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Although selective serotonin reuptake inhibitors (SSRIs) are often the therapeutic class of choice for depression, 20–50% of patients may be resistant or achieve only partial response. Therefore, clinicians often need to prescribe alternative therapies.OBJECTIVE: We compared patterns of medical resource use and one-year costs in a cohort of patients receiving venlafaxine versus tricyclic or tetracyclic (TCA) therapy for depression after switching from SSRI therapy. METHODS: Using claims data from a managed care organization, we identified patients diagnosed with depression who received second-line antidepressant therapy between 1993 and 1997. Second-line therapy was defined as a switch from SSRI therapy to either venlafaxine or TCA therapy. Patients with psychiatric comorbidities were excluded. We compared one-year medical expenditures using pairwise bivariate and multivariate statistical analysis. RESULTS: Median total one-year expenditures were $3,356 for venlafaxine (n=188) versus $4,661 for TCA (n=172) patients. Antidepressant expenditures were higher for venlafaxine (median =$661) than for TCA therapy (median =$158). However, this difference was offset by lower facility expenses ($159 venlafaxine versus $527 TCA) and by lower professional expenses ($1,410 venlafaxine versus $2,016 TCA). Multivariate analyses adjusting the age, gender, prescriber of second-line therapy, medication possession ratio, health plan, and six-month prior comorbidity expenditures showed that total one-year expenditures were lower among venlafaxine patients compared to TCA patients (−$313, p > 0.10). CONCLUSIONS: One-year medical expenditures are similar among depression patients receiving venlafaxine versus TCA therapy after switching from SSRI therapy. Higher antidepressant expenditures in the venlafaxine patients were offset by lower professional and facility costs.