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The Pharmacokinetics of Antidepressants Across Pregnancy: The MADRE Study

The Pharmacokinetics of Antidepressants Across Pregnancy: The MADRE Study. Marlene P. Freeman, M.D. Associate Professor of Psychiatry, Harvard Medical School Director of Clinical Services, Perinatal and Reproductive Psychiatry Program Medical Director, CTNI Massachusetts General Hospital.

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The Pharmacokinetics of Antidepressants Across Pregnancy: The MADRE Study

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  1. The Pharmacokinetics of Antidepressants Across Pregnancy:The MADRE Study Marlene P. Freeman, M.D. Associate Professor of Psychiatry, Harvard Medical School Director of Clinical Services, Perinatal and Reproductive Psychiatry Program Medical Director, CTNI Massachusetts General Hospital

  2. Disclosures and Funding • Funding from the U.S. Food and Drug Administration Office of Women’s Health 223-03-8723, Task Order #1And the National Institute of Mental Health (NIMH) K23 MH66265 (for the Principal Investigator’s time) • Disclosures (past 12 months): Research grants: Eli Lilly, Forest, Glaxo SmithKline; Consulting: Pepper Hamilton, LLC; no stocks, no promotional speaking

  3. Depression in Women • Higher rates of depression in women, in all age groups over 10 years old • Lifetime prevalence rates: • Women 21.3%; (12.7% Men), most pronounced before 45 years of age • Women have approximately 2 times risk as men Kessler et al, 1993

  4. Causes of Disability by Illness CategoryUnited States and Canada, 15-44 years old WHO World Health Report 2002

  5. Causes of Disability by Specific IllnessUnited States and Canada15-44 years old WHO World Health Report 2002

  6. Risks of Untreated Antenatal Depression Possible complications: • May negatively affect maternal weight gain • May increase the risk of low birth weight, prematurity, and small for gestational age (SGA) • Neonatal behavioral differences, such as irritability and decreased activity • May lead to less compliance with prenatal care • Wisner et al., 1999; Wisner et al., 2009; Mulder et al., 2002; Yonkers et al, APA/ACOG guidelines, Obstetric & Gynecology, 2009

  7. APA/ACOG Joint Recommendations ● Psychotherapy: first line for mild - moderate MDD ● Lifestyle components - nutrition, weight management, prenatal care, childbirth education; Treatment for substance abuse ● Document all exposures dating back to conception ● Women trying to conceive - histories of MDD: Encourage period of euthymia Sustained remission - may consider tapering and discontinuing. More recently depressed or with symptoms: consider remaining on medication, optimizing medication ● Pregnant women with severe MDD:medication first-line ● Pregnant women on antidepressants during pregnancy:take into account patient preferences, previous course of illness ● Medication selection should be based on known safety information • Yonkers et al, APA/ACOG guidelines, Obstetric & Gynecology, 2009

  8. Antidepressants and Pregnancy: Overview and Controversies www.womensmentalhealth.org

  9. SSRI use during pregnancy • Prevalence of SSRI use during pregnancy is 3-7% • Recent findings and more data inform the pharmacologic treatment of depression during pregnancy • Consistent conclusions that the absolute risk of SSRI exposure in pregnancy is small1-3 • Recent case-control studies reveal inconsistent data regarding teratogenic risk of individual SSRIs4-10 • Reproductive safety data on SSRI exceed what is known about most other medicines used in pregnancy 1 Louik C, et al. N Engl J Med 2007; 2 Einarson TR, Einarson A. Pharmacoepidemiol Drug Saf 2005; 3 Einarson A, et al. Am J Psychiatry 2008; 4 Alwan S, et al. N Engl J Med 2007; 5 Greene MF. N Engl J Med 2007; 6 Hallberg P, Sjoblom V. J Clin Psychopharmacol 2005; 7Wogelius P, et al. Epidemiology 2006; 8 www.gsk.ca/english/docs-pdf/PAXIL_PregnancyDHCPL_E-V4.pdf Dear Healthcare Professional (3/17/08); 9 www.fda.gov/medwatch/safety/2005/Paxil_dearhcp_letter.pdf Dear Healthcare Professional (3/17/08) 10 Pederson et al., BMJ, 2009

  10. Long term data • Limited conclusive data: TCAs and SSRIs • Fluoxetine • Two studies demonstrating absence of neurobehavioral differences with TCAs versus fluoxetine in exposed vs nonexposed children TCA = tricyclic antidepressant. Nulman I, et al. N Engl J Med. 1997;336:258-262. Nulman I, et al. Am J Psychiatry. 2002;159:1889-1895. Oberlander TF, et al. J Clin Psychiatry. 2004;65:230-237. Oberlander TF, et al. Arch Pediatr Adolesc Med. 2007;161:22-29. Misri S, et al. Am J Psychiatry. 2006;163:1026-1032.

  11. Antidepressants During Pregnancy:Later Pregnancy Considerations • Risk of persistent pulmonary hypertension of newborn (PPHN) with SSRIs? • INCONSISTENT • One report showed increased risk by 6-fold (Chambers 2006; approximately 1%) • Lower association seen with Källén and Olausson, 2008 (0.15%) • No association seen by Andrade.et al., 2009; Wichman et al., 2007; Wilson et al., 2010

  12. Antidepressants During Pregnancy:Later Pregnancy Considerations • Reports of suspected neonatal syndrome: “withdrawal” or “toxicity,” complications after in utero exposure to SSRIs; low birth weight; prematurity • Overall studies do not adequately control for maternal mental health condition, adequate blinding of exposure in neonatal assessments • No clear benefit of tapering in third trimester Suri et al., 2007; Moses Kolko et al., 2005; Jordan et al., 2008; Oberlander et al., 2006; Suri et al., 2007; Warburton et al., 2010

  13. Risk of Relapse for Major Depression (MDD) During Pregnancy • Cohen et al., JAMA, Jan 2006 • Prospective study of MDD during pregnancy N=201; • euthymic prior to pregnancy, currently/recently using antidepressants; patients decided to continue/discontinue medication (not randomized) • 43% relapsed during pregnancy • 26% of those who continued medication • 68% of those who discontinued medication • Predictors of Relapse • Unmarried; Younger (<32 y); More recurrent depression, earlier onset of depression

  14. Depression, Antidepressants During Pregnancy • The literature regarding risks of antidepressants in pregnancy is constantly changing, complicated to interpret risks and personalize the risk/benefit decisions • Pregnancy definitely does not protect against relapse of major depression, and the rates of relapse are, even with antidepressant continuation • APA/ACOG guidelines suggest psychotherapy as first line, although many women will need other interventions such as medication

  15. Postpartum Depression • Prevalence: 10-20% • Anxiety is common • Risks of untreated maternal depression • Risks of medication exposure via breastmilk • Nonacs and Cohen, 1998

  16. Negative Effects of Maternal Depression on the Child • Insecure attachment • Behavioral problems • Cognitive function • Increased risk of abuse, neglect • Childhood psychiatric diagnoses & symptoms • Compliance with preventative measures • Thoughts of harming infant • Civic & Holt, 2000; Cicchetti et al., 1988; Feldman et al., 1999; Murray et al., 1999; Murray et al., 1996; Sharp et al., 1995;Kotch et al., 1999; Cadzow et al., 1999; Jennings et al.,1999; McLennan & Kotelchuck, 2000; Weissman et al., 2006.

  17. Treatment Recommendations: Perinatal Depression • Moderate to severe depression • Consider role of antidepressants; discuss risks and benefits with mother • Use lowest effective doses • Consultation with experts • Maximize non-medication alternatives

  18. Previous PK preg studies • Tricyclic Antidepressants: Observed that blood levels decrease in the third trimester, higher doses required to maintain therapeutic benefit • SSRIs: Some women appear to require higher doses in pregnancy to maintain benefits; variable observation of increased metabolism in late pregnancy; limited data due to rare use of therapeutic drug monitoring with SSRIs Wisner et al., 1993; Altshuler and Hendrick, 1996; Hostetter et al., 2000; Kim et al., 2006; Heikkinen et al., 2003; Sit et al., 2008; Ververs et al., 2009

  19. MADRE Study (Maternal Antidepressant Research and Evaluation) Freeman MP, Nolan PE, Davis MF, Anthony M, Fried K, Fankhauser M, Woosley R, Moreno FA. Pharmacokinetics of sertraline across pregnancy and postpartum. J Clin Psychopharmacology, 2008

  20. MADRE Study • Objective: To assess the pharmacokinetics of sertraline across pregnancy and postpartum • Dual IRBs: Approved by the Institutional Review Board (IRB) at the University of Arizona and the Research Involving Human Subjects Committee (RIHSC) of the U.S. FDA • Implemented through the Women’s Mental Health Program, Department of Psychiatry, and the General Clinical Research Center (GCRC) at the University of Arizona College of Medicine

  21. Approach • We sought to determine the pharmacokinetics of sertraline across pregnancy with a rigorous approach • using serial blood levels • observed dosage administration in the second trimester, third trimester, and postpartum • Sertraline selected based on wide utilization, available reproductive/lactation safety data • Maternal sertraline use was previously observed to produce the lowest ratios of cord blood concentrations to maternal serum relative to other SSRIs • No previous pregnancy PK study at the time • At the time the protocol was developed, sertraline (brand Zoloft) was the most prescribed antidepressant in the U.S.

  22. MADRE: Inclusion Criteria • Pregnant women ages 18 – 45 years of age • First or second trimester of pregnancy • Currently receiving treatment with sertraline and planned to continue independent of study • At least 2 weeks on a stable daily dose • Able to provide written informed consent • History of Major Depressive Disorder (MDD), as defined by Diagnostic and Statistical Manual of Mental Disorders- IV (DSM-IV) criteria, verified by Structured Clinical interview for DSM-IV (SCID) • Initial target enrollment was N=20

  23. Exclusion Criteria • Active suicidal or homicidal ideation • Active substance abuse • Concurrent medication that would require continuation during the two weeks preceding each assessment in the General Clinical Research Center (GCRC) • Exceptions: thyroid hormone, prenatal vitamins, and iron supplements • “High risk” pregnancy as defined by the participant’s obstetrical provider, excluding uncomplicated “advanced maternal age”

  24. Protocol: Sample Collection • Participants came to the GCRC for serial blood sampling to measure sertraline (SER) and its major metabolite, norsertraline (NOR), at steady-state concentrations (at least 14 days on a constant dose) for up to three visits: • 1) Second Trimester 22-26 weeks gestation • 2) Third Trimester: 30-34 weeks gestation • 3) Postpartum: 12-52 weeks postpartum • Blood drawn for assays : 0 hours (before dose of sertraline) and at 1, 2, 4, 6, 8, 10, 12, and 24 hours after observed administration of sertraline) • Postpartum visit: Women served as their own non-pregnant controls to assess the non-pregnant state pharmacokinetics • Third GCRC visit to assess maternal sertraline and norsertraline levels 12-52 weeks postpartum after the mother had ceased breastfeeding

  25. Safety Parameters • For safety: • Complete blood count (CBC) prior to each GCRC visit • Contraindications for blood draws were:  • Hemoglobin < 8, baseline pulse > 120, orthostatic symptoms, orthostatic changes on vital signs  • If any of these were present the day of a scheduled GCRC visit, the visit was rescheduled to insure patient safety • Obstetrician on-call during days of GCRC assessments

  26. Serial Sample Collection • Participants fasted for >2 hours before observed sertraline administration • Received their usual oral dose of sertraline with 200 mL of water • Food and drink after 2 hours of drug administration • Refrained from caffeine-containing beverages for at least 4 hours after sertraline administration • Avoided consumption of grapefruit juice at least one full week before and during each GCRC visit due to possible inhibition of the CYP 3A/4 isoenzymes which can alter sertraline metabolism (i.e., increase sertraline concentrations) • Placement of a peripheral venous catheter, blood was drawn after sertraline administration: baseline (time 0), 1, 2, 4, 6, 8, 10, 12, and 24 hours after dosing. • Serum samples were kept frozen at -20°C until analyzed. 

  27. MADRE: Laboratory Methods • A sensitive high performance liquid chromatography (HPLC)/mass spectrometric method (LC-MS) for the simultaneous determination of serum concentrations of SER and NOR was developed and validated • Sensitive, precise, accurate • Allowed for simple and rapid sample preparation • Economical • Publication: Fried KM, Nolan PE, Anthony M, Woosley RL, Freeman MP. LC-MS Analysis of Sertraline and its Active Metabolite in Human Serum Using a Silica Column with a Non-Aqueous Polar Mobile Phase, Chromatographia, 2010

  28. Analytic Methods • For each sertraline sampling period the following calculated: • area under the serum concentration vs. time curve (AUC), • maximal serum concentration (Cmax), • and the time at which Cmax occurred (Tmax) • calculated using the noncompartmental pharmacokinetic model provided by WinNonlin version 5.1. • For NOR, AUC and the NOR/SER AUC ratios were also calculated. SER AUC, Cmax and NOR AUC were dose-normalized (i.e., values divided by the patient’s dose at the time of sampling), due to varying doses within and between subjects.

  29. Clinical Data • Protocol: Caveats • Patients not required to be in remission from depression at enrollment, Not a treatment study for acute MDD • Treatment was independent of the study, and dose changes were allowed (although stable dose necessary prior to GCRC assessments, and pharmacokinetic assessments were dose corrected) • Collection of Clinical Data • Assessment of MDD: Requirement of history for participation • N=2 in acute episodes at enrollment • Assessments with: Hamilton Rating Scale for Depression (HAM-D)- 21 item, Edinburgh Postnatal Depression Scale (EPDS), Zung Self-Rating Anxiety Scale, Clinical Global Impression Scale (CGI) at each visit

  30. Participants • All women elected to continue treatment with sertraline during pregnancy, independent of study participation • N=11 enrolled • All the participants that completed GCRC visits were Caucasian and non-Hispanic • One Hispanic mother who consented for participation was disenrolled due to major fetal abnormality discovered after enrollment and prior to GCRC visits • N=8 completed at least 1 GCRC visit; N=6 - 2 visits, N=3 completed all 3 total GCRC visits, including the postpartum assessment • Because the objective of the study was to determine pharmacokinetic changes across pregnancy and the postpartum, and because patients served as their own controls, we focus our results on those who completed at least two of the scheduled GCRC visits (N=6).

  31. Results

  32. Figure 1: Dose normalized sertraline AUC across the perinatal period

  33. Figure 2: Dose normalized norsertraline AUC across the perinatal period

  34. Figure 3: Dose normalized sertralineCmax

  35. Figure 4: Norsertralinesertraline ratio

  36. Pharmacokinetics: Results • Changes from the Second to Third Trimester: (N=6) • Increase in oral clearance of sertraline by 17.4 + 7% from the 2nd to the 3rd trimester, • Decreases in SER AUC during the 3rd trimester in 5/6 women • Cmax also declined in 5/6 women from the 2nd to 3rd trimester. • The ratio of norsertraline to sertraline highly variable between individuals and across time points, likely reflecting inter- and intra- individual differences in sertraline metabolism • The AUC for norsertraline highly variable • Postpartum data: (N=3) • In two of three, the sertraline AUC and sertralineCmax increased postpartum, compared with the third trimester • Safety: No visits needed to be rescheduled based on laboratory or clinical indications

  37. Clinical Data •  Interpretation limited by the small number of participants and variability of disease course • On a case-by-case basis, the clinical and pharmacokinetic data assessed in parallel demonstrate that there is heterogeneity in dosing requirements for antidepressants during pregnancy • Dosing requirement is likely impacted by: • individual course of illness • metabolic effects of pregnancy, and • biologically determined individual differences in metabolism

  38. Genetics • Assessed Cytochrome P-450 Enzymes and the Pharmacokinetics of Sertraline During the Second and Third Trimesters of Pregnancy • Sertraline is metabolized through Cytochrome P-450 (CYP) 2D6, 2C9, 2C19, 3A4 • Hypothesized that genetic variability in the genes encoding for these enzymes may explain the observed pharmacokinetic heterogeneity, • Estrogen changes in pregnancy may impact activity of various isoenzymes

  39. Genetics: Methods • N=5 consented to participate in genetics component • Association study between CYP isoenzymes involved in the metabolism of sertraline and plasma levels of sertraline and primary inactive metabolite norsertraline • At the time the study was conducted we were not able to genotype the CYP-3A4 gene. Moreno et al, under review

  40. Genetics: Results • Results: Only the CYP-2C19 had enough genotypic variability to allow the use of Pearson’s Correlation to explore the relationship between plasma levels and genotype at different time points. • Based on norsertraline/sertraline ratios in 2nd and 3rd trimenster, trend in 2nd trimester for role of 2C19 (p = .104) • Significant association in 3rd trimester (p =.033) • Consistent with a relationship between 2C19 and third trimester metabolism of sertraline Moreno et al, under review

  41. Strengths • Systematic entry criteria • Rigorous collection of samples after observed sertraline administration • Consistent procedures for assessments at follow-up • Sensitive assay • Safety parameters

  42. Limitations • Small sample size • Recruitment and Retention Challenges • Clinical Interpretation of data

  43. Challenges: recruitment/retention Ineligibility: Concomitant medications Patient plans to discontinue, possibly due to warnings about SSRIs released during study by FDA regarding risks during pregnancy (paroxetine data, etc) Pregnancy complications Difficulty with time commitment Diagnoses other than MDD Loss of postpartum patients: Some postpartum patients continued to breastfeed past 52 weeks (ineligible for GCRC visit 3), others did not wish to participate in postpartum visit due to time constraints (despite child care stipend and ability to bring baby to visit)

  44. Limitations: Clinical Data • Interpretation of clinical (pharmacodynamic) data limited by small sample size, variability of disease course • N=2 had dose increases between 2nd and 3rd trimester, based on clinical judgment of independent treater • Difficult to assess clinical data in meaningful way in association with pharmacokinetic data • Heterogeneity in dosing requirements for antidepressants during pregnancy • Dosing requirement is likely impacted by: • individual course of illness (including acute vs. maintenance treatment) • metabolic effects of pregnancy • biologically determined individual differences in metabolism

  45. Lessons • Recruitment: • Collaboration with obstetricians was key • Retention and recruitment were challenging • Patient burden of participation • 24-hour assessments for women during pregnancy/postpartum were difficult, even with modest compensation and stipend for childcare • IRB process • Education of IRB contacts around topic was important • Safeguards were appropriately in place • Important to emphasize independence of treatment decisions and monitoring protocol

  46. Lessons • Public education is necessary around the need for research to guide the care of pregnant women • Education around mental health topics is urgently needed to decrease the stigma experienced by women who need treatment for psychiatric disorders • Politics: How do we ensure that rigorous and careful research is conducted that is guided by science, clinical need, and compassion?

  47. Summary • Findings consistent with other studies showing decreasing levels of antidepressants in the third trimester • Systematic studies in pregnant women are needed to determine protocols for clinical monitoring of psychiatric disorders • When is therapeutic drug monitoring of antidepressants indicated in pregnant women?

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