Consistent with findings from clinical effectiveness trials, this study suggests that approximately a third of patients who are treated with an SSRI will continue with monotherapy, while the majority of patients will require a second-step intervention. Adjunctive or add-on therapy was favored as a second-step intervention as compared with switching, and this pattern was observed across different medical specialties. The most common second-step interventions observed in this claims-based analysis were benzodiazepines and tricyclic antidepressants (most commonly trazodone). One hypothesis is that the add-on therapy is being used for management of residual symptoms. Insomnia, fatigue, anxiety, and cognitive symptoms are frequent residual symptoms associated with MDD , and they can also be adverse events associated with SSRI therapy . Benzodiazepines are likely used for their anxiolytic effects, and trazodone may be prescribed for sleep-related symptoms. Similarly, a common use for bupropion is to augment antidepressant effects, but it may also be used to manage treatment-emergent sexual dysfunction . Interestingly, despite regulatory approval as add-on therapy for patients with inadequate response to an antidepressant during the time period studied, there was limited use of the second-generation antipsychotics.
While this study was restricted to patients who initiated therapy on SSRI medications only, Schulz and Joish  conducted a US claims study examining second-step interventions among 7,273 patients with MDD who initiated any antidepressant therapy from 2002 to 2006. In their sample, 40.3% experienced a switch following their initial antidepressant, 1.5% had an add-on medication, and 58.2% maintained their initial antidepressant monotherapy. Another similar study was conducted by Milea et al. . In this US claims analysis of 134,287 adults and children prescribed new antidepressant treatment in 2004–2006, 23.2% experienced a change in their treatment. The most frequent changes were switch to another antidepressant (9.5%) and combination with another antidepressant (9.1%). Augmentation with an antipsychotic, anticonvulsant, or lithium added an additional 4.2% of patients to the combination therapy group, totaling 13.3% receiving add-on therapy. In Europe, a retrospective cohort study of medical records from 2008 to 2009 was conducted in Spain . One advantage of this study was the availability of patient information regarding response to the therapy. In this work of 2,260 patients, 43% of patients were classified as having an inadequate response to their initial monotherapy antidepressant treatment and were treated with a switch (43.2%), an additional AD (15.5%), a dose increase (14.6%), or continuation (26.7%) .
The differences in the frequencies of second-step treatment interventions between the current study and the above studies may be related to the study period. Each study examined claims from years prior to the 2007 FDA approval of the antipsychotic aripiprazole for the indication of the treatment of patients with inadequate response to antidepressant monotherapy or prior to the EU approval of adjunctive treatment for MDD. The advent of the approval of aripiprazole along with a subsequent approval of quetiapine as an add-on therapy for MDD has garnered greater attention to both the unmet medical needs of patients with MDD and the therapeutic option of add-on treatments . Another difference among studies is that these prior studies only included medications classified as antidepressants as potential switch or add agents, whereas the present study captured a broader range of psychotropic drug classes commonly used in the treatment of patients with MDD and thus increased the coverage for add-on therapy.
Notably, approximately a third of patients in this analysis continued with their treatment with monotherapy, and only 15% discontinued pharmacological treatment altogether. The rate of continuation is consistent with expectations that approximately one third of patients may be expected to remit with monotherapy . The rates of continuation may be also related to the inclusion requirement that patients have at least two codes of MDD. In a previous database study based on health records from general practitioners, one of the stronger predictors of duration of treatment following new antidepressant treatment was whether or not a depressive illness was coded in the record .
With regard to costs, as might be expected, patients who required second-step interventions of either add-on therapy or switching were associated with higher total health-related costs, possibly due to a more difficult to treat illness. Previous work has demonstrated that patients who require a switch generally present with a more acute depressive illness that may include more previous episodes of depression, comorbid psychiatric disorders, and/or concurrent prescriptions of anxiolytic or hypnotic medications . Both US and international studies have demonstrated that patients who have a partial or non-response, and who require additional treatment, are more costly compared with patients who achieve remission with an initial treatment intervention [23, 24].
The findings presented here should be interpreted in the context of the limitations of the study design. First, this study was conducted using an administrative claims database and included only patients with medical and prescription benefit coverage. As a result, the results may not generalize well to other clinical populations. Second, as the medical claims database does not include patient assessments, the use of diagnostic codes served as a proxy and may not be as rigorous as direct diagnostic assessments for identifying individuals with MDD. Third, without measurement of patient response, the reasons behind the selection of second-step interventions cannot be ascertained. Fourth, this study did not examine the medication dosage, which may also be a factor in treatment selection. For example, quetiapine in low doses is used primarily to ameliorate insomnia symptoms, whereas higher doses are indicated for antidepressant efficacy. Recent publications have highlighted the great variability in dosing of second-generation antipsychotics in the depressed population and thus blurs these objectives [25, 26]. Finally, while the indirect costs of MDD have been found to be substantial , this analysis focused exclusively on direct medical costs.
The strengths of this study include the overall size of the sample and the real-world generalizability of data drawn from a broad claims database. The findings reinforce the medical needs of patients with MDD as prescription patterns suggest that the majority of patients who are prescribed an SSRI will need additional pharmacotherapy. Further, the findings highlight the necessity for physicians across different specialties to be aware that second-step treatments are to be expected in the treatment of MDD. With this perspective, physicians and patients can partner together more confidently to individualize treatment to achieve the goal of remission.