Treatment resistant depression in women with peripartum depression

We used the IBM MarketScan® Commercial Database (CCAE). This is a large US claims database that includes data from individuals enrolled in employer-sponsored insurance health plans. Data include adjudicated health insurance claims (e.g., inpatient, outpatient, and outpatient pharmacy) as well as enrollment data from large employers and health plans who provide private healthcare coverage to employees, their spouses, and dependents. Data elements are outpatient pharmacy dispensing claims (coded with National Drug Codes (NDC) and inpatient and outpatient medical claims, which provide diagnosis codes (ICD-9-CM or ICD-10-CM).

We included women with peripartum depression. Although peripartum depression is clinically diagnosed when mood symptoms of major depression occur during pregnancy or in the 4 weeks following delivery [4], it has been recommended that the onset be expanded from 4 weeks to 6 months after delivery [6]. Thus, we defined peripartum depression as having depression diagnosed during pregnancy or up to 6 months after the end of pregnancy.

Depression was defined using a validated algorithm that requires the presence of two depression diagnosis codes within 1 year or a hospitalization with a depression diagnosis [16]. We included both women with a history of depression prior to pregnancy (prevalent depression) and women with newly diagnosed depression (incident depression) any time during pregnancy or up to 6 months after the end of pregnancy.

Since women with peripartum depression may not be exposed to pharmacological treatments for depression early in their pregnancy because they discontinue them to conceive or after conception [17], or do not start them because of concerns of exposing the fetus to antidepressants [18], some of these women would not have the opportunity to develop treatment resistant depression, which is based on lack of response to pharmacological treatments. To address this, two groups of women were created: 1. all women diagnosed with peripartum depression; 2. only women with peripartum depression diagnosed 3 months before a live birth delivery or within 6 months after that delivery. The latter group is more likely to have the opportunity to be exposed to pharmacological treatments, even if pharmacological treatment had been postponed during early pregnancy. See Fig. 1.

Women with psychosis, bipolar disorder, or dementia before the index date (i.e., the date of the first depression diagnosis during pregnancy or 6 months after a delivery) were excluded to ensure that any antipsychotic received was for the treatment of depression and not for the treatment of psychosis. Women with bipolar disorder were excluded because when TRD is studied and defined this type of depression is often excluded [19, 20].

Pregnancy, pregnancy duration, and pregnancy outcomes were defined in the database using a validated algorithm developed for claims database studies [21]. The Systematized Nomenclature of Medicine-Clinical Terms (SNOMED) concepts used to identity depression were depression and major depression, excluding concepts for bipolar disorders and schizoaffective disorders. SNOMED is a standardized, multilingual vocabulary of clinical terminology that is used by physicians and other healthcare providers for the electronic exchange of clinical health information [22]. The ICD 9 and 10 codes included are listed in Additional file 1.

The outcome of interest was the development of treatment resistant depression (TRD) within 1 year after the first diagnosis of depression during pregnancy. There is no consensus definition of TRD, but one of the most common definitions requires a minimum of two prior treatment failures and confirmation of prior adequate dose and duration [13]. Implementing such a definition in claims databases is challenging because it is difficult to ascertain why medications were changed or stopped -- improvement, lack of efficacy or adverse events [23, 24]. Nonetheless, there is a definition of TRD to be used in claims database studies that has been validated [23]. Using this definition, TRD was defined as women with a diagnosis of depression who were dispensed 3 distinct antidepressants or 1 antidepressant and 1 antipsychotic in 1 year. Similar to the clinical definition of TRD, the ingredient of the antidepressant or antipsychotic is not germane. For example, a pregnant woman with depression who received sertraline, escitalopram and amitriptyline within a year after the diagnosis of depression is considered to have TRD. Similarly, a pregnant woman with depression who received sertraline and quetiapine within a year after the diagnosis of depression is considered to have TRD. This definition of TRD proved to be superior to definitions that attempted to define TRD based on adequacy of treatment dose and duration [23].

We calculated the proportion of pregnant women with incident or prevalent peripartum depression who went on to develop TRD. We described the population in terms of demographic characteristics and of medical conditions that have been associated with TRD [20]. The presence of these conditions was assessed in the year before the first diagnosis of depression during pregnancy and defined using SNOMED concepts.

The use of the CCAE database was reviewed by the New England Institutional Review Board (IRB) and was determined to be exempt, as this research project did not involve human subjects research.

To create the various cohorts, we used R, version 3.43. To make the statistical comparisons we used STATA SE, version 14.