANES) shows puberty onset in girls is occurring earlier (Table 2).^6-9

Tanner stage—a measure of pubertal status—is a more accurate predictor of depression in teen girls than age.¹⁰ Pubertal transition to Tanner stage 3 (development of pubic and axillary hair and breast buds) is associated with a sharp increase in depression rates. Girls at stage 3 and higher are approximately 3 times more likely to be depressed than girls at stages 1 or 2.¹¹

Pubic hair, breast development, and menstruation are markers for underlying hormonal changes (Table 3).^4,5 The onset of estrogen, progesterone, and testosterone surges closely correlates with the difference in depression rates between pre- and postpubertal girls.¹² After estrogen and progesterone surges begin at puberty, negative emotions exert an increased activating effect on the female brain,¹³ and social stressors more deeply affect girls than they do boys. This may explain why girls are more susceptible to depression when a friendship fails.¹⁴

CASE CONTINUED: Boy troubles

Kate tells you that in 9th grade she and her best friend, Ellen, would talk about boys for hours after school and try on sexually provocative outfits. They both liked Matt, a 10th grader, so when he asked Kate out, Ellen stopped speaking to her. Kate and Matt began some heavy petting, and Kate said she felt selfish and guilty about hurting Ellen. But when girls at school began spreading rumors that Kate was a “slut,” Kate blamed Ellen and told her, “I hate you!”

Soon after, Matt broke up with Kate. Distraught, she dreaded going to school and cried in her room at night for several weeks. She became chronically tired and had difficulty concentrating in class. She ruminated about losing Matt and worried that she was too fat, too ugly, or too flat-chested. She missed Ellen and felt no one liked her.

Table 2

Puberty’s developmental milestones in U.S. girls (averages)

Figure Hypothalamic-pituitary-ovarian axis: Turned on at puberty in girls

Puberty onset stimulates depression in genetically vulnerable girls; more likely after Tanner stage 3 (development of pubic and axillary hair and breast buds).

Male vs female teen brains

Depression after a relationship failure in teen girls often begins with ruminative thoughts about her flaws, mistakes, or appearance. These negative thoughts may preoccupy her day and night. Teen girls often feel confused by contradictory social pressures to look and dress provocatively but resist having sex. A sexual encounter can trigger shame and fear.

Although clinical and developmental studies indicate that teen girls respond more dramatically to relationship troubles than boys, the brain and hormone differences responsible for these effects remain unclear. Male hormones hugely increase in boys at puberty—up to 25-fold between ages 9 and 15—but do not cycle. Male brains do not have the same capacity as female brains to respond to cyclical hormonal activity because exposure to androgens during fetal development eliminates this ability. The fetal testosterone surge causes the area associated with sexual pursuit to double in the male brain.

Outside of fertility considerations, Baron-Cohen et al¹⁵ suggest that male brain circuits have been formed by fetal testosterone to focus more on systematization—which emphasizes figuring out how things work and performing tasks—rather than empathy and bonding in relationships. This difference has been shown in neuroimaging studies comparing the genders’ attentional systems.^16,17 In contrast to the systematizing male brain, female brains are more likely to activate the mirror neuron system—the area required for empathizing.¹⁸

Female brains, of course, respond to cyclical hormonal activity. However, the regular monthly waves of estrogen and progesterone do not affect all female brains the same. A subset of women who experience premenstrual dysphoric disorder appear to have brains that trigger depressed moods and irritability during the last 2 weeks of the menstrual cycle.¹⁹ A genetic difference in these women is suspected as the culprit; these genes may affect the way their brains metabolize progesterone.

CASE CONTINUED: An overdose of stress

Kate’s poor concentration lingered, and her grades continued to drop. She tells you her parents were having marital problems and she did not want to bother them with her difficulties. Two days before her period was due, she learned she had failed 2 classes. That night, as she got some acetaminophen for a headache, she impulsively took the rest of the bottle.

After swallowing the pills, Kate panicked. She forced herself to vomit and tearfully told her parents what she had done. They took her to the emergency room, where she was medically stabilized, evaluated by a psychiatrist, and referred to you for outpatient treatment.

Treatment recommendations

A combination of factors—genetic, hormonal, and neurodevelopmental—probably contributed to Kate’s acute depressed mood and overdose. Thus, to treat depression in adolescent girls, emerging evidence supports:

• stabilizing hormonal fluctuations such as rapidly falling progesterone just before the start of menstrual periods with an extended-cycle contraceptive (we would try an ethinyl estradiol/levonorgestrel combination such as Seasonale^®)
• treating depressive symptoms with a selective serotonin reuptake inhibitor such as citalopram, 10 mg once daily, with careful monitoring for suicidal thoughts or behavior
• providing tools to manage stress and impulsive behavior through weekly psychotherapy (such as cognitive-behavioral therapy, dialectical behavioral therapy, or supportive therapy).

Genetic factors. Kate’s mother’s history of postpartum depression suggests genetic risk for Kate. Studies have found that the expression of particular genes—such as the serotonin transporter (5-HTT) gene—may be associated with depression. Staley et al²⁰ found that depressed women show a significantly greater decrease in 5-HTT availability in the diencephalon (forebrain region containing the thalamus, hypothalamus, and part of the pituitary gland) when compared with healthy women and depressed men.

Table 3

3 stages of girls’ gonadal development

Although men and women have the same 5-HTT gene, women may possess a gender-specific factor—such as estrogen or progesterone—that differentially alters this and other genes’ expression in women with depression. Individuals who carry a short version of the gene may be at particular risk of becoming depressed when exposed to stressful life events.

Caspi et al²¹ found a polymorphism in the 5-HTT gene on chromosome 17 that can manifest differentially based on environmental factors. In this study, individuals with 2 copies of the long version of this gene were relatively resistant to stressful life events, whereas those with 1 or 2 copies of the short version were highly sensitive to stressful life events. The depression rate in short-gene individuals was:

• 9% in those who had not experienced stressful life events
• nearly 40% in those who had experienced ≥4 stressful life events.

Hormonal and stress factors. Stress responsiveness becomes sexually dimorphic at puberty. Compared with men, women are:

• at greater risk after puberty for heightened stress responsiveness, which is associated with major depressive disorder
• 3 times more likely to develop depression after a stressful life event.²²

Women’s and men’s different biological responses to stress might be related to the gender-specific hormones that emerge during puberty. Kate could be at increased risk for depression—especially immediately before her period—if she inherited a stress-sensitive gene and now has increased stress sensitivity triggered by the hormones of puberty.²³

Neurodevelopmental factors. Dorsolateral prefrontal cortex circuits associated with making good decisions and weighing the consequences of actions are immature in the adolescent and the last part of the brain to undergo myelination.^24-26 Teens are well-known for erratic, emotionally driven behaviors.^27,28 Kate’s impulsive overdose exemplifies the consequences of emotional reactivity without the benefit of inhibitory mature brain connections.

Related resources

• Brizendine L. Teen girl brain. In: The female brain. New York: Morgan Road Books; 2006:31-56. www.thefemalebrain.com.
• Strauch B. The primal teen: what discoveries about the teenage brain tell us about our kids. New York: Doubleday; 2003.
• Harter S. Self and identity development. In: Feldman S, Elliott G, eds. At the threshold: the developing adolescent. Cambridge, MA: Harvard University Press; 1990:352-87.

Drug brand names

• Ethinyl estradiol/levonorgestrel • Seasonale

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Kate, age 14, is referred for follow-up treatment of depression after she impulsively swallowed a bottle of acetaminophen. She says she is in academic trouble and has no friends. Kate describes her childhood as mostly happy except for her parents’ arguments. Her medical history indicates she began developing breasts at age 10 and had her first menstrual period at age 12.

Her father is largely absent, traveling and working long hours. Her mother developed postpartum depression and stopped working after Kate’s younger brother was born.

Girls and boys show similar depression risks during childhood, but girls are twice as likely as boys to become clinically depressed after puberty. The key to treating depression in teen girls is to recognize that brain development and fluctuating hormones can influence behavior in ways that confuse them and the people around them. Successfully treating teen girls’ depression may require a gender-specific approach.

3 stages of brain development

Fetal differentiation. All brains start out with female-type brain circuits. At 8 weeks of fetal life, however, tiny testicles in the male begin to produce large amounts of testosterone, which changes the brain and body to male. Thus, sex-specific genes and hormones guide aspects of the first phase of brain development.¹

Table 1

Female hormonal development: Gestation to puberty

Infantile puberty and the second phase of brain development begin in early childhood, as the ovaries and testicles start to produce large amounts of estrogen and testosterone soon after birth.

Puberty launches the final brain development phase. Up to 2 years before menstruation begins, pulsatile gonadotropin-releasing hormone cells in the hypothalamus wake up and start stimulating the ovaries to produce estrogen, thrusting the girl brain into puberty (Figure). The teen girl brain begins to experience not only estrogen surges from the ovary but progesterone and testosterone surges as well.

Although brain size and basic circuitry are mostly set by age 5, puberty stimulates new brain cells and increases myelin production.² Faster myelinated connections between emotionally impulsive limbic brain areas such as the amygdala and sensible, cognitive areas such as the prefrontal cortex are not finished until the early 20s.³

Hormonal changes at puberty

The female brain is remodeled during puberty, leading to sexually dimorphic brain activation and development that further differentiates it from the male brain.⁴

Estrogen surges are associated with increased production of neurohormones and neurochemicals, such as:

• oxytocin, which reinforces social bonding and intimacy
• dopamine, which stimulates motivation and pleasure circuits in the brain.

Hormonal changes and brain development alter gene expression and affect neurodevelopment. These events may trigger a first depression in pubertal girls with a family history of mood disorder (Table 1).^4,5 Although menarche has begun at an average age of 12 in the United States for decades, the most recent National Health and Examination Survey (NHANES) shows puberty onset in girls is occurring earlier (Table 2).^6-9

Tanner stage—a measure of pubertal status—is a more accurate predictor of depression in teen girls than age.¹⁰ Pubertal transition to Tanner stage 3 (development of pubic and axillary hair and breast buds) is associated with a sharp increase in depression rates. Girls at stage 3 and higher are approximately 3 times more likely to be depressed than girls at stages 1 or 2.¹¹

Pubic hair, breast development, and menstruation are markers for underlying hormonal changes (Table 3).^4,5 The onset of estrogen, progesterone, and testosterone surges closely correlates with the difference in depression rates between pre- and postpubertal girls.¹² After estrogen and progesterone surges begin at puberty, negative emotions exert an increased activating effect on the female brain,¹³ and social stressors more deeply affect girls than they do boys. This may explain why girls are more susceptible to depression when a friendship fails.¹⁴

CASE CONTINUED: Boy troubles

Kate tells you that in 9th grade she and her best friend, Ellen, would talk about boys for hours after school and try on sexually provocative outfits. They both liked Matt, a 10th grader, so when he asked Kate out, Ellen stopped speaking to her. Kate and Matt began some heavy petting, and Kate said she felt selfish and guilty about hurting Ellen. But when girls at school began spreading rumors that Kate was a “slut,” Kate blamed Ellen and told her, “I hate you!”

Soon after, Matt broke up with Kate. Distraught, she dreaded going to school and cried in her room at night for several weeks. She became chronically tired and had difficulty concentrating in class. She ruminated about losing Matt and worried that she was too fat, too ugly, or too flat-chested. She missed Ellen and felt no one liked her.

Table 2

Puberty’s developmental milestones in U.S. girls (averages)

Figure Hypothalamic-pituitary-ovarian axis: Turned on at puberty in girls

Puberty onset stimulates depression in genetically vulnerable girls; more likely after Tanner stage 3 (development of pubic and axillary hair and breast buds).

Male vs female teen brains

Depression after a relationship failure in teen girls often begins with ruminative thoughts about her flaws, mistakes, or appearance. These negative thoughts may preoccupy her day and night. Teen girls often feel confused by contradictory social pressures to look and dress provocatively but resist having sex. A sexual encounter can trigger shame and fear.

Although clinical and developmental studies indicate that teen girls respond more dramatically to relationship troubles than boys, the brain and hormone differences responsible for these effects remain unclear. Male hormones hugely increase in boys at puberty—up to 25-fold between ages 9 and 15—but do not cycle. Male brains do not have the same capacity as female brains to respond to cyclical hormonal activity because exposure to androgens during fetal development eliminates this ability. The fetal testosterone surge causes the area associated with sexual pursuit to double in the male brain.

Outside of fertility considerations, Baron-Cohen et al¹⁵ suggest that male brain circuits have been formed by fetal testosterone to focus more on systematization—which emphasizes figuring out how things work and performing tasks—rather than empathy and bonding in relationships. This difference has been shown in neuroimaging studies comparing the genders’ attentional systems.^16,17 In contrast to the systematizing male brain, female brains are more likely to activate the mirror neuron system—the area required for empathizing.¹⁸

Female brains, of course, respond to cyclical hormonal activity. However, the regular monthly waves of estrogen and progesterone do not affect all female brains the same. A subset of women who experience premenstrual dysphoric disorder appear to have brains that trigger depressed moods and irritability during the last 2 weeks of the menstrual cycle.¹⁹ A genetic difference in these women is suspected as the culprit; these genes may affect the way their brains metabolize progesterone.

CASE CONTINUED: An overdose of stress

Kate’s poor concentration lingered, and her grades continued to drop. She tells you her parents were having marital problems and she did not want to bother them with her difficulties. Two days before her period was due, she learned she had failed 2 classes. That night, as she got some acetaminophen for a headache, she impulsively took the rest of the bottle.

After swallowing the pills, Kate panicked. She forced herself to vomit and tearfully told her parents what she had done. They took her to the emergency room, where she was medically stabilized, evaluated by a psychiatrist, and referred to you for outpatient treatment.

Treatment recommendations

A combination of factors—genetic, hormonal, and neurodevelopmental—probably contributed to Kate’s acute depressed mood and overdose. Thus, to treat depression in adolescent girls, emerging evidence supports:

• stabilizing hormonal fluctuations such as rapidly falling progesterone just before the start of menstrual periods with an extended-cycle contraceptive (we would try an ethinyl estradiol/levonorgestrel combination such as Seasonale^®)
• treating depressive symptoms with a selective serotonin reuptake inhibitor such as citalopram, 10 mg once daily, with careful monitoring for suicidal thoughts or behavior
• providing tools to manage stress and impulsive behavior through weekly psychotherapy (such as cognitive-behavioral therapy, dialectical behavioral therapy, or supportive therapy).

Genetic factors. Kate’s mother’s history of postpartum depression suggests genetic risk for Kate. Studies have found that the expression of particular genes—such as the serotonin transporter (5-HTT) gene—may be associated with depression. Staley et al²⁰ found that depressed women show a significantly greater decrease in 5-HTT availability in the diencephalon (forebrain region containing the thalamus, hypothalamus, and part of the pituitary gland) when compared with healthy women and depressed men.

Table 3

3 stages of girls’ gonadal development

Although men and women have the same 5-HTT gene, women may possess a gender-specific factor—such as estrogen or progesterone—that differentially alters this and other genes’ expression in women with depression. Individuals who carry a short version of the gene may be at particular risk of becoming depressed when exposed to stressful life events.

Caspi et al²¹ found a polymorphism in the 5-HTT gene on chromosome 17 that can manifest differentially based on environmental factors. In this study, individuals with 2 copies of the long version of this gene were relatively resistant to stressful life events, whereas those with 1 or 2 copies of the short version were highly sensitive to stressful life events. The depression rate in short-gene individuals was:

• 9% in those who had not experienced stressful life events
• nearly 40% in those who had experienced ≥4 stressful life events.

Hormonal and stress factors. Stress responsiveness becomes sexually dimorphic at puberty. Compared with men, women are:

• at greater risk after puberty for heightened stress responsiveness, which is associated with major depressive disorder
• 3 times more likely to develop depression after a stressful life event.²²

Women’s and men’s different biological responses to stress might be related to the gender-specific hormones that emerge during puberty. Kate could be at increased risk for depression—especially immediately before her period—if she inherited a stress-sensitive gene and now has increased stress sensitivity triggered by the hormones of puberty.²³

Neurodevelopmental factors. Dorsolateral prefrontal cortex circuits associated with making good decisions and weighing the consequences of actions are immature in the adolescent and the last part of the brain to undergo myelination.^24-26 Teens are well-known for erratic, emotionally driven behaviors.^27,28 Kate’s impulsive overdose exemplifies the consequences of emotional reactivity without the benefit of inhibitory mature brain connections.

Related resources

• Brizendine L. Teen girl brain. In: The female brain. New York: Morgan Road Books; 2006:31-56. www.thefemalebrain.com.
• Strauch B. The primal teen: what discoveries about the teenage brain tell us about our kids. New York: Doubleday; 2003.
• Harter S. Self and identity development. In: Feldman S, Elliott G, eds. At the threshold: the developing adolescent. Cambridge, MA: Harvard University Press; 1990:352-87.

Drug brand names

• Ethinyl estradiol/levonorgestrel • Seasonale

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Kate, age 14, is referred for follow-up treatment of depression after she impulsively swallowed a bottle of acetaminophen. She says she is in academic trouble and has no friends. Kate describes her childhood as mostly happy except for her parents’ arguments. Her medical history indicates she began developing breasts at age 10 and had her first menstrual period at age 12.

Her father is largely absent, traveling and working long hours. Her mother developed postpartum depression and stopped working after Kate’s younger brother was born.

Girls and boys show similar depression risks during childhood, but girls are twice as likely as boys to become clinically depressed after puberty. The key to treating depression in teen girls is to recognize that brain development and fluctuating hormones can influence behavior in ways that confuse them and the people around them. Successfully treating teen girls’ depression may require a gender-specific approach.

3 stages of brain development

Fetal differentiation. All brains start out with female-type brain circuits. At 8 weeks of fetal life, however, tiny testicles in the male begin to produce large amounts of testosterone, which changes the brain and body to male. Thus, sex-specific genes and hormones guide aspects of the first phase of brain development.¹

Table 1

Female hormonal development: Gestation to puberty

Infantile puberty and the second phase of brain development begin in early childhood, as the ovaries and testicles start to produce large amounts of estrogen and testosterone soon after birth.

Puberty launches the final brain development phase. Up to 2 years before menstruation begins, pulsatile gonadotropin-releasing hormone cells in the hypothalamus wake up and start stimulating the ovaries to produce estrogen, thrusting the girl brain into puberty (Figure). The teen girl brain begins to experience not only estrogen surges from the ovary but progesterone and testosterone surges as well.

Although brain size and basic circuitry are mostly set by age 5, puberty stimulates new brain cells and increases myelin production.² Faster myelinated connections between emotionally impulsive limbic brain areas such as the amygdala and sensible, cognitive areas such as the prefrontal cortex are not finished until the early 20s.³

Hormonal changes at puberty

The female brain is remodeled during puberty, leading to sexually dimorphic brain activation and development that further differentiates it from the male brain.⁴

Estrogen surges are associated with increased production of neurohormones and neurochemicals, such as:

• oxytocin, which reinforces social bonding and intimacy
• dopamine, which stimulates motivation and pleasure circuits in the brain.

Hormonal changes and brain development alter gene expression and affect neurodevelopment. These events may trigger a first depression in pubertal girls with a family history of mood disorder (Table 1).^4,5 Although menarche has begun at an average age of 12 in the United States for decades, the most recent National Health and Examination Survey (NHANES) shows puberty onset in girls is occurring earlier (Table 2).^6-9

Tanner stage—a measure of pubertal status—is a more accurate predictor of depression in teen girls than age.¹⁰ Pubertal transition to Tanner stage 3 (development of pubic and axillary hair and breast buds) is associated with a sharp increase in depression rates. Girls at stage 3 and higher are approximately 3 times more likely to be depressed than girls at stages 1 or 2.¹¹

Pubic hair, breast development, and menstruation are markers for underlying hormonal changes (Table 3).^4,5 The onset of estrogen, progesterone, and testosterone surges closely correlates with the difference in depression rates between pre- and postpubertal girls.¹² After estrogen and progesterone surges begin at puberty, negative emotions exert an increased activating effect on the female brain,¹³ and social stressors more deeply affect girls than they do boys. This may explain why girls are more susceptible to depression when a friendship fails.¹⁴

CASE CONTINUED: Boy troubles

Kate tells you that in 9th grade she and her best friend, Ellen, would talk about boys for hours after school and try on sexually provocative outfits. They both liked Matt, a 10th grader, so when he asked Kate out, Ellen stopped speaking to her. Kate and Matt began some heavy petting, and Kate said she felt selfish and guilty about hurting Ellen. But when girls at school began spreading rumors that Kate was a “slut,” Kate blamed Ellen and told her, “I hate you!”

Soon after, Matt broke up with Kate. Distraught, she dreaded going to school and cried in her room at night for several weeks. She became chronically tired and had difficulty concentrating in class. She ruminated about losing Matt and worried that she was too fat, too ugly, or too flat-chested. She missed Ellen and felt no one liked her.

Table 2

Puberty’s developmental milestones in U.S. girls (averages)

Figure Hypothalamic-pituitary-ovarian axis: Turned on at puberty in girls

Puberty onset stimulates depression in genetically vulnerable girls; more likely after Tanner stage 3 (development of pubic and axillary hair and breast buds).

Male vs female teen brains

Depression after a relationship failure in teen girls often begins with ruminative thoughts about her flaws, mistakes, or appearance. These negative thoughts may preoccupy her day and night. Teen girls often feel confused by contradictory social pressures to look and dress provocatively but resist having sex. A sexual encounter can trigger shame and fear.

Although clinical and developmental studies indicate that teen girls respond more dramatically to relationship troubles than boys, the brain and hormone differences responsible for these effects remain unclear. Male hormones hugely increase in boys at puberty—up to 25-fold between ages 9 and 15—but do not cycle. Male brains do not have the same capacity as female brains to respond to cyclical hormonal activity because exposure to androgens during fetal development eliminates this ability. The fetal testosterone surge causes the area associated with sexual pursuit to double in the male brain.

Outside of fertility considerations, Baron-Cohen et al¹⁵ suggest that male brain circuits have been formed by fetal testosterone to focus more on systematization—which emphasizes figuring out how things work and performing tasks—rather than empathy and bonding in relationships. This difference has been shown in neuroimaging studies comparing the genders’ attentional systems.^16,17 In contrast to the systematizing male brain, female brains are more likely to activate the mirror neuron system—the area required for empathizing.¹⁸

Female brains, of course, respond to cyclical hormonal activity. However, the regular monthly waves of estrogen and progesterone do not affect all female brains the same. A subset of women who experience premenstrual dysphoric disorder appear to have brains that trigger depressed moods and irritability during the last 2 weeks of the menstrual cycle.¹⁹ A genetic difference in these women is suspected as the culprit; these genes may affect the way their brains metabolize progesterone.

CASE CONTINUED: An overdose of stress

Kate’s poor concentration lingered, and her grades continued to drop. She tells you her parents were having marital problems and she did not want to bother them with her difficulties. Two days before her period was due, she learned she had failed 2 classes. That night, as she got some acetaminophen for a headache, she impulsively took the rest of the bottle.

After swallowing the pills, Kate panicked. She forced herself to vomit and tearfully told her parents what she had done. They took her to the emergency room, where she was medically stabilized, evaluated by a psychiatrist, and referred to you for outpatient treatment.

Treatment recommendations

A combination of factors—genetic, hormonal, and neurodevelopmental—probably contributed to Kate’s acute depressed mood and overdose. Thus, to treat depression in adolescent girls, emerging evidence supports:

• stabilizing hormonal fluctuations such as rapidly falling progesterone just before the start of menstrual periods with an extended-cycle contraceptive (we would try an ethinyl estradiol/levonorgestrel combination such as Seasonale^®)
• treating depressive symptoms with a selective serotonin reuptake inhibitor such as citalopram, 10 mg once daily, with careful monitoring for suicidal thoughts or behavior
• providing tools to manage stress and impulsive behavior through weekly psychotherapy (such as cognitive-behavioral therapy, dialectical behavioral therapy, or supportive therapy).

Genetic factors. Kate’s mother’s history of postpartum depression suggests genetic risk for Kate. Studies have found that the expression of particular genes—such as the serotonin transporter (5-HTT) gene—may be associated with depression. Staley et al²⁰ found that depressed women show a significantly greater decrease in 5-HTT availability in the diencephalon (forebrain region containing the thalamus, hypothalamus, and part of the pituitary gland) when compared with healthy women and depressed men.

Table 3

3 stages of girls’ gonadal development

Although men and women have the same 5-HTT gene, women may possess a gender-specific factor—such as estrogen or progesterone—that differentially alters this and other genes’ expression in women with depression. Individuals who carry a short version of the gene may be at particular risk of becoming depressed when exposed to stressful life events.

Caspi et al²¹ found a polymorphism in the 5-HTT gene on chromosome 17 that can manifest differentially based on environmental factors. In this study, individuals with 2 copies of the long version of this gene were relatively resistant to stressful life events, whereas those with 1 or 2 copies of the short version were highly sensitive to stressful life events. The depression rate in short-gene individuals was:

• 9% in those who had not experienced stressful life events
• nearly 40% in those who had experienced ≥4 stressful life events.

Hormonal and stress factors. Stress responsiveness becomes sexually dimorphic at puberty. Compared with men, women are:

• at greater risk after puberty for heightened stress responsiveness, which is associated with major depressive disorder
• 3 times more likely to develop depression after a stressful life event.²²

Women’s and men’s different biological responses to stress might be related to the gender-specific hormones that emerge during puberty. Kate could be at increased risk for depression—especially immediately before her period—if she inherited a stress-sensitive gene and now has increased stress sensitivity triggered by the hormones of puberty.²³

Neurodevelopmental factors. Dorsolateral prefrontal cortex circuits associated with making good decisions and weighing the consequences of actions are immature in the adolescent and the last part of the brain to undergo myelination.^24-26 Teens are well-known for erratic, emotionally driven behaviors.^27,28 Kate’s impulsive overdose exemplifies the consequences of emotional reactivity without the benefit of inhibitory mature brain connections.

Related resources

• Brizendine L. Teen girl brain. In: The female brain. New York: Morgan Road Books; 2006:31-56. www.thefemalebrain.com.
• Strauch B. The primal teen: what discoveries about the teenage brain tell us about our kids. New York: Doubleday; 2003.
• Harter S. Self and identity development. In: Feldman S, Elliott G, eds. At the threshold: the developing adolescent. Cambridge, MA: Harvard University Press; 1990:352-87.

Drug brand names

• Ethinyl estradiol/levonorgestrel • Seasonale

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.