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Consider hormones and mood in adolescent girls
Prior to puberty, the rate of mood disorders in males and females is roughly the same; however in adolescence, depression doubles in (biological) girls. While the association isn’t clear, it is reasonable to consider that hormones may be involved, at least for some. For instance, we know that menstrual cycle–related mood changes have been noted since the time of Hippocrates. In this article, I will discuss premenstrual dysphoric disorder (PMDD), as well as potential mood-related side effects of hormonal contraceptives. Because I am talking about physiology, I will be referring to individuals born as biological females in the absence of any hormonal gender treatments, regardless of identified gender.
Many young women will acknowledge somatic and/or psychological symptoms that occur in the luteal phase of their cycle, most commonly in the week before menses begins. The most common somatic symptom is bloating, and mood symptoms are irritability and mood lability.1 To meet criteria for premenstrual syndrome (PMS), a woman must endorse one symptom that causes impairment in their functioning and reoccurs over consecutive cycles. PMDD is more specific and involves five or more affective symptoms, at least one of which is consistent with depressed mood, irritability, anxiety, or mood lability. The other potential symptoms include impaired concentration, fatigue, insomnia or hypersomnia, anhedonia, and appetite issues, all of which are included as criteria for major depression. The population prevalence has been quoted between 2% and 5% and is relatively stable across cultures.1 It tends to be highly genetic, as well as highly comorbid with other psychiatric disorders.2 Girls and women with higher rates of trauma appear to be more likely to experience symptoms,3 which indicates there are environmental influences that can interact with genetic vulnerability.
Interestingly, studies have not found differences in serum hormone levels between those with PMDD and others, which leads to the hypothesis that the main difference is in a woman’s sensitivity to circulating hormones,4 and there has been some evidence of different concentrations of neurotransmitters between affected and unaffected women. Many hormone-neurotransmitter interactions have been described, but two that have received the most attention include the relationship between progesterone, its main metabolite allopregnanolone, and gamma-aminobutyric acid (GABA) receptors. Allopregnanolone, which interacts with GABA receptors similarly to benzodiazepines, tends to be higher in the luteal phase, rising with progesterone, and the concentration quickly recedes at the onset of menses as progesterone levels drop off. The other highly notable relationship is the positive association between estradiol and the expression of the serotonin transporter (SERT) genes, which can potentially lead to higher levels of circulating serotonin in the follicular phase.
When PMDD is suspected in an adolescent who presents with intermittent mood and anxiety symptoms that lessen or disappear at baseline and appear unrelated to circumstances, it is important to check in regarding monthly patterns. It can be challenging for adolescents to make this connection, and even more so prior to achieving cycle regularity. Observational studies suggest that by age 14 years, about 82% of girls have a regular cycle.5 The best way to help a patient make the connection is to suggest a period tracking app on their smartphone or tablet. There are many available period trackers that track mood as well and are free to download. Sometimes, simply the act of tracking and bringing awareness to the pattern is therapeutic in itself; sometimes, more formal treatment is needed.
Once the diagnosis of PMDD has been established, there are several options for treatment that range from supplements and herbal remedies to SSRIs, as well as psychotherapy. Treatment may begin with calcium supplements (1,200 mg have been effective in reducing symptoms)6 and referral for cognitive-behavioral therapy (CBT). CBT appears to be associated with a shift in the ability to attribute symptoms to hormones,7 which can help decrease hopelessness and reactivity. SSRIs are another effective strategy to treat PMDD, both taken daily and continuously and also taken in a pulsed fashion, starting with the onset of symptoms or 7-10 days before the period starts and stopping on the first day of menses. Low doses of sertraline, fluoxetine, paroxetine, escitalopram and citalopram have been studied.8 There is some low-quality evidence for herbal supplements as well, probably the most consistent finding is for Vitex taken the week prior to menses.9 Finally, certain oral contraceptives have been associated with PMDD symptom reduction, specifically formulations with 3 mg of drospirenone (a fourth generation progesterone) and 20 mcg of ethinyl estradiol.10 Other formulations, including progesterone-only pills, have not been helpful and have been demonstrated to have a negative effect on mood.11
The literature on hormonal contraceptives and mood can be confusing. While oral agents containing drospirenone have been helpful for premenstrual dysphoria, other studies outside of the PMDD literature have found positive associations between oral contraceptives and depression in adolescents.11 Girls taking combined oral contraceptives seem to be at a 1.8-fold risk of depression, while girls taking progesterone-only formulations were at 2.2 times the risk of developing depression, compared with girls who weren’t taking anything. These days, more pediatricians are recommending long acting reversible contraceptives (LARCs), and there is some thought that even these may carry some risk, but this remains to be studied.
In conclusion, As a provider, you are in a special position to help your patients by bringing nonjudgmental awareness to the potential contribution of their own cyclical hormones or that of exogenous hormones associated with contraceptive choices. Whether it means switching contraceptives, adding calcium or starting a low dose SSRI for 1 week a month, there are many ways to approach symptoms. Often, simply helping make the connection between physiology and mood can be empowering.
Dr. Guth is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and the University of Vermont, both in Burlington. Email her at pdnews@mdedge.com.
References
1. Am J Psychiatry. 2012 May;169(5):465-75.
2. Arch Womens Ment Health. 2004 Feb;7(1):37-47.
3. Arch Womens Ment Health. 2011 Oct;14(5):383-93.
4. Curr Psychiatry Rep. 2015 Nov;17(11):87.
5. Ital J Pediatr. 2012 Aug 14;38:38.
6. Am J Obstet Gynecol. 1998 Aug;179(2):444-52.
7. J Clin Psychol Med Settings. 2012 Sep;19(3):308-19.
8. Cochrane Database Syst Rev. 2013 Jun 7;(6):CD001396.
9. J Psychosom Obstet Gynaecol. 2011 Mar;32(1):42-51.
10. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD006586.
11. PLoS One. 2018 Mar 22;13(3):e0194773.
Prior to puberty, the rate of mood disorders in males and females is roughly the same; however in adolescence, depression doubles in (biological) girls. While the association isn’t clear, it is reasonable to consider that hormones may be involved, at least for some. For instance, we know that menstrual cycle–related mood changes have been noted since the time of Hippocrates. In this article, I will discuss premenstrual dysphoric disorder (PMDD), as well as potential mood-related side effects of hormonal contraceptives. Because I am talking about physiology, I will be referring to individuals born as biological females in the absence of any hormonal gender treatments, regardless of identified gender.
Many young women will acknowledge somatic and/or psychological symptoms that occur in the luteal phase of their cycle, most commonly in the week before menses begins. The most common somatic symptom is bloating, and mood symptoms are irritability and mood lability.1 To meet criteria for premenstrual syndrome (PMS), a woman must endorse one symptom that causes impairment in their functioning and reoccurs over consecutive cycles. PMDD is more specific and involves five or more affective symptoms, at least one of which is consistent with depressed mood, irritability, anxiety, or mood lability. The other potential symptoms include impaired concentration, fatigue, insomnia or hypersomnia, anhedonia, and appetite issues, all of which are included as criteria for major depression. The population prevalence has been quoted between 2% and 5% and is relatively stable across cultures.1 It tends to be highly genetic, as well as highly comorbid with other psychiatric disorders.2 Girls and women with higher rates of trauma appear to be more likely to experience symptoms,3 which indicates there are environmental influences that can interact with genetic vulnerability.
Interestingly, studies have not found differences in serum hormone levels between those with PMDD and others, which leads to the hypothesis that the main difference is in a woman’s sensitivity to circulating hormones,4 and there has been some evidence of different concentrations of neurotransmitters between affected and unaffected women. Many hormone-neurotransmitter interactions have been described, but two that have received the most attention include the relationship between progesterone, its main metabolite allopregnanolone, and gamma-aminobutyric acid (GABA) receptors. Allopregnanolone, which interacts with GABA receptors similarly to benzodiazepines, tends to be higher in the luteal phase, rising with progesterone, and the concentration quickly recedes at the onset of menses as progesterone levels drop off. The other highly notable relationship is the positive association between estradiol and the expression of the serotonin transporter (SERT) genes, which can potentially lead to higher levels of circulating serotonin in the follicular phase.
When PMDD is suspected in an adolescent who presents with intermittent mood and anxiety symptoms that lessen or disappear at baseline and appear unrelated to circumstances, it is important to check in regarding monthly patterns. It can be challenging for adolescents to make this connection, and even more so prior to achieving cycle regularity. Observational studies suggest that by age 14 years, about 82% of girls have a regular cycle.5 The best way to help a patient make the connection is to suggest a period tracking app on their smartphone or tablet. There are many available period trackers that track mood as well and are free to download. Sometimes, simply the act of tracking and bringing awareness to the pattern is therapeutic in itself; sometimes, more formal treatment is needed.
Once the diagnosis of PMDD has been established, there are several options for treatment that range from supplements and herbal remedies to SSRIs, as well as psychotherapy. Treatment may begin with calcium supplements (1,200 mg have been effective in reducing symptoms)6 and referral for cognitive-behavioral therapy (CBT). CBT appears to be associated with a shift in the ability to attribute symptoms to hormones,7 which can help decrease hopelessness and reactivity. SSRIs are another effective strategy to treat PMDD, both taken daily and continuously and also taken in a pulsed fashion, starting with the onset of symptoms or 7-10 days before the period starts and stopping on the first day of menses. Low doses of sertraline, fluoxetine, paroxetine, escitalopram and citalopram have been studied.8 There is some low-quality evidence for herbal supplements as well, probably the most consistent finding is for Vitex taken the week prior to menses.9 Finally, certain oral contraceptives have been associated with PMDD symptom reduction, specifically formulations with 3 mg of drospirenone (a fourth generation progesterone) and 20 mcg of ethinyl estradiol.10 Other formulations, including progesterone-only pills, have not been helpful and have been demonstrated to have a negative effect on mood.11
The literature on hormonal contraceptives and mood can be confusing. While oral agents containing drospirenone have been helpful for premenstrual dysphoria, other studies outside of the PMDD literature have found positive associations between oral contraceptives and depression in adolescents.11 Girls taking combined oral contraceptives seem to be at a 1.8-fold risk of depression, while girls taking progesterone-only formulations were at 2.2 times the risk of developing depression, compared with girls who weren’t taking anything. These days, more pediatricians are recommending long acting reversible contraceptives (LARCs), and there is some thought that even these may carry some risk, but this remains to be studied.
In conclusion, As a provider, you are in a special position to help your patients by bringing nonjudgmental awareness to the potential contribution of their own cyclical hormones or that of exogenous hormones associated with contraceptive choices. Whether it means switching contraceptives, adding calcium or starting a low dose SSRI for 1 week a month, there are many ways to approach symptoms. Often, simply helping make the connection between physiology and mood can be empowering.
Dr. Guth is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and the University of Vermont, both in Burlington. Email her at pdnews@mdedge.com.
References
1. Am J Psychiatry. 2012 May;169(5):465-75.
2. Arch Womens Ment Health. 2004 Feb;7(1):37-47.
3. Arch Womens Ment Health. 2011 Oct;14(5):383-93.
4. Curr Psychiatry Rep. 2015 Nov;17(11):87.
5. Ital J Pediatr. 2012 Aug 14;38:38.
6. Am J Obstet Gynecol. 1998 Aug;179(2):444-52.
7. J Clin Psychol Med Settings. 2012 Sep;19(3):308-19.
8. Cochrane Database Syst Rev. 2013 Jun 7;(6):CD001396.
9. J Psychosom Obstet Gynaecol. 2011 Mar;32(1):42-51.
10. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD006586.
11. PLoS One. 2018 Mar 22;13(3):e0194773.
Prior to puberty, the rate of mood disorders in males and females is roughly the same; however in adolescence, depression doubles in (biological) girls. While the association isn’t clear, it is reasonable to consider that hormones may be involved, at least for some. For instance, we know that menstrual cycle–related mood changes have been noted since the time of Hippocrates. In this article, I will discuss premenstrual dysphoric disorder (PMDD), as well as potential mood-related side effects of hormonal contraceptives. Because I am talking about physiology, I will be referring to individuals born as biological females in the absence of any hormonal gender treatments, regardless of identified gender.
Many young women will acknowledge somatic and/or psychological symptoms that occur in the luteal phase of their cycle, most commonly in the week before menses begins. The most common somatic symptom is bloating, and mood symptoms are irritability and mood lability.1 To meet criteria for premenstrual syndrome (PMS), a woman must endorse one symptom that causes impairment in their functioning and reoccurs over consecutive cycles. PMDD is more specific and involves five or more affective symptoms, at least one of which is consistent with depressed mood, irritability, anxiety, or mood lability. The other potential symptoms include impaired concentration, fatigue, insomnia or hypersomnia, anhedonia, and appetite issues, all of which are included as criteria for major depression. The population prevalence has been quoted between 2% and 5% and is relatively stable across cultures.1 It tends to be highly genetic, as well as highly comorbid with other psychiatric disorders.2 Girls and women with higher rates of trauma appear to be more likely to experience symptoms,3 which indicates there are environmental influences that can interact with genetic vulnerability.
Interestingly, studies have not found differences in serum hormone levels between those with PMDD and others, which leads to the hypothesis that the main difference is in a woman’s sensitivity to circulating hormones,4 and there has been some evidence of different concentrations of neurotransmitters between affected and unaffected women. Many hormone-neurotransmitter interactions have been described, but two that have received the most attention include the relationship between progesterone, its main metabolite allopregnanolone, and gamma-aminobutyric acid (GABA) receptors. Allopregnanolone, which interacts with GABA receptors similarly to benzodiazepines, tends to be higher in the luteal phase, rising with progesterone, and the concentration quickly recedes at the onset of menses as progesterone levels drop off. The other highly notable relationship is the positive association between estradiol and the expression of the serotonin transporter (SERT) genes, which can potentially lead to higher levels of circulating serotonin in the follicular phase.
When PMDD is suspected in an adolescent who presents with intermittent mood and anxiety symptoms that lessen or disappear at baseline and appear unrelated to circumstances, it is important to check in regarding monthly patterns. It can be challenging for adolescents to make this connection, and even more so prior to achieving cycle regularity. Observational studies suggest that by age 14 years, about 82% of girls have a regular cycle.5 The best way to help a patient make the connection is to suggest a period tracking app on their smartphone or tablet. There are many available period trackers that track mood as well and are free to download. Sometimes, simply the act of tracking and bringing awareness to the pattern is therapeutic in itself; sometimes, more formal treatment is needed.
Once the diagnosis of PMDD has been established, there are several options for treatment that range from supplements and herbal remedies to SSRIs, as well as psychotherapy. Treatment may begin with calcium supplements (1,200 mg have been effective in reducing symptoms)6 and referral for cognitive-behavioral therapy (CBT). CBT appears to be associated with a shift in the ability to attribute symptoms to hormones,7 which can help decrease hopelessness and reactivity. SSRIs are another effective strategy to treat PMDD, both taken daily and continuously and also taken in a pulsed fashion, starting with the onset of symptoms or 7-10 days before the period starts and stopping on the first day of menses. Low doses of sertraline, fluoxetine, paroxetine, escitalopram and citalopram have been studied.8 There is some low-quality evidence for herbal supplements as well, probably the most consistent finding is for Vitex taken the week prior to menses.9 Finally, certain oral contraceptives have been associated with PMDD symptom reduction, specifically formulations with 3 mg of drospirenone (a fourth generation progesterone) and 20 mcg of ethinyl estradiol.10 Other formulations, including progesterone-only pills, have not been helpful and have been demonstrated to have a negative effect on mood.11
The literature on hormonal contraceptives and mood can be confusing. While oral agents containing drospirenone have been helpful for premenstrual dysphoria, other studies outside of the PMDD literature have found positive associations between oral contraceptives and depression in adolescents.11 Girls taking combined oral contraceptives seem to be at a 1.8-fold risk of depression, while girls taking progesterone-only formulations were at 2.2 times the risk of developing depression, compared with girls who weren’t taking anything. These days, more pediatricians are recommending long acting reversible contraceptives (LARCs), and there is some thought that even these may carry some risk, but this remains to be studied.
In conclusion, As a provider, you are in a special position to help your patients by bringing nonjudgmental awareness to the potential contribution of their own cyclical hormones or that of exogenous hormones associated with contraceptive choices. Whether it means switching contraceptives, adding calcium or starting a low dose SSRI for 1 week a month, there are many ways to approach symptoms. Often, simply helping make the connection between physiology and mood can be empowering.
Dr. Guth is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and the University of Vermont, both in Burlington. Email her at pdnews@mdedge.com.
References
1. Am J Psychiatry. 2012 May;169(5):465-75.
2. Arch Womens Ment Health. 2004 Feb;7(1):37-47.
3. Arch Womens Ment Health. 2011 Oct;14(5):383-93.
4. Curr Psychiatry Rep. 2015 Nov;17(11):87.
5. Ital J Pediatr. 2012 Aug 14;38:38.
6. Am J Obstet Gynecol. 1998 Aug;179(2):444-52.
7. J Clin Psychol Med Settings. 2012 Sep;19(3):308-19.
8. Cochrane Database Syst Rev. 2013 Jun 7;(6):CD001396.
9. J Psychosom Obstet Gynaecol. 2011 Mar;32(1):42-51.
10. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD006586.
11. PLoS One. 2018 Mar 22;13(3):e0194773.
Prenatal SSRI exposure’s effect on development
Unfortunately, the bottom line for most of these important questions is that we really don’t know as much as we probably should.
Just when we’ve read a convincing finding from a reputable journal that establishes a link between prenatal SSRI use and an untoward outcome, we see it disputed the next month. Why is this always happening, and why can’t we really know anything with certainty? Much of the confusion can be attributed to research methods and the obvious difficulty of using randomized, controlled trials to control for potential confounding factors. While statistical techniques have become increasingly sophisticated in addressing these confounding factors, they remain imperfect. For example, one of the most difficult challenges that remains is separating any effects of a medication from any effects caused by the condition it was designed to treat. Comparing women with the same underlying condition, some of whom are treated with a medication and some of whom are not, is a step forward, but there may be important reasons that one group decides to seek treatment and the other doesn’t. One clever research design that was employed to look at congenital anomalies in the offspring of women taking SSRIs accounted for siblings of these children who were born when their mother was not taking an SSRI. This study demonstrated that these women were more likely to have children with congenital malformations even when they weren’t taking the SSRIs.1 Other factors that render this literature difficult to interpret include small sample sizes when looking at specific SSRIs (many studies cluster them all), dose effects, timing (which trimester), duration of treatment, and method of recording compliance.
The potential link between SSRIs and autism has received a fair amount of attention lately, especially after a very well-designed study in 2016 suggested a significantly increased risk.10 However, as with many of the findings, this study was quickly disputed by other high-quality, well-powered research that found no increased risk after controlling for maternal illness.11,12
ADHD generally has not been found to be related to maternal SSRI use, although one study did find a link between ADHD and tricyclic antidepressants.12,13
In terms of other neurodevelopmental outcomes, there have been many negative studies examining IQ, nonverbal communication, as well as speech and motor skills.14,15,16 However, as with so many other outcomes, some other studies contradict these negative results. According to a recent, large cohort study, there may be some concern regarding SSRI exposure prenatally and an increase in speech disorders by age 14 years, as well as lower language competence at age 3 years.17,18 Likewise, mild motor abnormalities have been observed, with maternal depression severity as an independent but contributing factor.19
Several studies demonstrate a connection between prenatal SSRI exposure and childhood internalizing symptoms, such as depression and anxiety, independent of maternal depression.12,20 These findings must be balanced with our knowledge of the serious mental health conditions in offspring that are associated with untreated maternal illness, including both internalizing and externalizing disorders.21,22
How does one come to any firm conclusions to guide a primary care clinician’s practice and recommendations? Hopefully, the evidence will become clearer over time as we adopt more sophisticated designs and accumulate observations. A larger number of observations would allow us to decrease heterogeneity by studying subgroups according to type of SSRI and duration of exposure. Enhanced understanding of the role of genetic factors also may shed some light on individual variation as the serotonin transporter gene has been suggested as a potential moderator of sensitivity.23
Dr. Guth is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and the University of Vermont Robert Larner College of Medicine, both in Burlington. She works with children and adolescents as well as women in the perinatal period. She has no relevant financial disclosures.
References
1. BMJ. 2015 Apr 17;350:h1798.
2. Can J Clin Pharmacol. 2009 Winter;16(1):e66-7.
3. J Matern Fetal Neonatal Med. 2008 Oct;21(10):745-51.
4. PLoS ONE. 2014 Nov; 9(11): e111327.
5. Pediatr Res. 2017 Jun 30. doi: 10.1038/pr.2017.156. [Epub ahead of print].
6. J Clin Psychiatry. 2017 May;78(5):605-11.
7. Acta Psychiatr Scand. 2010 Jun;121(6):471-9.
8. Am J Psychiatry. 2016 Feb 1;173(2):147-57.
9. J Perinatol. 2011 Sep;31(9):615-20.
10. JAMA Pediatr. 2016 Feb;170(2):117-24.
11. JAMA. 2017 Apr 18;317(15):1544-52.
12. J Am Acad Child Adolesc Psychiatry. 2016 May;55(5):359-66.
13. Paediatr Perinat Epidemiol. 2017 Jul;31(4):363-73.
14. Acta Obstet Gynecol Scand. 2015 May;94(5):501-7.
15. J Psychopharmacol. 2017 Mar;31(3):346-55.
16. CNS Drugs. 2005;19(7):623-33.
17. JAMA Psychiatry. 2016 Nov 1;73(11):1163-70.
18. BJOG. 2014. doi: 10.1111/1471-0528.12821.
19. BJOG. 2016 Nov;123(12):1908-17.
20. Pediatr Res. 2015 Aug;78(2):174-80.
21. Neuroscience. 2017 Feb 7;342:154-66.
22. Depress Anxiety. 2014 Jan;31(1):9-18.
23. Neuroscience. 2017 Feb 7;342:212-31.
Unfortunately, the bottom line for most of these important questions is that we really don’t know as much as we probably should.
Just when we’ve read a convincing finding from a reputable journal that establishes a link between prenatal SSRI use and an untoward outcome, we see it disputed the next month. Why is this always happening, and why can’t we really know anything with certainty? Much of the confusion can be attributed to research methods and the obvious difficulty of using randomized, controlled trials to control for potential confounding factors. While statistical techniques have become increasingly sophisticated in addressing these confounding factors, they remain imperfect. For example, one of the most difficult challenges that remains is separating any effects of a medication from any effects caused by the condition it was designed to treat. Comparing women with the same underlying condition, some of whom are treated with a medication and some of whom are not, is a step forward, but there may be important reasons that one group decides to seek treatment and the other doesn’t. One clever research design that was employed to look at congenital anomalies in the offspring of women taking SSRIs accounted for siblings of these children who were born when their mother was not taking an SSRI. This study demonstrated that these women were more likely to have children with congenital malformations even when they weren’t taking the SSRIs.1 Other factors that render this literature difficult to interpret include small sample sizes when looking at specific SSRIs (many studies cluster them all), dose effects, timing (which trimester), duration of treatment, and method of recording compliance.
The potential link between SSRIs and autism has received a fair amount of attention lately, especially after a very well-designed study in 2016 suggested a significantly increased risk.10 However, as with many of the findings, this study was quickly disputed by other high-quality, well-powered research that found no increased risk after controlling for maternal illness.11,12
ADHD generally has not been found to be related to maternal SSRI use, although one study did find a link between ADHD and tricyclic antidepressants.12,13
In terms of other neurodevelopmental outcomes, there have been many negative studies examining IQ, nonverbal communication, as well as speech and motor skills.14,15,16 However, as with so many other outcomes, some other studies contradict these negative results. According to a recent, large cohort study, there may be some concern regarding SSRI exposure prenatally and an increase in speech disorders by age 14 years, as well as lower language competence at age 3 years.17,18 Likewise, mild motor abnormalities have been observed, with maternal depression severity as an independent but contributing factor.19
Several studies demonstrate a connection between prenatal SSRI exposure and childhood internalizing symptoms, such as depression and anxiety, independent of maternal depression.12,20 These findings must be balanced with our knowledge of the serious mental health conditions in offspring that are associated with untreated maternal illness, including both internalizing and externalizing disorders.21,22
How does one come to any firm conclusions to guide a primary care clinician’s practice and recommendations? Hopefully, the evidence will become clearer over time as we adopt more sophisticated designs and accumulate observations. A larger number of observations would allow us to decrease heterogeneity by studying subgroups according to type of SSRI and duration of exposure. Enhanced understanding of the role of genetic factors also may shed some light on individual variation as the serotonin transporter gene has been suggested as a potential moderator of sensitivity.23
Dr. Guth is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and the University of Vermont Robert Larner College of Medicine, both in Burlington. She works with children and adolescents as well as women in the perinatal period. She has no relevant financial disclosures.
References
1. BMJ. 2015 Apr 17;350:h1798.
2. Can J Clin Pharmacol. 2009 Winter;16(1):e66-7.
3. J Matern Fetal Neonatal Med. 2008 Oct;21(10):745-51.
4. PLoS ONE. 2014 Nov; 9(11): e111327.
5. Pediatr Res. 2017 Jun 30. doi: 10.1038/pr.2017.156. [Epub ahead of print].
6. J Clin Psychiatry. 2017 May;78(5):605-11.
7. Acta Psychiatr Scand. 2010 Jun;121(6):471-9.
8. Am J Psychiatry. 2016 Feb 1;173(2):147-57.
9. J Perinatol. 2011 Sep;31(9):615-20.
10. JAMA Pediatr. 2016 Feb;170(2):117-24.
11. JAMA. 2017 Apr 18;317(15):1544-52.
12. J Am Acad Child Adolesc Psychiatry. 2016 May;55(5):359-66.
13. Paediatr Perinat Epidemiol. 2017 Jul;31(4):363-73.
14. Acta Obstet Gynecol Scand. 2015 May;94(5):501-7.
15. J Psychopharmacol. 2017 Mar;31(3):346-55.
16. CNS Drugs. 2005;19(7):623-33.
17. JAMA Psychiatry. 2016 Nov 1;73(11):1163-70.
18. BJOG. 2014. doi: 10.1111/1471-0528.12821.
19. BJOG. 2016 Nov;123(12):1908-17.
20. Pediatr Res. 2015 Aug;78(2):174-80.
21. Neuroscience. 2017 Feb 7;342:154-66.
22. Depress Anxiety. 2014 Jan;31(1):9-18.
23. Neuroscience. 2017 Feb 7;342:212-31.
Unfortunately, the bottom line for most of these important questions is that we really don’t know as much as we probably should.
Just when we’ve read a convincing finding from a reputable journal that establishes a link between prenatal SSRI use and an untoward outcome, we see it disputed the next month. Why is this always happening, and why can’t we really know anything with certainty? Much of the confusion can be attributed to research methods and the obvious difficulty of using randomized, controlled trials to control for potential confounding factors. While statistical techniques have become increasingly sophisticated in addressing these confounding factors, they remain imperfect. For example, one of the most difficult challenges that remains is separating any effects of a medication from any effects caused by the condition it was designed to treat. Comparing women with the same underlying condition, some of whom are treated with a medication and some of whom are not, is a step forward, but there may be important reasons that one group decides to seek treatment and the other doesn’t. One clever research design that was employed to look at congenital anomalies in the offspring of women taking SSRIs accounted for siblings of these children who were born when their mother was not taking an SSRI. This study demonstrated that these women were more likely to have children with congenital malformations even when they weren’t taking the SSRIs.1 Other factors that render this literature difficult to interpret include small sample sizes when looking at specific SSRIs (many studies cluster them all), dose effects, timing (which trimester), duration of treatment, and method of recording compliance.
The potential link between SSRIs and autism has received a fair amount of attention lately, especially after a very well-designed study in 2016 suggested a significantly increased risk.10 However, as with many of the findings, this study was quickly disputed by other high-quality, well-powered research that found no increased risk after controlling for maternal illness.11,12
ADHD generally has not been found to be related to maternal SSRI use, although one study did find a link between ADHD and tricyclic antidepressants.12,13
In terms of other neurodevelopmental outcomes, there have been many negative studies examining IQ, nonverbal communication, as well as speech and motor skills.14,15,16 However, as with so many other outcomes, some other studies contradict these negative results. According to a recent, large cohort study, there may be some concern regarding SSRI exposure prenatally and an increase in speech disorders by age 14 years, as well as lower language competence at age 3 years.17,18 Likewise, mild motor abnormalities have been observed, with maternal depression severity as an independent but contributing factor.19
Several studies demonstrate a connection between prenatal SSRI exposure and childhood internalizing symptoms, such as depression and anxiety, independent of maternal depression.12,20 These findings must be balanced with our knowledge of the serious mental health conditions in offspring that are associated with untreated maternal illness, including both internalizing and externalizing disorders.21,22
How does one come to any firm conclusions to guide a primary care clinician’s practice and recommendations? Hopefully, the evidence will become clearer over time as we adopt more sophisticated designs and accumulate observations. A larger number of observations would allow us to decrease heterogeneity by studying subgroups according to type of SSRI and duration of exposure. Enhanced understanding of the role of genetic factors also may shed some light on individual variation as the serotonin transporter gene has been suggested as a potential moderator of sensitivity.23
Dr. Guth is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and the University of Vermont Robert Larner College of Medicine, both in Burlington. She works with children and adolescents as well as women in the perinatal period. She has no relevant financial disclosures.
References
1. BMJ. 2015 Apr 17;350:h1798.
2. Can J Clin Pharmacol. 2009 Winter;16(1):e66-7.
3. J Matern Fetal Neonatal Med. 2008 Oct;21(10):745-51.
4. PLoS ONE. 2014 Nov; 9(11): e111327.
5. Pediatr Res. 2017 Jun 30. doi: 10.1038/pr.2017.156. [Epub ahead of print].
6. J Clin Psychiatry. 2017 May;78(5):605-11.
7. Acta Psychiatr Scand. 2010 Jun;121(6):471-9.
8. Am J Psychiatry. 2016 Feb 1;173(2):147-57.
9. J Perinatol. 2011 Sep;31(9):615-20.
10. JAMA Pediatr. 2016 Feb;170(2):117-24.
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