The purpose of this study is to determine the impact of prescription opioid analgesic use (OAU) on the risks of depression, depression relapse and treatment resistant depression (TRD). The study approach is designed to establish the strongest evidence that OAU causes these depression outcomes independent of the known association between chronic pain and depression. Opioid analgesics are the most frequently prescribed medication in the US and in each state, with the total number of prescriptions exceeding 130 million annually. This represents a 10-fold increase in OAU since 1990, a period during which the number of outpatient visits for conditions associated with chronic pain remained relatively stable. OAU has recognized adverse effects on physical and emotional functioning and our preliminary studies reveal patients using opioids for >180 days are at increased risk of depression, compared to those who use < 90 days. This effect remained evident even after controlling for the reason for which the drug is prescribed, i.e. chronic pain. Veterans Administration (VA) electronic medical record data spanning 14 years provides information to establish temporal precedence relative to OAU, depression, relapse and TRD and provides measures of relevant covariates. We will compare results in a demographically distinct, nationally representative data base from a cohort of privately insured enrollees in United Healthcare (UHC). In each data base we will test hypotheses after correcting for the OAU- pain-depression confound by using instrumental variable methods to control for unmeasured confounding and propensity scores to balance the distribution of covariates across duration and dose of OAU. Cox proportional hazard models will then be computed and will account for the persistence of pain to demonstrate chronic OAU independently leads to new episode depression, relapse and TRD. Analysis will begin by creating a cohort of 500,000 unique VA patients with medical record data from 1999-2012. For the first aim, the cohort of patients will be free of depression and free of OAU for two years prior to baseline (2001). In this cohort we will determine the OAU duration and dose associated with increased risk of a new episode of depression. For aim 2, the cohort of patients will be free of OAU for two years and have a diagnosis of depression in the year prior to baseline. In this cohort we will determine whether OAU duration and dose increases the risk of relapse in patients who experience a period of remission and contributes to TRD. For aim 3, we will determine if findings differ in a non-VA patient population and, if so, identify patient characteristics that explain differences. Results wll have an immediate impact on determining the previously unmeasured public health burden of depression, relapse and TRD that may be occurring due to an exponential increase in opioid prescribing in the United States. This R21 will lead to a prospective cohort study to characterize lifetime depression histories and symptom level change in OAU associated depression and culminate in clinical trials of antidepressant therapy to reduce risk of depression for patients requiring opioid analgesics.