Depression is a complex mental illness associated with disability and reduced quality of life for the person with depression, as well as substantial societal burden. Major depressive disorder (MDD) is the second leading medical cause of long-term disability, the fourth leading cause of global burden of disease, and is predicted to become the second highest cause of disability by 2020. Depression exerts a negative impact on physical health; it reduces adherence to medical treatment, reduces participation in preventive activities, and increases the likelihood of risk factors such as obesity, smoking, and sedentary lifestyles. MDD may be associated with immune dysfunction and cardiovascular disease, endocrine and neurological diseases, and a general increase in chronic disease incidence. Pharmacological agents are one of several treatment modalities used for depression, and one of the most frequently utilized classes of antidepressant medications are the selective serotonin reuptake inhibitors (SSRIs). The rate of treatment response following first-line treatment with SSRIs is moderate, varying from 40 to 60 %; remission rates vary from 30 to 45 %. Up to one-third of persons taking antidepressant medications will develop recurrent symptoms of depression while on therapy. The target goal for acute treatment should be remission, which is defined as a resolution of depressive symptoms. Response to treatment may not be sufficient as a target outcome because residual depressive symptoms are risk factors for relapse and negative predictors of long-term outcome. Clinicians are faced with a number of treatment options following an inadequate response to an SSRI, and these include monotherapy or combined therapy. Monotherapy options include: (1) an optimization strategy (increasing the dose or extending the duration of the SSRI), (2) switching to another SSRI, (3) switching to another class of antidepressants, or, (4) switching to a nonpharmacological intervention. Combination or add-on therapy options include: (1) combining the SSRI with an augmenting agent, (2) combining antidepressants, or (3) combining the SSRI with a nonpharmacological therapy (such as psychological therapies, exercise, etc.). It is also an option to switch to a new antidepressant and simultaneously combine that antidepressant with a second pharmacological or nonpharmacological treatment. This is sometimes referred to as an acceleration strategy. The primary goal of this comparative effectiveness review is to examine the evidence guiding clinical treatment decisions and ultimately to aid clinicians in their care of patients when SSRI therapy for an index episode does not result in an adequate treatment response. Key Questions include: KQ1. Among adults and adolescents with major depressive disorder, dysthymia, and subsyndromal depression who are started on an SSRI and who are compliant with treatment but fail to improve either fully, partially, or have no response, what is the benefit (efficacy or effectiveness) of monotherapy and combined therapy? How does efficacy/effectiveness vary among the different monotherapies and combined therapies? KQ2. What are the harms of each of the monotherapies or combined therapies among these adults and adolescents? How do the harms compare across different interventions? KQ3. How do these therapies compare in different populations (e.g., different depressive diagnoses, disease severity, age, gender, racial and socioeconomic group, and medical or psychiatric comorbidities)? These subgroups will be considered with respect to the different interventions. KQ4. What is the range of recommended clinical actions following the failure of one adequate course of an SSRI based on current clinical practice guidelines published between 2004 and April 2011?