Mental Health Series for Perinatal Prescribers. Pharmacotherapy for depression and anxiety

Transcription

1 Mental Health Series for Perinatal Prescribers Pharmacotherapy for depression and anxiety

2 Non-medication Treatments Psychosocial support Prenatal education, Doula support, La Leche League, Mom s groups, internet groups, meditation groups Optimize physical health Exercise, Nutrition, Sleep Psychotherapy Bright light therapy

3 FDA pregnancy categories (1979) A B C D X Adequate and well-controlled (AWC) studies in pregnant women: no evidence of risk 1-3 rd trimesters Animal studies no risk ; no AWC studies in pregnant women,or Animal studies- risk; AWC studies in pregnant women, no evidence of risk Animal studies- risk; no AWC studies in humans, AND benefits may be acceptable despite risks, OR No Animal studies or AWC studies in humans. Evidence of human fetal risk, BUT benefits may be acceptable despite risks (ie: life-threatening situation, serious disease for which safer drugs ineffective). Animal & human fetal abnormalities AND the risk of the use of the drug in a pregnant woman clearly outweighs any possible benefit (ie:safer drugs or other therapies are available). 28 July 2010 Prescribing Risks in Women Veterans of Childbearing Age 3

4 FDA new Pregnancy and Lactation Labeling Rule (June 30, 2015) Summary of pertinent studies that bear upon perinatal use of individual medications Summary of the risks Discussion of the data

5 There is no NO-RISK option Risk-benefit decision making process Risks of untreated mental illness to mother & offspring Risks known about psychotropic Ilness Meds

6 How to make sense of the data?

7 Statistics 101 Odds Ratio (OR) OR = 1 OR < 1 OR > 1 to no difference in risk between the two groups. outcome is less likely to occur in the exposed relative to unexposed group outcome is more likely to occur in the exposed relative unexposed group Confidence interval (CI) If it includes 1, the result is not significant

8 Absolute Risk Absolute risk = Base population risk * Relative risk Example: Cardiac malformations Paxil was associated with a **1.5-fold** increased risk Base population risk is 1 per 100 Absolute risk = 1/100 x 1.5 = 1.5/100 New data suggests OR of 1.06 ( ) Absolute risk of 1.06/100 Wurst et al (2009) Birth Defects Research; Huybrechts et al (2014) NEJM

9 Confounding X and Y may seem to be associated, until Z is controlled for X Y Common unmeasured variables (residual confounding) Medical comorbidity (prior preterm birth, pre-eclampsia, gestational diabetes, prenatal care), Other medications Psychiatric severity &comorbidity Poverty Trauma Tobacco, drug & alcohol use Nutrition Paternal factors Epi/genetic factors

10 Confounding by indication Depression comparison group Propensity score probability of a patient being in the antidepressant exposure group given a set of observed covariates balanced propensity score across the medication and comparison groups allows estimate of the effect of medication exposure by accounting for the covariates that predict having the exposure

11 Confounding by indication Maternal depression Medical comorbidity Medications Psychiatric severity &comorbidity Poverty Trauma Tobacco, drug & alcohol use Nutrition Paternal factors Epi/genetic factors Child outcomes

12 Domains of reproductive toxicity 1. Spontaneous Abortion 2. Birth defects 3. Persistent Hypertension of the Newborn (PPHN) 4. Timing of delivery, Birth weight 5. Neonatal complications 6. Lactation 7. Neurobehavioral disorders Ilness Meds

13 1. Spontaneous Abortion Smaller studies OR 1.6 ( ) Meta-analysis of moderate and low quality studies OR 1.47 ( ) (no depression control group) Larger studies with more robust statistical analyses RR 1.14 ( ) Adjustment for registry-based depression diagnosis RR 1.0 ( ) Kjaersgaard et al (2103) Plos One; Ross et al (2013) JAMA Psych; Einarson et al (2009)JOGC

14 2. Birth Defects Grigoriadis et al (2014) J Clin Psych 0.93 ( )

15 2. Cardiac Defects Huybrechts et al (2014) NEJM

16 3. Persistent Pulmonary Hypertension of the Newborn Early studies: Late pregnancy SSRI exposure associated with risk Conflicting reports, OR 2-5 Recent, statistically robust, large study (n=~4 million) All PPHN cases SSRI -- OR 1.10 ( ) Non-SSRI antidepressant -- OR 1.02 ( ) Primary PPHN SSRI -- OR 1.28 ( ) Non-SSRI antidepressant -- OR 1.14 ( ) Huybrechts et al (2015) JAMA

17 4. Preterm birth Increased risk or synergistic effects MDD alone OR 1.2 ( ) SRI alone OR 1.6 ( ) SRI + MDD OR 2.1 ( ) No difference in risk 14% rates of preterm birth in depression samples with propensity score matching, regardless of antidepressant exposure Possible protective effect (SSRI vs unmedicated depressed) Early preterm OR 0.52 ( ) Late preterm birth OR 0.84 ( ) Malm et al (2015) Am J Psych; Yonkers et al (2012); Huybrechts et al 2014

18 5. Neonatal complications Onset from birth to 4 weeks of age Self-limited - Largely gone by 2 weeks of life Most common signs Tremulousness Hypertonia Respiratory disturbance Irritability Summary risk ratio RR 3.0 ( ) NICU risk OR 1.24 ( ) Moses-Kolko et al (2005) JAMA; Malm et al (2015) Am J Psych

19 6. Lactation Relative infant dose (%) Protein binding (%) Sertraline Paroxetine Nortriptyline Citalopram Fluoxetine Bupropion Quetiapine unquantifiable Hale, Medication and Mother s Milk 2004

20 7. Neurodevelopment Duration/# MDD episodes = negative predictors Perinatal depression is associated with cognitive delays, internalizing and externalizing problems Studies comparing TCA, venlafaxine, SSRIs, and no exposure No difference in motor, mental development, IQ, language, temperament Some studies of SSRIs suggest disturbance Lower score psychomotor development More internalizing behaviors and decreased attention Slowed 6 month, but normal 19 month development Nulman et al 1997, 2002, 2012; Casper et al 2003, Pederson et al 2010, Deave et al 2008, Wisner, Santucci

21 7. Autism Spectrum Disorders Positive studies Boukhris et al 2015: HR 1.87 ( ) Rai et al 2013 : OR 3.34 ( ) Croen et al 2011: OR 2.2 ( ) Negative studies Castro et al 2016: OR 0.90 ( ) Sorenson et al 2013: OR 1.2 ( ) Hviid et al 2013: OR 1.2 ( ) Increasing methodological rigor and control for confounding magnitude and significance of the association goes down for SSRI Goes up for maternal psychiatric disorder

22 Key Points Risk is conferred by virtue of having a diagnosis Antidepressant medications are markers of that diagnosis, which have associated conditions and behaviors Low absolute risk conferred by antidepressants the increase in risk is low (<1%) Maximize maternal well-being Select treatments based upon the medicine that effectively treats your patient s depression

23 Thanks for your attention!

24 Heritability: genetic, epigenetic, environment Maternal depression Child outcomes 24

25 Checklist when reading new articles How was exposure defined? Prescriptions written medications taken Is exposure to other important factors also considered, ie: nicotine, diabetes Are diagnoses of mother and child accurate? Outcome:>1 documentation of malformation/illness code How were confounding variables accounted for? Illness subgroup analysis Propensity score matching How high is the OR or RR (>2 is preferable) and what is the increase in absolute risk? Huybrechts et al 2016

26 Barriers for prescribing to perinatal women (psychiatrist specialist perceptions) Stigma Women s fears, heightened by drug company suits Prescriber fear of legal ramifications Difficulty understanding the science Other health care provider misperceptions of risk Lack of professional guidelines for treating perinatal mental illness 26 Einarson 2016