There has been limited prior research examining depression treatment sequences and the current work substantially expands upon this groundwork. Gauthier et al  examined patterns of switches, combinations, dose escalation, and discontinuation of antidepressants in general, but did not look at individual drugs or classes, and did not include non-antidepressant treatment classes. Hripcsak et al. , used a similar methodology to identify depression treatment sequences in multiple databases; however, this analysis did not capture combination therapy or use of non-antidepressant medication classes, among other differences in the approach.
Our study leveraged prescription claims data from four patient populations representing a broad cross-section of the US population, including commercially insured individuals, those receiving Medicare, and individuals on Medicaid. There was a relatively low prevalence of first-line SSRI use (occurring in less than half of patients) in contrast to many of the treatment guidelines recommending starting with monotherapy SSRI [15, 16]. Furthermore, use of anxiolytics, anticonvulsants, and hypnotics/sedatives were commonly used as the first treatment choice in these patients newly diagnosed with depression, potentially pointing to a reluctancy of physicians to prescribe antidepressants  but being more comfortable using other classes of drugs such as anxiolytics [18, 19]. High use of benzodiazepines, which comprised the majority of anxiolytic use in this study, is concerning because they are not recommended as a first-line therapy  and they carry concerns of abuse [20-22] and risk of overdose [23, 24].
This study showed that while general trends across these populations were relatively similar there were some important differences. Specifically, patients covered by Medicaid tended to have treatment patterns that were different than the other three groups – more than half of patients diagnosed with depression were untreated, first-line SSRI use was lower, and use of alternative treatment classes outside of antidepressants occurred more often. The Medicaid sample represents a population of vulnerable individuals of lower socio-economic status and high burden of disease and it appears they are receiving different care when compared with the other patient populations.
The results of this real-world assessment of treatment practices appear to contradict some common treatment recommendations regarding treatment with pharmacotheapy. Many patients, ranging from one-third to one-half, received no pharmacotherapy for their depression during the entire follow-up, a period covering a minimum of three years in all patients. This was not limited to only Medicaid patients, as mentioned above, but also affected patients from the other databases. More so, this could be an underestimate of the true prevalence of untreated depression patients, because a significant proportion of individuals go undiagnosed and therefore are not able to receive treatment. Previous research screening individuals for depression rather than relying on a physician diagnosis has found that just 29%-46% received a treatment for their depression [25, 26]. The results found in our study may be due to patients receiving alternative forms of treatment, such as psychotherapy, rather than pharmacologic treatment. It may also be that individuals who did not have dispensings had less severe depression or were prescribed non-pharmacological interventions. The American College of Physicians recommends clinicians choose between cognitive behavior therapy or second-generation antidepressants after discussing the pros and cons of the treatment choices with their patient . And the American Psychiatric Association (APA) recommends psychotherapy alone as an initial treatment for patients with mild to moderate major depressive disorder .
The high prevalence of non-antidepressant treatment classes could reflect the high rates of comorbid conditions, such as anxiety disorder or sleep disorders ; however, these medications are largely being prescribed as monotherapy and not in combination with an antidepressant.
There are limitations to this study. This analysis focused only on pharmacotherapy for the treatment of depression and did not examine rates of psychotherapy or procedures such as ECT or TMS, which play an important role in the overall care patients receive, and may account for the proportion of patients that were classified as untreated. Patients with depression were identified using diagnoses codes which are not a perfect tool; however, we used a previously published algorithm for identifying depression in claims data which achieved high validity (PPV=99%) . Because the algorithm requires two outpatient or one inpatient diagnosis, there is less of a chance of falsely classifying a patient as having depression due to a rule-out or misdiagnosis that may happen if only requiring a single diagnosis. However, we do not capture depression patients who received only a single diagnosis of depression in an outpatient setting. This is a trade-off we deliberately made to improve certainty that we only included subjects with depression.
This analysis did not capture any within-class switching or combination; for example, receiving two SSRIs is simply captured as monotherapy SSRI use and switching from one SSRI to another does not appear as a change in therapy. This is because the goal of this study was to understand the order in which different therapy classes are first received over time, but this provides opportunity for future research to look in detail at the individual drug level to assess in-class treatment changes.
This study did not examine the average time patients were actively receiving each treatment, or how long patients may have been with no treatment between switching from one class to the next, as it was outside of the scope of this research. Discontinuation of antidepressant treatment is common and has been identified as a risk factor for relapses [29-33].
There is no diagnosis associated with prescription claims, thus receiving treatment for non-antidepressant classes is not guaranteed to have been prescribed for treating the underlying depression or its symptoms. To mitigate this misclassification due to receiving therapy for reasons unrelated to depression, we required treatment to occur at the time of or following the first diagnosis of depression with no prior history of treatment in the database; however, this does not guarantee that treatments could not have been for other conditions that began treatment following a patient’s first depression diagnosis. Additionally, the pharmacy claims are a record of medication dispensed to a patient, they do not capture prescriptions that were written by a physician but never filled by the patient.
Our study required three-years of continuous observation following the index depression diagnosis. This follow-up requirement was chosen to capture sufficient follow-up across the population to allow us to see multiple lines of therapy and various treatment changes. It’s possible, and even likely, that by doing so we are excluding a certain subset of individuals with depression, but the alternative of requiring too short of a follow-up period would have prevented us from seeing what happens during later lines of therapy and would distort the observed treatment patterns in the population as a whole. By making this decision we sacrificed broader generalizability of results but increased the validity of what was observed.
This study included more than a quarter-million individuals diagnosed with depression across four major claims databases representing a full-spectrum of ages and types of insurance coverage. When examined together, these databases provide generalizability to a broad cross-section of the United States. We were able to leverage the infrastructure of the common data model and the tools from the OHDSI network to achieve a uniform and consistent approach across each of these four databases whose underlying data structures differ. This work expands upon previous work by not limiting the analysis to only drugs that are specifically classified as antidepressants. It is widely known that medications in various other classes are commonly used to treat patients with depression and this study reflects real-world prescribing practices.