Trazodone

The setting for this study is Kaiser Permanente Northern California, a large group practice within an integrated health care delivery system that provides comprehensive medical services to over 3.6 million members and has approximately 37,000 pregnancies and deliveries in a 14-county region. Kaiser Permanente Northern California employs more than 500 obstetric physicians and nurse practitioners and over 100 Certified Nurse-Midwives. All 15 regional medical centers (with 48 associated office facilities) have Obstetrics and Gynecology, Adult Family Medicine, Pediatric, and Behavioral Medicine/Psychiatry Departments. Coverage is provided for approximately 30% of the northern California population and is similar demographically, racially and ethnically to the population living in the geographic area. Information on diagnoses, procedures, hospitalizations, outpatient visits, laboratory tests, and prescribed medications are maintained within administrative and comprehensive electronic health records (EHR).
From 2009 to 2012, Kaiser Permanente Northern California progressively implemented a universal perinatal depression screening program, with women being screened three times using the Patient Health Questionnaire (PHQ-9): twice during pregnancy (first prenatal visit and 26-28 weeks/the glucola visit) and 3-8 weeks postpartum. Details about the development and implementation of the screening program are described in detail elsewhere¹³ . Briefly, prior to 2009 women were not screened routinely, generally only if they were symptomatic, but depression diagnoses during pregnancy and postpartum were recorded in the EHR.
In 2009 three medical centers began piloting universal perinatal depression screening with screening during at least of one of three pregnancy and postpartum periods (early pregnancy, late pregnancy andpostpartum). From 2009-2012, referred to as the “roll-out phase”, several guidelines for the program were developed and implemented. Medical assistants asked patients to complete the PHQ-9 form at rooming at the designated visits and the clinician reviewed the form during the visit. If a woman's PHQ-9 score was 10 or higher, the guideline recommendations included symptom assessment and review of related current and past medical history. Using their clinical judgement, if indicated, the clinician documented a depression diagnosis in the EHR for screen positive women. Perinatal Depression Champions and Chiefs were responsible for educating clinicians and staff at the sites. Medical centers developed varying collaborations with Behavioral Health to facilitate referrals for treatment for screen positive women. Over this time the guidelines evolved to include reassessments of women identified with depression with a subsequent PHQ-9 evaluation during a follow-up encounter (office visit, online encounter or telephone visit) within 120 days. By 2010, all medical centers region-wide conducted screening during at least one of the pregnancy and postpartum periods.
By 2012, all obstetric offices in the region had implemented the universal perinatal depression screening program, which included screening at all three time periods, referring for treatment or providing treatment, and conducting follow-up assessments. This is referred to as the Fully-Implemented Phase.
The PHQ-9 has been validated in many studies as an instrument for screening for depression with high sensitivity (> 88%) and specificity (> 88%) in obstetric patients^{14 (link)-18 (link)}, as well as a tool to establish depression severity and outcome^{19 (link)}. The nine question screener scores range from 0-27. A score of 1-4 suggests minimal depression, 5-9 mild depression, 10-14 moderate depression, 15-19 moderately severe depression and 20-27 suggests severe depression. The PHQ-9 was chosen as the single screening instrument, to enable its use across the obstetric, adult family medicine, and behavioral health departments, knowing that this choice balanced out many factors including scientific validity and feasibility for a large scale population-based screening program.
A population-based retrospective cohort study of pregnant women aged 18 years and older was conducted and included women who had at least one obstetric visit during each of the following three periods of pregnancy and postpartum: the first 20 weeks of pregnancy (early pregnancy), 20 weeks of pregnancy through delivery (late pregnancy), and three months postpartum (postpartum). Inclusion criteria also required the first prenatal visit to occur during one of the three distinct phases in relation to the implementation of the Universal Perinatal Depression Screening Program: 1) Pre-Implementation-first prenatal visit date after April 1, 2007 and birth date prior to January 1, 2009; 2) Roll-out- first prenatal visit date after April 1, 2009 and birth date prior to January 1, 2012; 3) Fully Implemented- first prenatal visit date after April 1, 2012 and birth date prior to October 1, 2014. The timeframes for each phase were established to minimize the possibility of a woman's prenatal and postpartum visits crossing two phases and confounding the ability to attribute results to one phase. If a woman had more than one pregnancy during the study period, only the first pregnancy was included to avoid non-independent observations. The final study population included 97,678 pregnant women. This study was approved by the Kaiser Permanente Northern California Institutional Review Board.
Women were considered to have a new depression diagnosis if they had at least one depression ICD-9 diagnosis codes (296.20-296.25, 296.30 - 296.35, 298.0, 300.4, 309.0, 309.1, 648.4, or 311) during pregnancy or up to three months after delivery and no depression diagnosis or antidepressant drug dispensing in the year prior to their last menstrual period. Treatment for a new depression diagnosis was defined as having at least one antidepressant medication dispensed or at least one individual counseling visit or attendance at a group class that occurred on the same date or after the new depression diagnosis through 6 months postpartum. Antidepressant medications were predominantly SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) but also included tricyclic acids (amitriptyline, clomipramine, desipramine, nortriptyline, doxepin, imipramine, protriptyline, and trimipramine), SNRIs (desvenlafaxine, duloxetine, milnacipran, and venlafaxine), monoamine oxidase inhibitors (phenelzine and tranylcypromine), and others (trazodone, bupropion, atomoxetine, mirtazapine, nefazodone, and vilazodone).
Data on maternal demographic and socioeconomic characteristics including age at delivery, marital status, race/ethnicity, and Medicaid status during pregnancy, as well as previous mental health diagnoses any time prior to their last menstrual period were ascertained.
Data are reported as frequencies and percentages. Tests of trend were conducted to compare overall PHQ-9 screening rates, and rates of depression diagnoses across each of the three phases of the universal perinatal depression screening program (Pre-Implementation, Roll-Out and Fully-Implemented) while chi-square tests were used to compare PHQ-9 scores (<10, 10-14, 15+) and screening rates for each pregnancy and postpartum period (i.e., early pregnancy, late pregnancy, and postpartum). Treatment rates and type of treatment received were also compared across the three phases of the program, for all women with a depression diagnosis and separately for women with a PHQ-9 score of 15 or greater indicating moderately severe to severe depression. Additional analyses were conducted to address limitations in comparing the percentage of women receiving treatment across the phases including: 1) the increasing number of women in each phase, 2) under ascertainment of depression diagnoses prior to the screening program and thus a smaller number of women identified as needing treatment, 3) the potential that women diagnosed with depression prior to the screening program were more severe. Under the assumption that the screening program more accurately identified the true percentage of women with depression in the population, the percentage of women with depression in the Fully-Implemented phase was used to calculate the expected number women with depression in the other two phases. An expected percentage of treatment was then calculated using the observed number of women in treatment as the numerator and the expected number of women with a depression diagnosis in the denominator (Pre-Implementation and Roll-out Phases). This was conducted for both new depression diagnosis and new depression diagnosis and PHQ-9 score of 15 or greater. A Cochran-Armitage test for trend was conducted.
Improvement in depressive symptoms was assessed within each phase of the program through three metrics: 1) the percentage of women whose PHQ-9 score improved by 50% or more; 2) the percentage of women with a final PHQ-9 score less than 10; and 3) the percentage of women with a 5-point or greater drop in PHQ-9 score from the highest PHQ-9 to the final PHQ-9 score up to 180 days postpartum, which was considered to indicate clinical improvement^{19 (link),20 (link)}. Improvement in depressive symptoms was evaluated overall and separately for women with high severity (PHQ-9 score of 15 or greater).
Additional Chi-square analyses were conducted using the Fully-Implemented Phase to address potential bias. First we compared women in our sample to women excluded due to not having a prenatal or postpartum visit during all three time periods. Among women with a depression diagnosis or PHQ-9 scores of 15 or greater, we also compared those with a follow-up PHQ-9 to those without. Analyses were performed using SAS 9.3 (Cary, NC, USA; 2012).

Participants with a history of depression before WAFACS randomization (n=1,111) were excluded from this analysis, leaving 4,331 women (Fig. 1). History of depression at baseline was determined by: 1) self-report of ever having physician-diagnosed depression; 2) self-reported use of select antidepressants (described further below), along with an appropriate International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) depressive disorder code (i.e., 296.2x, 296.3x, 300.4, 309.0, 309.1, 309.28, 311), as entered by trained data coders. Women who had ICD-9-CM codes for bipolar disorder or nonaffective psychosis were also excluded. ICD-9-CM codes could be generated because participants specified physician diagnoses for which they were prescribed medications; participants did so by either writing down the diagnosis or verbally relaying this information to trained research staff over the phone.
The above exclusion process provided reassurance for assembling a baseline sample that was at risk for true incident depression. Regarding the requirement that antidepressant use be accompanied by a relevant ICD-9-CM code, this procedure was driven by clear evidence in our data of varying susceptibility to misclassification by class/type of antidepressant. For example, among all participants reporting use of selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs, excluding low-dose [5 mg daily] selegiline), tri- or tetracyclics widely-known for mood indications (e.g., nortriptyline, desipramine, imipramine, maprotiline) or newer/atypical antidepressants (e.g., bupropion, nefazodone), over 70% had a depression code and nearly 80% had a mood, anxiety or other mental health-related code. By contrast, only ~25% of participants reporting use of certain tricyclic antidepressants (TCAs) (e.g., sinequan, amytriptyline) or trazodone had any mental health-related code – depression or otherwise; these women were frequently prescribed for sleep or pain conditions. Thus, our data suggested that antidepressant use alone could not function as a reliable proxy of depression and likely reflected the shift away from TCAs in favor of newer agents during the post-1990s period of the WAFACS trial(17 (link)).