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Depression across women life cycle

  1. Depression across Women Life Cycle Dr. Magda Fahmy Professor of Psychiatry Suez Canal University
  2. 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.
  3. 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).
  4. 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.
  5. 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)
  6. 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
  7. 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
  8. Depression: Differences in Women Compared with Men Differences in women compared with menParameters 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.
  9. 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.
  10. 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
  11. • 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
  12. 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).
  13. 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
  14. Neurobiology of Female Hormone 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.
  15. Neurobiology of Female Hormone 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.
  16. Depression: Sex differences in antidepressant response Differences in women compared with menParameters 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
  17. Depression: Sex differences in antidepressant response 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
  18. Sex differences in antidepressant response 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.
  20. 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
  21. Life Phases • Puberty • Reproductive years/premenopausal • Menopausal transition • Post-menopausal
  22. 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.
  23. 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.
  24. 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
  25. Depression and Puberty
  26. 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
  27. Premenstrual dysphoric disorder (PMDD) May cause 1400-2800 symptomatic days across childbearing years of affected women Equivalent to 3-8 years of symptoms!
  28. 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.
  29. Management of PMDD Management: Treatment of PMDD includes both: • Nonpharmacologic and • Pharmacologic therapies.
  30. Nonpharmacologic therapy for PMDD Patients with mild to moderate symptoms: • Relaxation techniques • Light therapy • Sleep deprivation • Cognitive-behavioral therapy
  31. 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
  32. Pharmacologic therapy for PMDD • 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.
  33. Pharmacologic therapy for PMDD • 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.
  34. Pharmacologic therapy for PMDD 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. • treatment#sthash.KLl2DYn1.dpuf
  35. Pharmacologic therapy for PMDD • 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.
  36. Depression during the perinatal period (Pregnancy & Lactation)
  37. 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
  38. Pregnancy
  39. 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.
  40. 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.
  41. 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
  42. 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).
  43. 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.
  44. Pharmacotherapy in Pregnancy All psychotropics cross the placenta and none are approved by the FDA for use during pregnancy
  45. 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.
  46. 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.
  47. • 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).
  48. 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
  49. 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.
  50. • 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
  51. 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
  52. 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
  53. 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
  54. 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
  55. 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.
  56. Postpartum
  57. 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.
  58. 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
  59. 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
  60. 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
  61. 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.
  62. 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
  63. 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)
  64. Treatment of Postpartum Depression
  65. 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
  66. 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.
  67. 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.
  68. Safety of Antidepressants During Pregnancy and Lactation Drug FDA pregnancy category* AAP rating 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
  69. Safety of Antidepressants During Pregnancy and Lactation Drug FDA pregnancy category* AAP rating 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 †— Lactation risk categories are as follows: L1 = safest; L2 = safer; L3 = moderately safe; L4 = possibly hazardous; L5 = contraindicated.
  70. Antidepressants During Lactation 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.
  71. Antidepressants During Lactation 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.
  72. Antidepressants During Lactation • 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).
  73. Safety of Antipsychotics During Pregnancy and Lactation Drug FDA pregnancy category* AAP rating 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 †— Lactation risk categories are as follows: L1 = safest; L2 = safer; L3 = moderately safe; L4 = possibly hazardous; L5 = contraindicated. Medications and Mothers’ Milk (2014) by Thomas W. Hale, PhD
  74. Safety of Antiepileptics and mood stabilizers During Pregnancy and Lactation Drug FDA pregnancy category* AAP rating 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 †— Lactation risk categories are as follows: L1 = safest; L2 = safer; L3 = moderately safe; L4 = possibly hazardous; L5 = contraindicated. 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%)
  75. Perimenopause and Menopause
  76. 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)
  77. 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.
  78. Reproductive life cycle 10 20 30 40 50 60 70 80 years menopause Perimenopause PostmenopausePremenopausa ↓↓
  79. 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).
  80. Perimenopausal symptoms Clinical symptoms during the perimenopausal period include: • Mood changes • Insomnia • Fatigue • Memory problems.
  81. 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“
  82. 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.
  83. Menopause
  84. Menopause • Average age: 51.2 • Complete cessation of menses for 12 months
  85. 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
  86. 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
  87. 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
  88. 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.
  89. Perimenopausal & Menopausal Depression Treatment
  90. Perimenopausal & Menopausal Depression Treatment Psychotherapy Antidepressants Estrogen+ Antidepressants Major Depression
  91. Perimenopausal & Menopausal 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.
  92. Perimenopausal & Menopausal 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.
  93. Available Interventions for MDD • Healthy lifestyle: exercise, vitamin supplements, reduce caffeine and alcohol • Pharmacotherapy • Light therapy • Psychotherapy • Electroconvulsive therapy (ECT) • Combination therapy
  94. Thank you