Depression across women life cycle

Depression across Women
Life Cycle
Dr. Magda Fahmy
Professor of Psychiatry
Suez Canal University

Introduction
• Depression is the most significant mental health risk for
women and is still underdiagnosed and undertreated.
• Studies reported gender-related differences in:
Prevalence Clinical presentation Treatment response
• Clinicians must be aware of these gender differences in order
to improve the recognition, management and outcome of
these disorders in women.

Introduction
• Depression considered “the greatest disease burden for
women when compared with other diseases”.
• Unipolar depression is the most disabling illness for women,
accounting for 41.9% of the disability from neuropsychiatric
disorders among women compared with 29.3% among men
(WHO 2000).

Sex differences in the prevalence of mental disorders
across the life-cycle
Male : female differenceMental disorderLife-cycle stage
Males >> Females
Males >> Females
Males >> Females
Males >> Females
Pervasive developmental disorder
ADHD
Conduct disorders
Learning disability
Childhood
Females >> Males
Females > Males
Females >> Males
Males >> Females
Depression
Deliberate self-harm
Eating disorders
Substance abuse
Adolescence
Females > Males
Males = Females
Males = Females
Males >> Females
Depression and anxiety
Schizophrenia
Bipolar disorder
Substance abuse
Adulthood
Females > Males a
Females > Males
Females >> Males
Dementias
Depression
Psychoses
Old age
> prevalence is approximately two- to threefold greater; >> greater than a threefold difference in prevalence.
a The difference in old age is likely to be due to the greater longevity of women.

Lifetime Prevalence of Psychiatric Illness Based on National
Comorbidity Survey Data
Female (%)Male (%)
17.935.4Substance Use Disorders
23.914.7Mood Disorders
21.312.7Major depression
1.71.6Mania
30.519.2Anxiety Disorders
5.02.0Panic Disorder
Mood and anxiety disorders are more common in women. Peak incidence of
psychiatric illness during the childbearing years. WHO (2005)

Gender Differences in Depression
Many neuropsychiatricdisorders express themselves
differently in the two sexes, why? :
1. Brain dimorphism
2. Physiological and hormonal differences
3. Gender-specific behavior

Depression:
Differences in Women Compared with Men
Differences in women compared with menParameters
20 percent (10 percent in men)Lifetime prevalence rate
May be earlierAge of onset
May be longerDuration of episodes
May more often be recurrentCourse of illness
GreaterSeasonal effect on mood
More frequentAssociation with stressful life events
Experienced more oftenAtypical symptoms of depression
(e.g., hypersomnia, hyperphagia)
May be greater if self-ratedSeverity of depression
May be experienced moreGuilt feelings
Suicide attempted more oftenSuicidal behavior

Depression:
Differences in Women Compared with Men
GreaterAssociation of anxiety disorders
( panic and phobic symptoms)
GreaterAssociation of eating disorders
Usually lessAssociation of alcoholism and substance use
GreaterAssociation of thyroid disease
GreaterAssociation of migraine headaches
lessAssociation of antisocial, narcissistic
and obsessive-compulsive personalities
GreaterEffect of exogenous and endogenous
gonadal steroids on mood
Kornstein SG. Gender differences in depression: implications for treatment. J Clin Psychiatry 1997; 58(suppl
15):12-8. Seeman MV. Psychopathology in women and men: focus on female hormones. Am J Psychiatry
1997;154:1641-7.

Crying Differences
• By age 18, women cry four times more than men, possibly because of
higher levels of prolactin in women.
• Prolactin is present in tears and contributes to the amount of crying a
person does.
• The difference in levels of crying between men and women could also
be the result of cultural expectations.
• Wilson, Tracy V. "How Women Work" How Stuff Works. Accessed April 2, 2008.

Risk Factors for Women
• A family history of mood disorders
• Loss of a parent before the age of 10
• Childhood history of physical or sexual abuse
• Use of an oral contraceptive, especially with a high
progesterone content
• Use of gonadotropin stimulants as part of an infertility treatment
• Persistent psychosocial stressors
• Loss of social support system or the threat of such a loss
10
Copyright © 2011. World Psychiatric
Association

• Barriers:
• Stigma attached to mental care
• The important role women play in family functioning
• Greater family tolerance to less potentially dangerous
disorders
• The somatoform expression of depression leading to the
misdiagnosis of a medical condition
• Lack of knowledge about mental health services and
treatments
Limited Access to Care
11
Copyright © 2011. World Psychiatric
Association

Physiological and hormonal differences
• Women's Sex hormones variations may have impact on the
psychiatric illness, psychotropic medication used, dosage required for
efficacy, and response.
• Women have monthly variations in gonadal hormones
• Women become pregnant, breastfeed, go through menopause, and
may take hormone replacement therapy (HRT).

Neurobiology of Female Hormone
Estrogen
Interacts with multiple neurotransmitter systems
• Increases NE; Ach synthesis
• Increases serotonin levels
• Modulates serotonin: mood, sleep, appetite, migraines,
concentration/memory
• Acts as an MAO inhibitor
• Estrogen helps the brain to use glucose, enabling the
brain to acquire energy.
• Verbal memory/neuronal growth

Estrogen and neurotransmitters
• Fluctuating levels of estrogen contribute to dysregulation of
monoaminergic neurotransmitters circuits mediating
depressive symptoms, contributing to the potential
development of a major depressive episode.
----------------------------------------------------------------------
• Stahl SM. Antidepressants. In: Stahl’s Essential Psychopharmacology. 3rd ed. New York, NY: Cambridge University Press; 2008:511-666.
• Wise DD, Felker A, Stahl SM. CNS Spectr. Vol 13, No 8. 2008.

Progesterone
• The progesterone metabolite, allopregnanolone (ALLO) works on
GABA receptors.
• ALLO is a powerful anxiolytic, anticonvulsant, and anesthetic agent
which decreases anxiety and depression.
• Prozac, Seroxate and Lustral increase Serotonin and also increase ALLO
production
• Imipramine (Tofranil) had no effect on ALLO production.

Depression:
Sex differences in antidepressant response
GreaterAbsorption of antidepressant
GreaterRatio of body fat to muscle
LargerVolume of drug distribution
May be higherPlasma concentration of antidepressant
May need to be lowerAntidepressant dosage
More frequentSide effects of antidepressants
Increased monoamine oxidase enzyme activity
with decreased monoamine
neurotransmitters
Effect of progesterone
women have greater bioavailability and slower clearance of drugs , experience side effects twice as
often as men

Depression:
Differences in women
compared with men
Parameters
Decreased monoamine oxidase enzyme
activity with increased monoamine
neurotransmitters, Estradioldown regulate
COMT
Effect of estrogens
May need to be longerDuration of therapy
SimilarEfficacy of cognitive-behavioral and
interpersonal therapy
Similar or may be greaterEfficacy of combined medication and
psychotherapy
GreaterNeed for treatment of comorbid anxiety,
panic, phobic and eating disorders
MoreNeed for thyroid screening frequent

Class Response: Male vs female
Monoamine oxidase inhibitors M<F
Serotonin-norepinephrine reuptake
inhibitors
M=F
Selective serotonin
reuptake inhibitors
Age <50: M< F
Age ≥50: M=F
Tricyclic antidepressants M=F
Parker G, Parker K, Austin MP , et al. Gender differences in response to differing antidepressant drug classes: two negative
studies. Psychol Med. 2003; 33(8): 1473 7–147.
•Kornstein SG, Wohlreich MM, Mallinckrodt CH , et al. Duloxetine efficacy for major depressive disorder in male vs. female patients: data
from 7 randomized, double-blind, placebo-controlled trials. J Clin Psychiatry. 2006; 67(5): 761 –770.

DEPRESSIVE DISORDERS SPECIFIC TO WOMEN

DSM-5
Depressive Disorders
1. Disruptive Mood Dysregulation Disorder
2. Major Depressive Disorder, Single and Recurrent Episodes
3. Persistent Depressive Disorder (Dysthymia)
4. Premenstrual Dysphoric Disorder
5. Substance/Medication-Induced Depressive Disorder
6. Depressive Disorder Due to Another Medical Condition
7. Other Specified Depressive Disorder
8. Unspecified Depressive Disorder

Life Phases
• Puberty
• Reproductive years/premenopausal
• Menopausal transition
• Post-menopausal

Depression across lifecycle
• Normal PMS (Premenstrual Syndrome): 80% of women
• PMDD (Premenstrual Dysphoric Disorder): Affects 3%- 8% or 8-10% of
women
• During pregnancy 20% of women may experience depressive symptoms;
with 10% developing major depression.
• Postpartum depression 10-15% of new mothers usually within 2 weeks-6
months after delivery.
• Perimenopausal period Many women experience minor mood changes
and some have onset of major depression
• Menopause more incidence in pts. with previous episodes of depression
(premenstrually, postpartum, etc.)
• Kornstein SG. Gender differences in depression: implications for treatment. J Clin Psychiatry 1997;58:12-18.

Depression across lifecycle
• Oral contraceptives and hormone implants may trigger the onset of
depression.[1, 2]
• Hormone treatments for infertility may significantly affect mood.[1]
• HRT especially the progesterone, was associated with depressive
symptoms in postmenopausal women.[1,2]
• 1. Kornstein SG. Gender differences in depression: implications for treatment. J Clin Psychiatry 1997;58:12-18.
• 2. Wagner KD, Berenson AB. Norplant-associated major depression and panic disorder. J Clin Psychiatry 1994;55:478-80.

Female Hormones across life Phases
PMDD Pregnancy and lactation Perimenopause menopause
No gonadal hormone
abnormality
Continuous increase in
hormone through the 40 weeks
of pregnancy
Sudden drop at parturition of:
Estrogens, progesterone,
testosterone, CRH and cortisol
Hormonal changes are gradual
in onset and in termination
with
irregular menses and increase
FSH
Estrogen no longer
fluctuates
1. Heightened CNS
sensitivity to normal
ovarian cycling of
gonadal steroids.
2. Increased amygdala
activity (low
progesterone).
3. Acute endogenous
opioid withdrawal
Postpartum Decreased:
Serum levels of BDNF
5-HT , GABA
Postpartum Increase
• MAO activity in the early
postpartum period
• Immune system
dysregulation
1. Hypofunctional 5-HT
system
2. HPA axis hyperactivity
3. Changes in sex steroids
4. Vasomotor symptoms
Vasomotor symptoms.
Insufficient numbers of
brain glucose
transporters
Hypothalamic centers,
react by triggering a
noradrenergic and
vasomotor response to
increase blood flow to
the brain

The Spectrum of Premenstrual Variations
Women presenting with premenstrual depressive symptoms:
1. Premenstrual Symptoms
Up to 75- 95% of women have at least 1 symptom
2. Premenstrual Syndrome (PMS)
2-3 symptoms, 30-50% of women
3. Premenstrual Dysphoric Disorder (PMDD)
5 or more symptoms, difficulty functioning, 3-5% of women
4. Premenstrual exacerbation of depression (PMED), and of many other
psychiatric and medical disorders
1. Major depression, Panic disorder, Generalized anxiety, PTSD, OCD, Bulimia nervosa, Substance abuse, Mania,
Psychosis
2. Asthma, Epilepsy, Allergies, Migraines

Premenstrual dysphoric disorder
(PMDD)
May cause 1400-2800 symptomatic days
across childbearing years of affected women
Equivalent to 3-8 years of symptoms!

Significance of PMDD
• Severe moods swings, depressed mood, irritability, anxiety and
physical symptoms (occurring exclusively during the luteal phase
(weeks 3-4) and remitting within 3 days of the onset of menses The
symptoms met for most menstrual cycles that occurred in the
preceding year.

Management of PMDD
Management: Treatment of PMDD includes both:
• Nonpharmacologic and
• Pharmacologic therapies.

Nonpharmacologic therapy for PMDD
Patients with mild to moderate symptoms:
• Relaxation techniques
• Light therapy
• Sleep deprivation
• Cognitive-behavioral therapy

Pharmacologic therapy for PMDD
Options for pharmacologic therapy for PMDD include the following:
1. Hormones
2. Diuretics
3. Nonsteroidal anti-inflammatory drugs (NSAIDs)
4. Anxiolytics, antidepressants, and mood stabilizers

• FDA approved 2 pharmacological options for PMDD:
4 (SSRIs):
• Fluoxetine, was approved 2000.
• Sertraline was approved in 2002
• Paroxetine HCI
• Escitalopram Oxalate
low-dose oral contraceptive pill
• Rapkin AJ, Winer SA. The pharmacologic management of premenstrual dysphoric disorder. Expert Opin Pharmacother. 2008;9:429-445.

• SSRIs can be administered intermittently, limited to the luteal phase
of the cycle (2 weeks prior to menses).
• Increased dosing of SSRIs in the luteal phase to reduce premenstrual
exacerbation of depression.1
• Dopaminergic or noradrenergic agents not efficious.
• GABAergic treatments, such as benzodiazepines, may be efficioaus . 2
• 1. Miller MN, Newell CL, Miller BE , et al. Variable dosing of sertraline for premenstrual exacerbation of depression: a pilot study. J
Womens Health (Larchmt). 2008; 17(6): 993 –997.
• 2.Rapkin AJ, Winer SA. The pharmacologic management of premenstrual dysphoric disorder. Expert Opin Pharmacother. 2008;9:429-445.

The rapid action of the SSRIs in PMDD
• SSRIs may work by a different mechanism in PMDD.
• Typically, SSRIs take 2 to 4 weeks to begin working in depressed
patients.
• Allopregnenolone : lower in luteal phase in patients with PMDD
• SSRIs In patients with PMDD may work by indirectly increasing
allopregnenolone synthesis from progesterone.
• http://www.psychiatrictimes.com/articles/premenstrual-dysphoric-disorder-update-diagnosis-and-
treatment#sthash.KLl2DYn1.dpuf

• Buspirone has been shown to be efficacious in the treatment of both
premenstrual syndrome (PMS) and PMDD.
• Diuretics: are used widely (symptoms of PPDD may be secondary to
fluid retention).
• If the woman also has severe physical symptoms (headache, cramps,
bloating, or water retention), combine the antidepressant with a
medication such as a diuretic, and over-the-counter pain medicine.

Depression during the perinatal period
(Pregnancy & Lactation)

Risk Factors for Perinatal Mood Symptoms
• A history of depression during the antenatal phase is strongest
predictors of depression during pregnancy and the puerperium
• Rapid hormonal changes
• Physical and emotional stress of pregnancy
• Physical discomforts
• Emotional letdown after pregnancy and/or birth
• Increased responsibility
• Fatigue and sleep deprivation
• Disappointments including the birth, spousal support, nursing, and
the baby

DIAGNOSIS OF POSTPARTUM PSYCHIATRIC
DISORDERS
DSM5-Specifiers for Depressive Disorders
With péripartum onset:
• If onset of mood symptoms occurs during pregnancy or in the 4
weeks following delivery.
• Postpartum mood (major depressive or manic) episodes with
psychotic features appear to occur from 1 in 500 to 1 in 1,000
deliveries and may be more common in primiparous women.

Depression During Pregnancy
• In the past, pregnancy was viewed as a period of well-being that
made women feel biologically "complete" and that provided
"protection" against psychiatric disorders.
• However, the prevalence rates for depression are now known to be
similar in pregnant and nongravid women.
• Altshuler LL, Hendrick V, Cohen LS. Course of mood and anxiety disorders during pregnancy and the postpartum period. J Clin Psychiatry
1998;59(suppl 2):29-33.

Treatment of Perinatal Depression
• Treatment must include both psychological and/or biological
interventions
• Psychotherapy (individual and/or group)
• Increased social supports
• Exercise, good nutrition, adequate sleep
• Antidepressant medications if appropriate
• Careful monitoring

Pregnancy and Medications Exposure Risks
• The risks of fetal medication exposure must be weighed against the
risks of no treatment
Triad of medication exposure risks
1. Congenital malformations medication during the first trimester
(time of organogenesis).
2. Perinatal complications medication exposure or withdrawal late in
the third trimester
3. Behavioral teratogenesis, disturbances in behavior and cognition in
a developing child exposed to medication in utero (long term
effects).

Malformations with maternal drug use
Depends on the properties of the drug and the point of exposure:
• Up to 32 days post-conception can affect neural tube development
and closure
• Days 21-56 after conception may affect normal heart formation
• During days 42-63 may influence development of the lip and palate.
• Craniofacial anomalies can also occur after the first trimester.

Pharmacotherapy in Pregnancy
All psychotropics cross the placenta and none
are approved by the FDA for use during
pregnancy

Pharmacotherapy in Pregnancy
Important issues to consider:
• Consider untreated or inadequately treated maternal depression vs.
risk of antidepressant exposure
• First trimester exposure
• Third trimester exposure and risk of “discontinuation syndrome”
• Must weigh risk/benefit ratio.

Risks of No Treatment- Pregnant Women
 Relapse of major depression
 Poor self-care
 Self-harm
 Low maternal weight gain, preterm birth
 Impaired bonding between mother and infant
 Increased risk of suicide and infanticide
 Bennett HA, Einarson A, Taddio A, Koren G, Einarson TR. Depression during pregnancy: overview of clinical factors. Clin Drug
Invest. 2004;24:157-179.

• Higher maternal cortisol
concentrations in early
gestation are associated with
larger right amygdala volume
and affective problems in
girls at 6-9 years age.
Buss et al., Proceedings of the National Academy of Science, 2012, 109, E1312-1319
Fetal exposure to maternal cortisol
and child brain development
Chronic early life stress (CES) have enduring adverse consequences, these may
emerge during adulthood and progress with age (Wilson, 2007) including:
 depression (Heim et al., 2008)
cognitive impairments (Nelson et al., 2007).

Fetal exposure to maternal cortisol
and Child Behavior Problems at 6 to 8 years
1
1.5
2
2.5
3
3.5
4
4.5
5
Anxious/Depressed
Low Prenatal
Cortisol
High Prenatal
Cortisol
N=181
Maternal Report
Sample Items
• Clings to adults
• Fears going to
school
• Nervous, high-
strung, or tense
Davis & Sandman, 2012 Psychoneuroendocrinology

Plan of management during pregnancy
Do not abruptly change or discontinue medications at
knowledge of conception.
1. Changing medications exposes the fetus to additional drugs.
2. The change may increase the risk for maternal symptoms.
3. Abruptly discontinuing medications increase the risk for relapse
4. The window of highest teratogenic risk for exposure have
already passed.

• Monotherapy is preferable to multiple medications
• Over the course of pregnancy, maternal daily-dose adjustment
may be required to maintain maternal well-being.
• Consider adjusting medications proximate to delivery.
• Reduce other risk factors, including smoking, obesity and illicit
drug use
Plan of management during pregnancy

Agent Category Range (mg/day)
Selective serotonin reuptake inhibitors
Citalopram C 20–40
Escitalopram C 10–20
Fluoxetine C 20–80
Paraxetine D 20–50
Sertraline C 50–200
Tricyclic antidepressants
Amitriptyline C 50–200
Desipramine C 50–200
Imipramine C 75–200
Nortriptyline D 20–150
Selective norepinephrine reuptake inhibitors
Desvenlafaxine C 50–400
Duloxetine C 30–60
Venlafaxine C 75–225
Other antidepressants
Bupropion C 150–450
Mirtazapine C 15–45
Nefozodone C 200–600
Trazodone C 150–400
Pregnancy and Dosages of Antidepressants
C. Risk Cannot Be Ruled
Out
D. Positive Evidence of Risk

The Risks of Treating — Pregnant Women*
Risks to fetus/infant
• Congenital cardiac malformations (first trimester; paroxetine, modest
risk)
• Neural tube defects (first trimester; SSRIs, modest risk)
• Newborn persistent pulmonary hypertension (third trimester; SSRIs,
moderate risk)
• Neonatal withdrawal syndrome (third trimester; SSRIs, especially
paroxetine)
• Prematurity, low birth weight
• Long-term neurodevelopmental abnormalities

TCAs in the third trimester
 Newborns exposed to TCAs in utero have exhibited symptoms,
including diarrhea, jitteriness, and muscle weakness, that may
be due to rebound cholinergic hyperactivity.[1] These potential
cholinergic side effects limit the use of TCAs during pregnancy.
 Feucht C. Treatment of depression during pregnancy. US Pharm. 2007;32(9):34#x2013;44

Dosing of Antidepressants during
Pregnancy
 Dose adjustments may be necessary to prevent relapse (eg,
when net metabolism is increased) or side effects (eg, when
net metabolism is reduced).
 Dose should increase during the second half of pregnancy
for:
1. increased drug metabolism and drug elimination (higher renal
blood flow and glomerular filtration rate (GFR).
2. Increased body fat drop in drug concentration

Discontinuing antidepressant medications before
delivery
 Recommendation: lowering or discontinuing antidepressant
medications 2 weeks before the expected date of delivery to
reduce the possibility of side effects, toxicity, and withdrawal in
the newborn, others are concerned that discontinuing drugs at
this time may increase the risk of postpartum psychiatric
disorders.[1]
 1. Stewart DE, Robinson GE. Psychotropic drugs and ECT during pregnancy and lactation. In: Stotland NL, Stewart DE (eds).
Psychological Aspects of Women's Health, Second Edition. Washington, DC: American Psychiatric Press Inc.; 2001: 67-93.

Spectrum of postpartum mood disorders
Postpartum Psychosis
(PP): 1–2/1000
within first 2–4 weeks following delivery ( may be early as 2–3 days) . The onset
is sudden and acute.
Postpartum Depression
(PPD) :10–13%
Postpartum Blues
50–75%
within first 2 weeks – time limited
None
Postpartum
Severity

Postpartum blues (PBs)
• “Baby blues” or “maternity blues,” incidence 70-75%
• Emotional lability, crying episodes, irritability, confusion, sleep
disturbance and anxiety.
• Minimal or no impairment of functioning
• Self-limiting
• No requirement for active intervention, only personal and
interpersonal adaptation and social support especially in case of
primigravida.
• PBs if more than 2 weeks; more vulnerability to severe mood
disorders

Postpartum depression (PPD)
• However, in PPD:
1. Negative thoughts mainly related
to the newborn.
2. Feelings of guilt or inadequacy.
3. Preoccupation with the infant's
well-being or safety severe to be
considered obsessional.
4. High anxiety symptoms.
Past history of:
• MDD increases the risk by 25%
• PPD increases the risk of recurrence
to 50%.
10–15% of postpartum women
The diagnostic criteria is difficult
to differentiate from MDD
Comorbid symptoms
panic attacks, OCD or psychotic features

DIAGNOSIS OF POSTPARTUM PSYCHIATRIC
DISORDERS
• Postpartum psychiatric disorders-----under-diagnosed
• Use of a specific screening tool such as the “Edinburgh Postnatal
Depression Scale,” and the “Mood Disorder Questionnaire”
• Laboratory investigations and physical examination to exclude organic
etiology (CBC, electrolytes, BUN, creatinine, glucose, Vitamin B12,
folate, thyroid function tests, calcium, urine analysis and culture in
the patient with fever).
• Neurological evaluation, brain scan to rule out organicity.

Suicides among depressed women during the
perinatal period
• Suicides account for up to 20% of postpartum deaths.
• Thoughts of self-harm during pregnancy and the postpartum
ranging from 5 to 14%.
• Arch Womens Ment Health. 2005 Jun;8(2):77-87. Epub 2005 May 11

Neonaticide and Infanticide
• Neonaticide is the killing of an infant within 24 hours of the birth.
• Infanticide is the killing of young children, in the first year of life.
• Filicide is the killing by a parent of their own child(ren) of any age.
• Infanticide is most often associated with:
1. Severe postpartum depression
2. Postpartum psychotic episodes (command hallucinations to kill the
infant or delusions that the infant is possessed (DSM5)

Treatment of Postpartum Depression

Treatment of Postpartum Depression in
Breastfeeding Women
• Mild to moderate depression: first line is PSYCHOTHERAPY
• Moderate to severe depression: antidepressant +
psychotherapy
• Clinical point:
No antidepressant has proven safer or more effective than another
No specific algorithm for antidepressant choice

Antidepressants During Lactation
No antidepressants FDA approved for use during lactation
Infants should be monitored for symptoms as persistent irritability, sedation,
decreased feeding, or poor weight gain.

Safety of Antidepressants
During Pregnancy and Lactation
Drug
FDA pregnancy
category* AAP rating
Lactation risk
category†
Antidepressants
Tricyclics and heterocyclics
Amitriptyline C Unknown, of
concern
L2
Clomipramine
(Anafranil)
C Unknown, of
concern
L2
Imipramine
(Tofranil)
C Unknown, of
concern
L2
Nortriptyline C Unknown, of
concern
L2
†— Lactation risk categories are as follows: L1 = safest; L2 = safer; L3 = moderately safe; L4 = possibly hazardous; L5 = contraindicated.

Drug
FDA pregnancy
Lactation risk
category†
Selective serotonin reuptake inhibitors
Citalopram C NA L3
Escitalopram C NA L3 in older infants
Fluoxetine (Prozac) C Unknown, of
concern
L2 in older infants;
L3 in neonates
Fluvoxamine C Unknown, of
concern
L2
Paroxetine D Unknown, of
concern
L2
Sertraline C Unknown, of
concern
L2
†— Lactation risk categories: L1 = safest ; L2 = safer; L3 = moderately safe; L4 = possibly hazardous; L5 = contraindicated
C. Risk Cannot Be Ruled Out; D. Positive Evidence of Risk

Drug
FDA pregnancy
Lactation risk
category†
Other antidepressants
Bupropion B Unknown, of
concern
L3
Duloxetine
(Cymbalta)
C NA NA
Mirtazapine
(Remeron)
C NA L3
Trazodone C Unknown, of
concern
L2
Venlafaxine (Effexor) C NA L3
AAP = American Academy of Pediatrics; FDA = U.S. Food and Drug Administration; NA = not applicable

Preferred choices:
• Sertraline, paroxetine and nortriptyline
• Sertraline preferable to fluoxetine (long half-life, may accumulate in
the serum of the infant).
• SNRI; Dopamine-reuptake inhibitor and Mirtazapine — no adequate
information
• Tricyclic antidepressants — excreted into breast milk in low
concentrations. No adverse effects documented for amitriptyline,
nortriptyline, imipramine, desipramine, or clomipramine.

All psychotropic drugs are excreted in breast milk
at varying concentrations
• Breast feeding decision made after careful weighing the risks and
benefits to the mother as well as the infant.
• Women with PPD with psychosis, may be advised against breast
feeding. Dopamine agonists to suppress lactation, used cautiously as may result in psychosis
in vulnerable women.
• In premature infants breastfeeding should be postpone if the
mother is on psychotropic medication.

• The amount of medication to which an infant is exposed depends on
several factors like:
 Maternal dosage and drug metabolism; infant metabolism
Timing and frequency of dosing: Breastfeeding restricted to just
before or after taking medication (drug concentration is lowest, as
peak concentrations in breast milk 6–8 h after ingestion of
medication).

Safety of Antipsychotics
Drug
FDA pregnancy
Lactation risk
category†
Antipsychotics
Aripiprazole C NA L3
Chlorpromazine C Unknown, of concern L3
Clozapine B Unknown, of concern L3
Haloperidol (Haldol) C Unknown, of concern L2
Olanzapine (Zyprexa) C NA L2
Pimozide (Orap) C NA L4
Quetiapine C Unknown, of concern L4
Risperidone (Risperdal) C NA L3
Trifluoperazine (Stelazine)‡ C Unknown, of concern NA
Medications and Mothers’ Milk (2014) by Thomas W. Hale, PhD

Safety of Antiepileptics and mood stabilizers
Drug
FDA pregnancy
Lactation risk
category†
Antiepileptics and mood stabilizers
Carbamazepine (Tegretol) D Compatible L2
Lamotrigine (Lamictal) C Unknown L3
Lithium D Contraindicated L4
Valproic acid (Depakene) D Compatible L2
AAP = American Academy of Pediatrics; FDA = U.S. Food and Drug Administration; NA = not applicable
During Pregnancy
Valprote: neural tube defect (lumbosacral) rates of 5% to 9%. (TTT daily folic acid)
Carbamazepine: neural tube defects 0.5% and 1%. Neonatal bleeding and mid-facial abnormalities (TTT daily folic acid + Vit K)
Lithium: Ebstein's anomaly between 1 per 1000 (0.1%) to 2 per 1000 (0.2%)

Perimenopause
• Perimenopause (time of irregular menses and increase FSH), until the
periods have stopped completely.
• However, the hormonal changes are gradual, both in onset and in
termination.
• Perimenopausal symptoms may appear up to 7 yrs prior to last
menses (mild mood symptoms)

Menopause:
• The official date is determined retroactively, once 12 months have
passed after the last appearance of menstrual blood.
Postmenopause
• The women who have not experienced a menstrual bleed for a
minimum of 12 months, assuming that they do still have a uterus, and
are not pregnant or lactating.

Reproductive life cycle
10 20 30 40 50 60 70 80 years
menopause
Perimenopause
PostmenopausePremenopausa
↓↓

Perimenopause
• Perimenopause can be a time of chaotic change for a woman’s
body and mind.
• Hormonal fluctuations is a risk for depression (The elevated risk
subside in postmenopause ; estrogen levels are low and vasomotor symptoms subside).
• Risk factors:
1. Midlife women with a history of depression
2. Premenstrual syndrome & Postpartum depression
3. Vasomotor symptoms (four times more likely to be depressed than
perimenopausal women without vasomotor symptoms).

Perimenopausal symptoms
Clinical symptoms during the perimenopausal period include:
• Mood changes
• Insomnia
• Fatigue
• Memory problems.

Causes of Depression in Perimenopause and Menopause
Psychosocial stressors
Life stressors
1. Sense of loss related to the end of fertility
2. The so-called "empty-nest syndrome" when children leave
home.
3. Having to deal with caring for, and/or the death of, elderly
parents .
4. The birth of grandchildren, which places people of "middle
age" into a new category of "older people“

Causes of Depression in Perimenopause and Menopause
Common Physiologic Abnormality
1. Hypofunctional central 5-HT system (low serotonin tone or blunted 5-
HT responsivity).
2. 5-HT abnormality may contribute to HPA abnormality
3. HPA axis hyperactivity
4. Changes in sex steroids
5. Irregular fluctuation of estrogen levels can interact with
monoaminergic neurotransmitter projections to the hypothalamus,
which can lead to the vasomotor symptoms (vasomotor symptoms and depression
regulated by monoamine neurotransmitters)
Clayton 2003; Wise DD, Felker A, Stahl SM. CNS Spectr. Vol 13, No 8. 2008.

Menopause
• Average age: 51.2
• Complete cessation of menses for 12 months

Clinical Features of Menopause
• Vasomotor symptoms
– HOT FLASHES, night sweats
• Sleep disruption
• Psychological complaints
– Forgetfulness
– Mood changes
• Reduced skin collagen and skin thickness
• Urogenital changes
– Vaginal dryness, atrophy
– Frequent urogenital tract infections
• Sexual dysfunction

Clinical Features of Menopause
Menopausal depression
Atypical Symptoms:
• Mood reactivity, hypersomnia, hyperphagia or weight gain,
rejection sensitivity.
• Atypical features may respond better to noradrenergic agents

Comorbid Conditions in menopausal depression
Medical ConditionsPsychiatric Conditions
Thyroid disorders
Migraines
Fibromyalgia
Irritable bowel syndrome
Obesity
Anxiety disorders
Panic and phobic disorders
Somatoform disorders
Eating disorders
Sexual disorders

Menopause
• Although estrogen no longer fluctuates, vasomotor symptoms are often
still experienced.
• Vasomotor symptoms:
1. Insufficient numbers of brain glucose transporters due to the lack of
estrogen
2. Hypothalamic centers, react by triggering a noradrenergic and
vasomotor response to increase blood flow to the brain and to
generate a compensatory increase in brain glucose transport.
• In women with diabetes and prediabetes, this situation could be
exacerbated.

Perimenopausal & Menopausal
Depression Treatment

Depression Treatment
Psychotherapy Antidepressants
Estrogen+
Antidepressants
Major Depression

Pharmacotherapy
• SSRIs: inconsistent benefit of vasomotor symptoms,1 positive
results for paroxetine (have some noradrenergic activity),
making it a weak serotonin-norepinephrine reuptake inhibitor
(SNRI).
• SNRIs: a clearer benefit for relief of mood and vasomotor
symptoms, 2 although are not approved for this use.
• 1.Rapkin AJ. Vasomotor symptoms in menopause: physiologic condition and central nervous system approaches to treatment. Am J Obstet Gynecol. 2007;196:97-106.
• 2. Archer DF, DuPont C, Constantine G, Pickar J, Olivier S. Desvenlafaxine succinate (DVS), a novel serotonin and norepinephrine reuptake inhibitor, improves mood and
menopausal symptoms in women with hot flushes (HFS) associated with menopause. Fertil Steril. 2007;88:S246.

Pharmacotherapy
• In women less than ~40 years of age, depression is more
responsive to SSRIs than to a TCAs or to a norepinephrine
reuptake inhibitor.
• However, this advantage of SSRIs never exists in men of any
age and is lost in women past ~44 years of age, which suggests
the mode of action of SSRIs may benefit from the presence of
estrogen.1
• 1. Martenyi F, Dossenbach M, Mraz K, Metcalfe S. Gender differences in the efficacy of fluoxetine and maprotiline in depressed patients: a double-blind trial of
antidepressants with serotonergic or norepinephrinergic reuptake inhibition profile. Eur Neuropsychopharmacol. 2001;11:227-232.

Available Interventions for MDD
• Healthy lifestyle: exercise, vitamin supplements,
reduce caffeine and alcohol
• Pharmacotherapy
• Light therapy
• Psychotherapy
• Electroconvulsive therapy (ECT)
• Combination therapy

Depression across women life cycle

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