Depression In Women Psychiatric Medications - PDF of Slides.pdf · • Menstrual Cycle (PMS) • Pregnancy/Postpartum Depression • Menopause • Summary Depression In Women Psychiatric

1

Depression In WomenLeading Cause Of Disease Related

Disability Among Women In The World Today*

Stephen F. Pariser, M.D.Professor of Psychiatry and Obstetrics and Gynecology

Nick Votolato, Pharm BCPPClinical Assistant Professor

Ohio State University Medical Center

*Kessler, R. C. (2003). "Epidemiology of women and depression." J Affect Disord 74(1): 5-13.*The World Health Organization’s Global Burden (Murray and Lopez, 1996). Kessler, R. C., P. Berglund, et al. (2003).

• Introduction/Epidemiology• Comorbidity• Menstrual Cycle (PMS)• Pregnancy/Postpartum Depression• Menopause• Summary

Depression In Women

Psychiatric MedicationsPregnancy and Lactation

• 500,000 pregnancies in U.S. each year involvehave psychiatric illness that either predate oremerge during pregnancy

• Advising a pregnant or breastfeeding womanto discontinue medication exchanges fetal orneonatal risk of medication exposure for therisks of untreated maternal illness

ACOG Practice Bulletin, Clinical Management Guidelines for Obstetrician-Gynecologists, Number 87, November 2007.

ImpactInadequate or Untreated

Maternal Psychiatric Illness• Poor compliance with prenatal care• Inadequate nutrition• Exposure to additional medication or herbal

remedies• Increased alcohol and tobacco use• Deficits in maternal-infant bonding• Disruptions within family environment


2

All Psychotropic Medications

• All psychotropic medications studied to date cross the placenta

• Are present in amniotic fluid

• Can enter breast milk


• 2 forms of 5-HTT gene: the short form (“s” allele) and the long form (“l” allele)

• Each person inherits 1 copy of the gene from each parent; an individual may inherit: 2 short copies (s/s),1 short and 1 long copy (s/l) or 2 long copies (l/l)

• In relation to stressful life events, people with 1 or 2 copies of the short form of the 5-HTT gene exhibit more diagnosable depression and suicidality than people with 2 copies of the long allele

Genetic Variation: A Polymorphism in 5-HTT Gene

Caspi A et al. Science. 2003;301:386; Lesch KP et al. Science. 1996;274:1527Taylor SE, Way BM, Welch WT, Hilmert CJ, Lehman BJ, Eisenberger NI. Early Family Environment, Current Adversity, the Serotonin Transporter Promoter Polymorphism, and Depressive Symptomatology. Biol Psychiatry. Aug 23 2006.Gonda X, Rihmer Z, Zsombok T, Bagdy G, Akiskal KK, Akiskal HS. The 5HTTLPR polymorphism of the serotonin transporter gene is associated with affective temperaments as measured by TEMPS-A. J Affect Disord. Apr 2006;91(2-3):125-131.

Depressive Episodes

0.50

0.40

0.30

0.20

0.10

0.000 1 2 3 4+

No. of stressful life events

Prob

abili

ty o

f maj

or

depr

essi

on e

piso

de s/s

l/s

l/l

0 1 2 3 4+

0.02

0.00

0.04

0.06

0.08

0.10

0.12

0.14

0.16

No. of stressful life events

Prob

abili

ty o

f sui

cide

id

eatio

n/at

tem

pt

s/s

l/s

l/l

Suicide/Suicidal Ideation

Caspi A et al. Science. 2003;301:386

s/s (short/short allele)l/s (long/short allele)l/l (long/long allele)

Interaction of 5-HTT Gene Polymorphism and Life Stress in

Depression Outcomes

Results of multiple regression analyses estimating the association between number of stressful life events

(between ages 21 and 26 years) and depression outcomes at age 26 as a function of 5-HTT genotype

17% s/s; 31% l/l; 51% s/l

• Boys and girls (16-19 years old) carrying short 5-HTTLPR allele react to different kinds of environmental stressors:

a) Males affected by living in public housing rather than in own owned homes and by living with separated parents

b) Females were affected by traumatic conflicts within the family

Development of Depression: Sex and the Interaction Between Environment

and a Promoter Polymorphism of the Serotonin Transporter Gene

Sjoberg RL, Nilsson KW, Nordquist N, et al. Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene. Int J Neuropsychopharmacol. Aug 2006;9(4):443-449.

3

• Short allele response to environmental stress:

a) With environmental stress, females tend to develop depressive symptoms

b) Males seem to be protected from depression

• The results suggest that both the molecular and the psychosocial mechanisms underlying depression may differ between boys and girls

Development of Depression: Sex and the Interaction Between Environment

and a Promoter Polymorphism of the Serotonin Transporter Gene

Sjoberg RL, Nilsson KW, Nordquist N, et al. Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene. Int J Neuropsychopharmacol. Aug 2006;9(4):443-449.

Kessler RC, McGonagle KA, Zhao S, et al. Arch Gen Psych 1994; 51:8-19.http://www.nimh.nih.gov/healthinformation/stard_qa_general.cfm

Mood Disorders Lifetime Prevalences

21%

13%

2% 2%

8%

5%

24%

15%

0.00%

6.25%

12.50%

18.75%

25.00%

Women Men

Maj Dep EpisodeManic episodeDysthymiaAny Affective Episode

12-month Prevalence MDD*6.6% of Adults in USA (13-14 million adults)

78.5

51.641.9

21.7

0102030405060708090

12-month cases

%

Comorbid CICI/DSM-IVdisordersReceived healthcaretreatmentTreatment was adequate

month cases being-12adequately treated

Kessler RC, Berglund P, Demler MS, et al. The Epidemiology of major depressive disorder. JAMA, June 18, 2003-Vol. 289, 3095-3105.

*Major Depressive Disorder

Kessler RC, McGonagle KA, Zhao S, et al. Arch Gen Psych 1994; 51:8-19.http://www.nimh.nih.gov/healthinformation/stard_qa_general.cfm

Mood Disorders Lifetime Prevalences

21%

13%

2% 2%

8%

5%

24%

15%

0.00%

6.25%

12.50%

18.75%

25.00%

Women Men

Maj Dep EpisodeManic episodeDysthymiaAny Affective Episode

4

• Later MDD, anxiety disorders -13% of cohort developed depression between ages 14 and 16

• Nicotine dependence

• Alcohol abuse or dependence

• Suicide attempt, educational underachievement

• Unemployment

• Early parenthood

Fergusson, D. M. Woodward, L. J. Mental health, educational, and social role outcomes of adolescents with depression. Arch Gen Psych 2002;59:225-231.

Depression In Mid Adolescence (ages 14-16*)

Increases the Risk* (ages 16-21) of:

(P<.05)*

Introduction/Epidemiology

Comorbidity

Menstrual Cycle (PMS)

Pregnancy/Postpartum Depression

Menopause

Summary

Depression In Women

Gender Differences in Depression: Findings From the STAR*D Study

Marcus SM, Young EA, Kerber KB, et al. Gender differences in depression: findings from the STAR*D study. J Affect Disord. Aug 2005;87(2-3):141-150.

19.7

8.3

26.3

13.8

26.3 29.4

05

101520253035

Prior suicide attempt Hazzardous drinking Hazzardous use ofother drugs

(including Rx)

%

Women Men

STAR*D: Sequenced Treatment Alternatives to Relieve Depression

Dansky BS, Brewerton TD, Kilpatrick DG, et al. Comorbidity of bulimia nervosa and alcohol use disorders: results from the National Women’s Study. Int j EatDisord 2000;27:180-190.

Comorbidity Bulimia and Alcohol Use Disorders

31

37

28

37

18

1315

9

15

4

0

10

20

30

40

Bulimia PTSD Major Dep PTSD+Dep Controls

ETOH Abuse ETOH Dependence

5

Stein, M. B., Kennedy, C. Major depressive and post-traumatic stress disorder comorbidity in female victims of intimate partner violence. J Affect Disord 2001;66:133-8.

Victims of Intimate Partner ViolenceComorbidity MDD and PTSD

44 women who were victims of IPV within the preceding 2 years

68

50

0.0

17.5

35.0

52.5

70.0

Lifetime Prevalence In Female Victims of PTSD

Major Dep PTSD

• Introduction/Epidemiology• Mood Disorder Issues• Menstrual cycle (PMS/PMDD)• Pregnancy/Postpartum Depression• Menopause• Summary

Depression In Women

• Approximately 3-8% of women of reproductive age meet strict criteria for premenstrual dysphoric disorder (PMDD)

• 13-18% of women of reproductive age may have premenstrual dysphoric symptoms severe enough to induce impairment and distress, though the number of symptoms may not meet the arbitrary count of 5 symptoms on the PMDD list

Halbreich, U., J. Borenstein, et al. (2003). "The prevalence, impairment, impact, and burden of premenstrual dysphoric disorder (PMS/PMDD)." Psychoneuroendocrinology 28 Suppl 3: 1-23.

Premenstrual Dysphoric Disorder (PMDD)

• Disrupted relationships and impairment in work productivity

• Prior major depression (30% to 70% ) • Postpartum depression (29%)• Increased risk of subsequent major

depression• Exacerbation of mood symptoms in

women with primary mood disorders

Burt VK and Stein K. Epidemiology of depression throughout the female life cycle. J Clin Psychiatry 2002;63 (suppl 7)9-15.

PMDD

6

Yonkers KA, Pearlstein T, Rosenheck RA. Premenstrual disorders: bridging research and clinical reality. Arch Womens Ment Health. Nov 2003;6(4):287-292.

Women were recruited from 6 primary care obstetric-gynecological practices for participation in an open trial assessing the effectiveness of a serotonin reuptake inhibitor as a treatment for

subsyndromal (3-4 symptoms) and syndromal (>4 symptoms) PMDD. 904 women were screened.

47%

41%

36%

10% 10%

0.0%

12.5%

25.0%

37.5%

50.0%

Endorsed Symptoms

Current PMS symptomsPMS symptoms but not interested in research projectPMS symptoms not eligible for research project because of lack of symptom severityLost to follow-up or incomplete chartPMS Symptoms and agreed to chart

47%

41%

36%

10% 10%

0.0%

12.5%

25.0%

37.5%

50.0%

Endorsed Symptoms

Current PMS symptomsPMS symptoms but not interested in research projectPMS symptoms not eligible for research project because of lack of symptom severityLost to follow-up or incomplete chartPMS Symptoms and agreed to chart

PMDD in Obstetric and Gynecologic Practices

• Antidepressants (SSRIs-3 have indications*)

• GnRH agonists require hormonal add-back• Non-pharmacologic: phototherapy, aerobic

exercise, cognitive behavior therapy (CBT)• OCs - 24/4 regimen of drospirenone 3 mg

and ethinyl estradiol 20 mug*

Yonkers KA, Brown C, Pearlstein TB, Foegh M, Sampson-Landers C, Rapkin A. Efficacy of a New Low-Dose Oral Contraceptive With Drospirenone in Premenstrual Dysphoric Disorder. Obstet Gynecol. Sep 2005;106(3):492-501.Parry BL, Mahan AM, Mostofi N, Klauber MR, Lew GS, Gillin JC. Light therapy of late luteal phase dysphoric disorder: an extended study. Am J Psychiatry. Sep 1993;150(9):1417-1419Halbreich U, O'Brien PM, Eriksson E, Backstrom T, Yonkers KA, Freeman EW. Are there differential symptom profiles that improve in response to different pharmacological treatments of premenstrual syndrome/ premenstrual dysphoric disorder? CNS Drugs. 2006;20(7):523-547.

PMDD Treatment Options

*fluoxetine, sertraline and paroxetine

*Indicated for the treatment of symptoms of PMDD in women who choose to use an oral contraceptive as their method of contraception. The effectiveness of YAZ for PMDD when used for more than three menstrual cycles has not been evaluated.

• Accepted treatments have similar overall efficacy (60%)

• Suppression of ovulation ameliorates broad range of behavioral and physical symptoms

• SSRIs (considered first line therapy by many) most effective for irritability and anxiety symptoms

PMDD Treatment Efficacy

Halbreich U, O'Brien PM, Eriksson E, Backstrom T, Yonkers KA, Freeman EW. Are there differential symptom profiles that improve in response to different pharmacological treatments ofpremenstrual syndrome/ premenstrual dysphoric disorder? CNS Drugs. 2006;20(7):523-547. Kroll R, Rapkin AJ. Treatment of premenstrual disorders. J Reprod Med. Apr 2006;51(4 Suppl):359-370.Steiner M, Pearlstein T, Cohen LS, et al. Expert guidelines for the treatment of severe PMS, PMDD, and comorbidities: the role of SSRIs. J Womens Health (Larchmt). Jan-Feb 2006;15(1):57-69.

• Introduction/Epidemiology• Mood Disorder Issues• Menstrual Cycle (PMS)• Pregnancy/Postpartum Depression• Menopause • Summary

Depression In Women

7

• 10.9% of miscarrying women experienced an episode of MDD compared with 4.3% of community women (RR 2.5)

• Among miscarrying women, 72% of cases of MDD began within the first month

• Among miscarrying women with a history of MDD, 54% experienced a recurrence

JAMANeugebauer R, Kline J, Shrout P, et al. Major depressive disorder in the 6 monthsafter miscarriage. JAMA 1997;277:383-8.

Early Pregnancy LossMajor Depressive Disorder (MDD)In The 6 Months After Miscarriage

(229 women evaluated following spontaneous pregnancy loss before 28 weeks gestation were compared to a population

based cohort of 230 women)

• Prior history of depression• Maternal youth• Maternal isolation• Insufficient social support• Marital discord• Ambivalence toward pregnancy• Greater number of children

Burt VK and Stein K. Epidemiology of depression throughout the female life cycle. J Clin Psychiatry 2002;63 (suppl 7)9-15.

*20% of women affirm depressive symptoms during

pregnancy

Increased Risk of Depression in Pregnancy*

Uncontrolled depression during pregnancy triples the risk of postpartum depression.

• Independent of biomedical risk, perceived life-event stress and anxiety during pregnancy significantly predicted infant birth weight and gestational age

• Low birth weight and prematurity mediated by peptides derived from activated HPA axis, including ACTH and beta endorphin

• Activation of HPA axis well established in nonpregnant depressed patients

Wisner KL, Gelenberg AJ, Leonard H, et al. Pharmacologic treatment of depression during pregnancy JAMA 1999;282:1264-1269.Sandman CA, Wadhwa PD, Dunkel-Schretter C, et al. Psychobiological influences of stress and HPA regulation on the human fetus and infant birth outcome. Ann NY Acad Sci 1994;739:198-210.Dayan, J., C. Creveuil, et al. (2002). "Role of anxiety and depression in the onset of spontaneous preterm labor." Am J Epidemiol 155(4): 293-301.Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. Jama. Feb 1 2006;295(5):499-507.Yonkers KA, Wisner KL, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry. Apr 2004;161(4):608-620.

Depression Not IdealFor Pregnancy

Untreated Maternal Depression

• Premature low birthweight infants

• Fetal growth restrictions

• Postnatal complication

• Newborns cry more and are more difficult toconsole

Dayan, J., C. Creveuil, et al. (2002). "Role of anxiety and depression in the onset of spontaneous preterm labor." Am J Epidemiol 155(4): 293-301.Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. Jama. Feb 1 2006;295(5):499-507.Yonkers KA, Wisner KL, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry. Apr 2004;161(4):608-620.


8

Antenatal Depression and Birthweight

There is a high prevalence of depression in south Asian women. Examined the association between antenatal depression and low birthweight (LBW) in infants in a rural community in Rawalpindi, Pakistan. METHOD: 143 physically healthy

mothers with ICD-10 depression in the third trimester of pregnancy and 147 non-depressed mothers of similar gestation were followed from birth. Infant weight was measured and information collected on socioeconomic status, maternal body-

mass index and sociodemographic factors.

rr=1.9

Rahman, A., J. Bunn, et al. (2007). "Association between antenatal depression and low birthweight in a developing country." Acta Psychiatr Scand 115(6): 481-6.Stewart, R. C. (2007). "Maternal depression and infant growth: a review of recent evidence." Matern Child Nutr 3(2): 94-107.

2910

3022

2850

2900

2950

3000

3050

Depressed

Infant Birth Weights

Weight in Grams

DepressedNon-depressed

• History of major depression• History of mania (also increases risk of

postpartum mania)• History of PMDD• Psychosocial stress• Inadequate social support

Miller LJ. Postpartum depression. JAMA 2002;287:762-765.

Postpartum Depression Risk Factors

(Major Depression within first 4-6 weeks postpartum)

• Episodes of depression with onset within 4 weeks of delivery clustered in families, but there was no significant evidence of familial clustering of broadly defined postpartum depression (onset within 6 months).

• Among women with a family history of narrowly defined postpartum episodes, 42% experienced depression following their first delivery, whereas only 15% of women with no such family history experienced depression following first delivery.

Familiality of Postpartum Depression in Parous Female/Female Sibling Pairs (N=45) With Recurrent Major Depressive Disorder by

Week of Postpartum Depression Onset

Forty L, Jones L Macgregor s, et al. American Journal of Psychiatry 163:1549-1553, September 2006

The evidence for familiality maximized with a postpartum onset definition of 6–8 weeks

• Prenatal diagnosis is key; prenatal counseling is ideal

• Teratogenesis is a treatment issue (lithium, carbamazepine, valproate, lamotrigine); second generation antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole) (?)

• Breast-feeding issues (unsafe: lithium); other agents?

• Patients can be symptomatic during pregancy; postpartum mania or depression is common (20%-45%)

Bipolar Disorder and Pregnancy

Gentile S. Prophylactic treatment of bipolar disorder in pregnancy and breastfeeding: focus on emerging mood stabilizers. Bipolar Disord. Jun 2006;8(3):207-220.Yonkers KA, Wisner KL, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry. Apr 2004;161(4):608-620.

9

• >90% of suicides have a psychiatric illness• Mood disorders associated with 60% of 80% of

suicides are untreated at time of death• Lower during pregnancy and postpartum than in

the general population of women• Suicides account for up to 20% of postpartum

deaths• During pregnancy and postpartum 5%-14% have

self-harm ideation• Best predictor of suicide appears to be prior

attemptLindahl V, Pearson JL, Colpe L. Prevalence of suicidality during pregnancy and the postpartum.Arch Women Ment Health. Jun 2005;8(2):77-87. Mann JJ,Apter A, Bertolote J, et al. Suicide prevention strategies: a systematic review. Jama. Oct 26 2005;294(16):2064-2074.

Suicide Deaths and AttemptsDuring Pregnancy and

Postpartum

Relapse Of Major Depression During Pregnancy

Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. Jama. Feb 1 2006;295(5):499-507.

(hazard ratio, 5.0, p<.001)

43

26

68

0

10

20

30

40

50

60

70

80

Relapse During Pregnancy

%

Relapsed duringpregnancyMaintainedmedication

Discontinuedmedication

• The potential risk of SSRIs during pregnancy mustbe weighed against the risk of depression relapse if the medication is discontinued. Untreated depression has its own risks, including low weight gain, alcohol and substance abuse, and sexually transmitted diseases, all of which have negative maternal and fetal health implications. Fetal echocardiography should be considered for women who were exposed to Paxil® in early pregnancy.

Committee Opinion #354, "Treatment with Selective Serotonin Reuptake Inhibitors During Pregnancy," is published in the December 2006 issue of Obstetrics & Gynecology

The American College of Obstetricians and

Gynecologists

• ACOG's Committee on Obstetric Practice emphasizes that decisions about depression treatment should involve the obstetrician and the mental health clinician, along with the patient, ideally prior to pregnancy. However, because approximately 50% of pregnancies are unplanned, preconception planning for women with depression will not always be feasible, and treatment decisions about SSRIs will undoubtedly occur during pregnancy.

Committee Opinion #354, "Treatment with Selective Serotonin Reuptake Inhibitors During Pregnancy," is published in the December 2006 issue of Obstetrics & Gynecology

The American College of Obstetricians and

Gynecologists

10

• Introduction/Epidemiology• Mood Disorder Issues• Menstrual Cycle (PMS)• Pregnancy/Postpartum Depression• Menopause• Summary

Depression In Women

44 4

2

8

4

6

5

0.000

2.125

4.250

6.375

8.500

15-24 yrs. 25-34 yrs. 35-44 yrs. 45-54 yrs.

30-Day M 30-Day W

Kessler RC, McGonagle KA, Zhao S, et al. Arch Gen Psych 1994; 51:8-19.

Major Depressive Episodes30-Day Prevalence By Sex

• Premenopausal women with no lifetime history of major depression who entered the perimenopause were twice as likely to develop significant depressive symptoms as women who remained premenopausal, after adjustment for age at study enrollment and history of negative life events

• Perimenopause is associated with increased risk of recurrent depression-depression linked to bone density concerns

Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles. Arch Gen Psychiatry. Apr 2006;63(4):385-390.

Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry.Apr 2006;63(4):375-382.Altindag, O., A. Altindag, et al. (2007). "Relation of cortisol levels and bone mineral density among premenopausal women with major depression." Int J Clin Pract 61(3): 416-20.

(12 consecutive months of amenorrhea in the absence of causes such as pregnancy and lactation-perimenopause is 5-7 year period of transition from regular ovulatory cycles to complete anovulation)

Menopause, Perimenopause and Depression

• Introduction/Epidemiology• Mood Disorder Issues• Menstrual Cycle (PMS)• Pregnancy/Postpartum Depression• Menopause• Summary

Depression In Women

11

• Prior history of depressive episodes• Persistence of dysthymic symptoms after recovery

from an episode of depression• Presence of an additional, nonaffective psychiatric

diagnosis• Presence of a chronic general medical disorder• Consider symptom severity and longevity

Practice guideline for the treatment of patients with major depressive disorder. Am J. Psychiatry 2000; 157 (suppl):1-45.

Major Depressive DisorderFactors Suggesting Lifetime

Maintenance Treatment

Patients experiencing an initial episode of major depression have at least a 50% chance of having a second episode, and by the third episode of major depression, there is a 90% chance of recurrence. All patients having a third depressive episode and some patients experiencing a second episode should be evaluated for maintenance antidepressant treatment.

• Remission is the goal• Perimenopause is a zone

of increased risk• SSRIs ideal (comorbidity,

experience)• Phototherapy, exercise

and natural or nutritional remedies deserve more attention*

• Risk/benefit ratio is key to all clinical decisions

• Mood disorders are linked to the reproductive life cycle

• Pharmacologic treatment has benefit and risks (pregnancy, lactation)

• PMDD appears to respond to SSRIs and venlafaxine

• Hx of mood disorder confers increased risk of postpartum mood syndromes

Epperson, C. N., M. Terman, et al. (2004). "Randomized clinical trial of bright light therapy for antepartum depression: preliminary findings." J Clin Psychiatry 65(3): 421-5.

Depression In WomenSummary

ResourcesPregnancy & Lactation Medication

• http://toxnet.nlm.nih.gov/cgi-bin/sis/search

• http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT

• http://www.obfocus.com/resources/medications

• http://www.perinatology.com/exposures/druglist

Depression In WomenTreatment

12

Neonatal Outcomes After Prenatal Exposure to Selective Serotonin

Reuptake Inhibitor Antidepressants and Maternal Depression Using Population-

based Linked Health Data

Oberlander, T. F., W. Warburton, et al. (2006). "Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data." Arch Gen Psychiatry 63(8): 898-906.

13.9

9.4

3.9

7.8 7.5

2.4

02468

10121416

NeonatalDistress

Jaundice FeedingProblems

%

Treated with SSRIs

Not Treated withSaris

• “Neonates exposed to SSRI/SNRI late in 3rd trimester have developed complications requiring prolonged hospitalization, respiratory support, tube feeding. AE may arise immediately upon delivery.*”

Oberlander, T. F., S. Misri, et al. (2004). "Pharmacologic factors associated with transient neonatal symptomsfollowing prenatal psychotropic medication exposure." J Clin Psychiatry 65(2): 230-7.

*respiratory distress cyanosis, apnea, seizures, temperature instability, feeding difficulty,vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying

SSRI/SNRI and NeonatesDiscontinuation Syndrome?

Risks Should Be Described In Patient Labeling, FDA’s Pediatric Subcommittee Of Its

Anti-infective Drugs Advisory Committee Recommended June 9, 2004

• Hypoglycemia • Hypertonia• Hyperreflexia• Tremor• Jitteriness• Irritability • Constant crying

Nordeng H, Spigset O. Treatment with selective serotonin reuptake inhibitors in the third trimester of pregnancy: effects on theinfant. Drug Saf. 2005;28(7):565-581.

Neonatal Antidepressant Discontinuation Symptoms*Pharmacological treatment should not be withheld

from a depressed pregnant woman in late pregnancy*

• Respiratory Distress • Cyanosis • Apnea • Seizures • Temperature

instability • Feeding Difficulty • Vomiting

*The neonate should be monitored for possible adverse effects after maternal use of an SSRI in the third trimester

• Occurs in as many as 6.8 of 1000 live births

• Mortality is approximately 10% to 20% with high-frequency ventilation, surfactant, inhaled nitric oxide, and extracorporeal membrane oxygenation but is much higher when these therapies are notavailable

Persistent Pulmonary Hypertension of Newborn

Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics. Apr 2006;117(4):1077-1083.

13

SSRIs and PPHN*• Infants exposed to SSRIs in late pregnancy

may have an increased risk• In a retrospective case-control study of 377

women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not** been exposed to antidepressants during pregnancy

*July 2006 from package insert

Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. NEngl J Med. Feb 9 2006;354(6):579-587.1.Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blindedstudy. Pediatrics. Apr 2006;117(4):1077-1083.

**.37% of 377 women whose infants had PPHN vs. .07% of controls

• Infants born to women who had first trimester paroxetine exposure had an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs)*

• Pregnancy precaution revised from Pregnancy Category C to Pregnancy Category D (indicative of positive evidence of human fetal risk) as well as placement of the usage in pregnancy language in the WARNINGS section of the label.

Paroxetine and Risk of Cardiovascular Malformations

*US United Healthcare Study increased risk of CV malformations: Paxil 1.5% vs. 1% who were dispensed other antidepressants (5956 mothers

who were dispensed paroxetine or other antidepressants)From PaxilCR prescribing information (July 2006)

Suri, R., L. Altshuler, et al. (2007). "Effects of antenatal depression and antidepressant treatment on gestational age at birth and risk of preterm birth." Am J Psychiatry 164(8): 1206-13.

Effects of Antenatal Depression and Antidepressant Treatment on

Gestational Age at Birth

Participants included 49 women with major depressive disorder who were treated with antidepressants during pregnancy (group 1), 22 women with major depressive disorder who

were either not treated with antidepressants or had limited exposure to them during pregnancy (group 2), and 19 healthy comparison subjects (group 3).

38.5

39.439.7

37.5

38

38.5

39

39.5

40


Wee

ks Group 1Group 2Group 3

14.3

0

5.3

02468

10121416

Preterm Birth Rates

%

Group 1Group 2Group 3



Gestational Age at Birth(before 37 weeks gestation)



14






21

9

00

5

10

15

20

25

Admission to Special Care Nursery

%

Group 1Group 2Group 3

Use of Selective Serotonin-Reuptake Inhibitors in Pregnancy

and the Risk of Birth Defects*

• Specific SSRIs may increase the risk of specific birth defects-further studies with sufficient power needed

• Absolute risk of these rare defects are small

• Risk/benefit ratio is key

Louik, C., A. E. Lin, et al. (2007). "First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects." N Engl J Med 356(26): 2675-83.

• Like Louik, et al. found no significant association between SSRI use overall and congenital heart defects

• Louik et al. showed significant associations between SSRI use overall and congenital heart defects (paroxetine and RVOFTO) and neural tube defects

• Alwan et al. did find maternal SSRI use was associated with anencephaly, craniostenosis and omphalocele-yet absolute risks were small

Alwan, S., J. Reefhuis, et al. (2007). "Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects." N Engl J Med 356(26): 2684-92.

*Data on 9622 case infants with major birth defects and 4092 control infants born from 1997 through 2002 from the National Birth Defects Prevention Study

Use of Selective Serotonin-reuptake Inhibitors in Pregnancy

and the Risk of Birth Defects*

Schizophrenia, Mania, Mixed Episodes, Bipolar DepressionQuetiapine (Seroquel)-C

Schizophrenia, Mania, AntiD augmentAripiprazole (Abilify)-C

Indication(s)Generic Name/Pregnancy Category

Lithium-D (CV-Ebstein’s) Mania, Maintenance

Carbamzeine (Tegretol)-D (NTDs) Mania, Epilepsy, Trigeminal Neuralgia

Divalproex (Depakote)-D (NTDs, DD) (antenatal folate reommended)

Mania, Mixed Episodes, Epilepsy, Migraines

Olanzapine (Zyprexa)-C Schizophrenia, Mania, Mixed Episodes, Maintenance (bipolar)

Risperidone (Risperdol)-C Schizophrenia, Mania, Autism (agitation)

Ziprasidone (Geodon)-C Schizophrenia, Mania, Mixed

Lamotrigine (Lamictal)-C Epilepsy, Maintenance Phase Bipolar I Disorder

FDA Prescribing Information August 2007

Bipolar Disorder Medications & Pregnancy

15

Atypical Antipsychotic Administration During Late Pregnancy:

Placental Passage and Obstetrical Outcomes

• Exposure to lipophilic fetal tissue such as lung and brain

• Statistical tendencies toward more low birth weight babies (4-8%, p<.06) and neonatal intensive care unit admissions (7-9%, p<.09)

• Haloperidol-40 years of clinical use may be preferred but has limitations: anticholinergicsmay be teratogenic, therapeutic benefits other than possible symptoms of psychosis limited

METHOD: The authors conducted a prospective observational study of women treated with an atypical antipsychotic or haloperidol during pregnancy. Maternal and umbilical cord plasma samples collected at

delivery were analyzed for medication concentrations. Placental passage was defined as the ratio of umbilical cord to maternal plasma concentrations (ng/ml).

Newport, D. J., M. R. Calamaras, et al. (2007). "Atypical antipsychotic administration during late pregnancy: placental passage and obstetrical outcomes." Am J Psychiatry 164(8): 1214-20.

72.1 65.5

49.2

23.8

0

20

40

60

80

Placental Passage

%

Olanzapine HaloperidolRisperidone Quetiapine

• Of drugs currently used, fluoxetine produces the highest proportion (22%) of infant levels that are elevated above 10% of the average maternal level

• Citalopram indicate produces elevated levels in 17% of infants

Weissman, A. M., B. T. Levy, et al. (2004). "Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants." Am J Psychiatry 161(6): 1066-78.Burt VK, Suri R, Altshuler L, Stowe Z, et al. The use of psychotropic medications during breast-feeding. Am J Psychiatry 2001;158:1001-1009.

Antidepressants and Breast Milk

• Nortriptyline, paroxetine, and sertraline may be preferred choices in breast-feeding women

• Current data do not support monitoring breast milk levels in individual patients

• When administrating valproate to nursing mothers, clinical pediatric status, LFTs and platelets should be carefully monitored

Weissman, A. M., B. T. Levy, et al. (2004). "Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants." Am J Psychiatry 161(6): 1066-78.Burt VK, Suri R, Altshuler L, Stowe Z, et al. The use of psychotropic medications during breast-feeding. Am J Psychiatry 2001;158:1001-1009.

Antidepressants and Breast Milk

• Transient neonatal symptoms common after use of antidepressants in late pregnancy

• Few firm data available on possible impact on the long-term neuropsychological development of the infants

• Magnitude of actual contribution from drugtherapy is unclear; underlying pathology of the mother may explain part of the anomalies

• When non-pharmacological treatments are not enough, the relatively small risk with drugtherapy has to be weighed against the considerable risk for a relapse of the disease if therapy is interrupted

Safety of Antidepressant Drugs During Pregnancy

Kallen, B. (2007). "The safety of antidepressant drugs during pregnancy." Expert Opin Drug Saf 6(4): 357-70.

Documents

Depression In Women Psychiatric Medications - PDF of Slides.pdf · • Menstrual Cycle (PMS) • Pregnancy/Postpartum Depression • Menopause • Summary Depression In Women Psychiatric