Perinatal Anxiety Disorders: Etiology, Diagnosis and Treatment in 2019 Nicole Cirino MD, Reproductive Psychiatrist Associate Professor, Dept

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Perinatal Anxiety Disorders: Etiology, Diagnosis and Treatment in 2019 Nicole Cirino MD, Reproductive Psychiatrist Associate Professor, Dept. of Psychiatry and Dept. of OB/GYN Chief, Division of Women’s Mental health and Wellness OHSU Center for Women’s Health No Relevant Financial Disclosures or Conflicts of Interest Metro health objectives Perinatal Anxiety Disorders: Etiology, Diagnosis and Treatment in 2019

• Identify how reproductive hormonal fluctuation can influence anxiety in reproductive age women. • List three office based diagnostic tools for identification of perinatal anxiety disorders. • Develop a biopsychosocial treatment plan for patients with perinatal anxiety disorders. Male/Female Brain Differences in Etiology of Anxiety

Biologic

Psychologic Social/Cultural Anxiety Rates by Gender across the Female Reproductive Cycle

Anxiety Disorder Female Male

Panic Disorder 5.0% 2.0%

Agoraphobia 7.0 % 3.5%

PTSD 10.4% 5.0%

GAD (Generalized Anx. Dis) 6.6% 3.6%

SAD (Social Anx. Dis) 15.5% 11.1%

OCD (Obsessive Compulsive 3.1% 2.0% Dis) Biological Etiology Perinatal Anxiety Disorders

• Rapid shifts in hormones which acutely affect neurotransmitters in the brain – Estrogen – Progesterone – Oxytocin • Thyroid disorders • Sleep Deprivation • Obstetric factors • Genetic factors

Cirino, Nicole MD Perinatal Mood and Anxiety Disorders 6 Entering motherhood is the most significant biological event that happens in your life causing profound and permanent brain changes Jodi Pawluski PHD 8 9 A “sensitive period” – Brain changes in motherhood

• Enable her to multitask to meet her babies needs • Emphasize with the infants emotion and pain (and others) • Regulate how she responds to stimuli or threats • Sync her brain with her babies for life – Synchronized brain responses – Matching responses in gaze, touch and vocalization

Elseline Koekzema Leiden U, Netherlands 2016 A mother’s unique special connection to the child is vital for infants care and survival.

The ability to attach and remain the parent caregiver is the remarkable step that has marked our evolution from reptiles to mammals.”

Women’s Moods – Deborah Sichel MD Types of PMADs (Perinatal Mood and Anxiety Disorders)

• Baby blues • Antenatal depression* • Postpartum depression* • Perinatal anxiety: Prevalence: Pregnancy: 13-21% Postpartum: 11-17% – Specific Phobia – Generalized Anxiety Disorder (GAD)* – Obsessive Compulsive Disorder (OCD)* – Posttraumatic Stress Disorder (PTSD)* – Panic Disorder* – Tokophobia (fear of childbirth) • Postpartum mania/hypomania • Postpartum psychosis

* First line treatment is SSRIs

Perinatal Mood and Anxiety Disorders 12 Untreated Perinatal Anxiety Risks

Pregnancy: Assoc. with preterm birth, low birth rate and preeclampsia Neonatal: elevated infant cortisol, disrupted emotional regulation, negative behavioral reactivity and impaired cognitive performance in infants Childhood: impaired attention, increased risk of childhood psychiatric disorders, decreased brain volumes, increased behavioral and emotional problems

Thorsness et al American Journal of Obstetrics & Gynecology OCTOBER 2018 Estrogen

• Facilitates gender specific behaviors in women – Interpersonal aptitude – Verbal Agility • Inhibits Fear Response “The female brain has tremendous unique aptitudes: verbal agility, the ability to connect deeply in friendships, a nearly psychic capacity to read faces and tone of voice for emotions and states of mind, and the ability to diffuse conflict.

These are talents that women are born with that men frankly, are not.”

Women’s Moods – Deborah Sichel MD Estrogen – Mood Enhancing Effects

• A 1000 fold increase during pregnancy with rapid drop postpartum • Estrogen supports Serotonin – Increases synthesis (tryptophan) – Increased 5HT1 receptors in Dorsal Raphe – Reduces metabolism of serotonin (Decrease MAO activity) • Estrogen potentiates Norepinephrine • Antidopaminergic effects

Cirino, Nicole MD Perinatal Mood and Anxiety Disorders 16 Progesterone and the female brain

• Elevated in pregnancy with rapid drop postpartum • Progesterone and allopregnanolone are GABA agonists • Progesterone can have hypnotic and anxiolytic effects in postmenopausal women

Cirino, Nicole MD Perinatal Mood and Anxiety Disorders 17 Oxytocin (OT) and the female brain

• Fosters attachment b/w all mammalian mothers and infants • Improves ability to interpret social situations and facilitates attending to other – May increase sensitivity to interpersonal trauma • OT activates limbic structures assoc. with emotion and attention • Postpartum women: Lactation suppresses physiologic response to stress and decreases anxiety symptoms. • Promotes amnesia during labor HPA axis and Pregnancy

Fight Flight Freeze Anna “What's wrong with me, I would do anything for my baby, why can’t I do this?”

• 35 y/o female 30 weeks GA with uncontrolled GDM and limited PNC is referred for “anxiety”. • Patient is tearful, EPDS is negative, no past psych history. • She reports when she tries to inject herself with insulin she feels heart racing, dizziness, intense fear. On history she has always avoided doctors “unsure why”. Missed several PNVs. Risk = ? Benefit Treatment Approach to Perinatal Anxiety

Biologic

Psychologic Social/Cultural Anxiolytics: Dosing Clinical Pearls Benzodiazepines

• Only use for acute, discrete panic symptoms on as needed Starting dose: basis Alprazolam (Xanax) 0.25mg • Most addictive, short half life Range: 0.25 – 2mg • Notable rebound anxiety • AVOID when possible

Clonazepam (Klonopin) Starting dose: 0.25mg • Longest half life Range: 0.25 – 2mg • Can use Q12h dosing

• Can dose BID – TID Starting dose: 0.5mg Lorazepam (Ativan) • No active metabolites Range: 0.5 – 2mg • Lowest levels in lactation

. BDZ are associated with an increased risk of spontaneous abortion (adjusted OR, 1.85; 95% CI, 1.61-2.12). Sheehy et al JAMA Psychiatry. 2019 . BDZ are not likely strongly assoc. with congenital abnormalities. DevReprodToxicol 2008 . BDZ are assoc. with increased NICU admissions, smaller head circumference. Gen Hosp Psychiatry. 2018

•Why is this patient taking the medication? Anxiety symptoms? Insomnia? Phobia? •How is the medication taken? On a daily basis or as needed? •Is it possible to gradually taper the benzodiazepine? •If symptoms recur, are non-pharmacologic treatments, such as cognitive-behavioral therapy, effective in this setting? •If non-pharmacologic options are not successful, could treatment with an SSRI or an SNRI alone be an option? Specific Phobia: Trypanophobia- the fear of needles

• Behavioral therapy – Exposure • PRN lorazepam low dose • Involve partner and medical team Audience experiment

Susan: 38 y/o female G1P0 34 weeks GA “I am very worried about getting Postpartum Anxiety”

• Past Psych Hx: “Low grade anxiety started at age 13 (social anxiety, fear of flying and one panic attack). • Fam HX: Sister with obsessive thoughts about earthquake PP. • SX: Began this pregnancy -Images: Holding her niece and had violent image of dropping infant 2) spilling hot liquid on infant 3) image of her driving off a bridge 4) Panic on recent flight • ROS: Checking locks at night, has to push door knob several times, has been obsessed with led and led dust Neurobiology of OCD OCD -Postpartum

• Pregnancy and Postpartum period most common precipitant to new onset OCD in women • 1/3 of OCD patients report postpartum exacerbation • Violent images more common postpartum • Preliminary evidence that breast feeding alleviates OCD – anxiolytic effects of oxytocin • Incidence: • 3.5% in third trimester of pregnancy • 4%-11% 6 weeks postpartum • Prognosis: Symptoms continue >6months Postpartum Depression

• Prevalence 10%-13% • Onset: 2 weeks – 6 months postpartum • Peak: 9 weeks postpartum • Other symptoms – Feeling inadequate as a parent – Obsessive thoughts or compulsions (57%) – Ego-dystonic thoughts of harming the infant (10- 30%) – Suicidal thoughts – Panic Attacks Perinatal Harming Obsessions

• Common: Unwanted thoughts of harm coming to the infant (100% of new mothers) • Unwanted thoughts that you are going to cause direct harm to infant (50% of new mothers) • Frequent examples are drowning, stabbing, choking, throwing, hitting, smothering, cooking • No increased risk of harming infant – unless patient is suicidal. • At Risk for neglect, avoidance, attachment disorders. Postpartum Obsessions vs. Psychosis – Similarities and Differences

Obsessions (OCD or Depression) Psychosis (Psychotic Disorder) Intrusive thoughts that cause distress Aggressive thoughts without guilt or (Ego dystonic) distress (Ego syntonic) Anxiety, hypervigilance Confusion, agitation Fear of acting on or thinking the Hearing voices or seeing things that thoughts other people don’t see Avoidance or rituals Bizarre or violent behavior Personal or family history of anxiety Personal or Family history of Bipolar No history of violence, over controlled History of violence, impulsivity Rapid Onset of Symptoms Rapid Onset of Symptoms Peak incidence 2-4 weeks PP Peek incidence first 3 weeks PP May screen negative for depression May screen negative for depression Screening and Monitoring Instruments • EPDS -3 - Anxiety • GAD-7- Generalized Anxiety Disorder: >13 Positive* • PCL-5 - PTSD • YBOCS - OCD

Can J Psychiatry. 2014 Aug Antidepressants- First Line Treatment for Perinatal Anxiety

SSRI Dosing Clinical Pearls

Starting dose: 10 mg • EKG above 40mg due to concern Citalopram (Celexa) Range: 20-40+ mg over QTC prolongation

Starting dose: 5 mg • Works a little faster than other SSRIs Escitalopram (Lexapro) Range: 10-20+ mg • Not as activating for some patients

• Longest half life Starting dose: 10 mg Fluoxetine (Prozac/Sarafem) • Minimal withdrawal effect if missed Range: 20-80 mg dose • Dose at bedtime Starting dose: 50mg Fluvoxamine (Luvox) • Used for OCD Range: 100-300mg • Not indicated for anxiety, panic • Short half life Starting dose: 10 mg Paroxetine (Paxil) • Notable withdrawal effects if Range: 20-40+ mg late/missed dose • Most commonly prescribed in Starting dose: 25 mg Sertraline (Zoloft) pregnancy and postpartum Range: 50-200+ mg • GIhttp://www.postpartum.net distress common at initiation © 2018 PSI SNRI Dosing Clinical Pearls (all 2nd line)

Starting dose: 25 mg • Very little safety data on use in Desvenlafaxine (Pristiq) Range: 50 or 100 mg pregnancy and lactation

• Recent increasing amount of Starting dose: 20mg safety data on use in pregnancy Duloxetine (Cymbalta) Range: 60-120mg and lactation • Withdrawal in the neonate

• XR formulation most used • Short half life • Notable withdrawal effects if Starting dose: 25 mg Venlafaxine (Effexor) late/missed dose Range: 75-300 mg • Most safety data in pregnancy/lactation of SNRI class

Anxiolytic Dosing Clinical Pearls (non-benzodiazepine) • Dosing BID or TID standing (not PRN) • Preferred over benzodiazepine Starting dose: 5mg in patient with history of Buspirone (Buspar) Range: 5 – 60mg max/day substance abuse/dependence • Not always effective • Minimal data in pregnancy / lactation

• Dosing BID – QID Starting dose: 25mg Hydroxyzine (Vistaril) • Antihistamine Range: 25 – 50mg • Frequently used in pregnancy

• Atypical antipsychotic • Low doses effective for insomnia and anxiety Starting dose: 12.5mg Quetiapine (Seroquel) • Doses > 100mg for bipolar and Range: 25-100+mg psychotic disorders • Orthostatic hypotension common first few mornings

• Psychotherapy - CBT • Medication – SSRI now or 38 weeks • Perinatal support groups

Biologic

Psychologic Social/Cultural

Michelle:35 y/o G2P1 with severe PPH, hemorrhagic shock and ICU admission.

• Presents at 4 weeks PP • Social worker by trade and was “very intuitive.” • Had a young son at home. Single mother. • Several services were involved in her 5 day hospital stay: Fam Med, OB, MFM, ICU, Anesthesia, medical students, RNs, LCSWs

• PCL-5 Positive PTSD. Feared she would die, and never see her son again. Flashbacks, nightmares, avoidance. Perinatal PTSD: A vulnerable time for women.

Exacerbation of PTSD Initial Triggering Event - Difficult labor and delivery - Obstetric Exams – Preterm delivery - Labor and delivery – Emergency c-section - Unknown providers – Postpartum hemoglobin <9 g/dl - Genital exposure/touch – Instrumental delivery - Sensation of neonate in - Miscarriage the canal - Stillbirth - Breastfeeding - Skin to skin contact - Milk-ejection reflex - Infant smiling or playing with breast

Sentilhes et al. (2017) Prevalence of PTSD

• Prevalence of PTSD @ 6 weeks post-partum 2-6% – High risk perinatal population 15% • Prevalence of PTSD @ 6 months post-partum 1.5%

• General pop. who develop PTSD after a trauma 20%

Grekin and O’Hara 2014 PTSD criteria: DSM-5 Both A) and B), C), D) and E) criteria must be present for >1 month* *Acute Stress Disorder 3 days -1 month

A.Exposure to actual or threatened death, serious injury or sexual violence

. To you or a loved one . Repeated exposure to others’ trauma (first responders, doctors, medical or social workers)

The person’s response involves intense fear, helplessness, or horror PTSD criteria (cont.): Present for >1 month* 1 or more symptoms from each category B) Intrusive symptoms . Recurrent, Intrusive or involuntary memories, dreams . Dissociative reactions (flashbacks) . Psychologic/Physiologic reactions to cues, reminders C) Avoidance . Avoidance of reminders (cognitive or behavioral) . Amnesia D) Negative cognitions . Blaming, guilt, fear, horror, . Foreshortened future . Isolation loss of interest, detached from others E) Alterations in arousal and reactivity . Hypervigilance, irritable, anger outbursts . Insomnia, anxiety, increased startle Michelle: Psychiatric visit 4 weeks PP

• “When I woke up with a tube in my throat, I was not sure where I was, I felt like I was choking and I did not know where my baby was or if he was alive. I was alone in the room.” • “Several doctors and nurses I did not recognize kept coming to see me during recovery wanting to talk about what happened to me. I found myself feeling the need to help them emotionally as they were visibly upset. Seeing their fear brought the memories back to when I was in that room two days ago. Each time one of them left the room the images stayed with me and I felt like I was going to vomit.” • “One of the worst memories involved me being partially conscious and the nurse trying to pump my breasts for milk.”

Treatment: • Responded to Trauma focused therapy/ Exposure • Re evaluated how to approach PPH patients in the first 72 hours Interventions after a trauma – Subacute (2 weeks- 8 weeks)

1. Acute: < 7 days. Low light, don’t debrief, educate. 2. Subacute: 2 weeks – 6 months a) PTSD screen at 2-6 week visit and referral if positive. b) Debriefing: Reintegration . Fill in details to help them process. . Interpersonal validation, empathy. . Educate on trauma response. c) Medication intervention a) SSRI (adjunctive Prazosin, Propanolol) 3. Chronic:> 6 months . Exposure therapy and medication Brexanolone 3/19 FDA 2019 Update approved New medication for moderate to sever postpartum depression An allosteric modulator of GABA-A receptors 3 days inpatient IV infusion Remission of depression often within 24 hours up to 30 days SE: Sedation effects ranged from somnolence to loss of consciousness. All resolved within 60 minutes of infusion discontinuation. Breastfeeding –12 women/infant dyads. Relative infant dose 1-2%.

1. Kanes SJ, et al. Hum Psychopharmacol. 2017 Mar;32(2)) 2. 1. Hoffmann E, Wald J, Colquhoun H. Evaluation of breast milk concentrations following brexanolone iv administration to healthy lactating women. Am J Obstet Gynecol. 2019;220:S554. Abstract. DOI: doi:10.1016/j.ajog.2018.11.873 3. Hoffmann E, Wald J, Dray D et al. Brexanolone injection administration to lactating women: Breast milk allopregnanolone levels. Obstet Gynecol. 2019;133 (Suppl 1):115S. Abstract 30J. doi:10.1097/01.AOG.0000558846.15461.70 DOI: doi:10.1097/01.AOG.0000558846.15461.70 http://www.postpartum.net © 2018 PSI Resources:

For Clinicians:

Traumatic Childbirth: Cheryl Tatano Beck Trauma and Recovery: Herman The Body Keeps the Score: Dessel Van Der Kolk

Resources for patients: 1. Trauma and Birth Stress Resources: http://www.tabs.org.nz/ 2. Solace for Mothers: http://www.solaceformothers.org 3. Online Support Groups: http://www.postpartum.net/psi-online- support-meetings/ Perinatal OCD resources

Resources for Medications in Pregnancy and Breastfeeding

• Reprotox: www.reprotox.org • Motherisk.org: www.motherisk.org 1-877-439-2744 • www.infantrisk.com ; (806) 352-2519; phone app also available • Organization of Teratology Information Services: www.mothertobaby.org; good handouts • MGH Women’s Mental Health Program: www.womensmentalhealth.org • LactMed: www.lactmed.nlm.nih.gov • E-Lactania: http://www.e-lactancia.org/ingles/inicio.asp • Tox Net www.toxnet.nlm.nih.gov