Major depressive disorder (MDD) is almost exclusively recurrent. The vast majority of patients who experience one episode of MDD will eventually experience at least one more episode during their lifetime. The recurrent nature of MDD increases the burden to both the individual and society. Hence, it is imperative that treatment strategies focus on achieving remission acutely, as well as maintaining of remission and preventing recurrence. The articles in this supplement are based on presentations and a dialogue among a group of experts who convened for a roundtable discussion on improving long-term outcomes with antidepressant therapy.

Improving long-term treatment of MDD begins with understanding the clinical course of recurrent depression and the ability to recognize those patients who are at greatest risk for recurrence. James H. Kocsis, MD, reviews the course of recurrent depression, emphasizing the tendency for it to progressively worsen. He also discusses patient characteristics and other risk factors for recurrence as well as current recommendations for long-term management of recurrent depression.

Although long-term antidepressant maintenance treatment studies are somewhat limited in number, they provide the evidence base that shapes existing guidelines for long-term management of recurrent depression. Michael E. Thase, MD, examines this evidence for the different classes of antidepressants. In addition, Thase reviews evidence for the efficacy of psychotherapy and discusses its potentially important role in long-term depression management.

A significant proportion of depressed patients will experience multiple episodes of depression throughout their lifetimes, and, in recent years, attention has been paid to the identification of risk factors associated with a recurrent course of major depression. Residual depressive symptoms following acute phase therapy appears to be the most important clinical risk factor leading to recurrence. However, advances in empirically-supported treatment algorithms and guidelines, and in pharmacotherapy and psychotherapy, provide physicians with the tools necessary to improve short- and long-term outcomes in the treatment of depression. Additionally, recent developments in genetic and psychological vulnerability research have sought to further improve outcomes by identifying markers in patients who may likely experience multiple depressive episodes.

Depression is increasingly recognized as a highly recurrent and potentially chronic illness that imposes a substantial burden on individuals, families, and society. Evidence indicates that the risks of depressive recurrence, treatment resistance, and chronicity increase as the illness becomes more highly recurrent. Up to 1 year of continuation phase therapy is now recommended for virtually all depressed patients who respond to antidepressants, with a longer course of maintenance phase pharmacotherapy recommended for those who have experienced multiple episodes. Antidepressants, when effective during the acute phase of therapy, reduce the risk of depressive relapse (continuation phase) and recurrence (maintenance phase) by at least 50%. Longer-term antidepressant pharmacotherapy is most effective when the full dose of medication effective during acute-phase treatment is continued. As combined treatment with antidepressants and psychotherapy may improve shorter-term outcomes for patients with more severe recurrent depression, ongoing combined therapy may be indicated, especially for patients at particularly high risk. Approximately 5% to 10% of patients maintained on antidepressants relapse yearly, leading some to implicate tachyphylaxis. However, before attributing relapse or recurrence to diminished responsiveness to antidepressant medication at the neurochemical level, clinicians should ensure that the patient has been adherent to therapy as prescribed and consider other explanations.

Optimal management of depression remains a long-term challenge. Long-term maintenance treatment with antidepressants has been shown to be effective for preventing or delaying recurrence for many patients with a history of previous multiple episodes. However, aside from a history of multiple recurrences, it remains difficult to identify patients who are most likely to experience recurrence and when. Thus we do not really know who might particularly benefit from maintenance therapy and what type may be efficacious. In patients with depression, research has shown there are structural and functional alterations in the brain, particularly in patients with recurrent or chronic depression. These changes have been generally viewed to be consequences of the disease, which are seen to worsen with a longer duration of untreated illness and with a greater number of depressive episodes. However, these neurobiological characteristics may also represent risk factors or vulnerabilities that predispose some patients to chronic or recurrent depression. Additional research has demonstrated that antidepressant treatment may reduce or modulate these functional and structural changes, suggesting that long-term treatment may, in fact, benefit patients not only by controlling symptoms but also by managing these underlying vulnerabilities. A new treatment paradigm, which focuses on identifying patients with risk factors and managing the disease process rather than suppression of symptoms, is needed for recurrent depression.

Recurrent major depressive disorder (MDD) is a common and disabling illness, but few studies have addressed long-term antidepressant treatment of recurrent MDD (ie, beyond 1 year of maintenance therapy) or compared the efficacy and safety of different antidepressant classes in this population. This article describes the rationale and design of a unique multi-phase trial in patients with recurrent MDD. The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) study is a large double-blind, randomized, multi-center trial designed to assess the long-term efficacy of venlafaxine extended release (ER) in the prevention of depressive recurrence. Approximately 1,100 adult outpatients with MDD and a history of ≥3 lifetime episodes (with at least two occurring in the past 5 years) were randomized to 10 weeks of acute-phase treatment with either venlafaxine ER 75–300 mg/day or fluoxetine 20–60 mg/day, followed by 6 months of continuation-phase treatment for patients experiencing a satisfactory therapeutic response or remission during the acute phase. Responders and remitters to continuation phase treatment were then entered into a 2-year maintenance phase study, in which those receiving venlafaxine ER were re-randomized to either venlafaxine ER or placebo at the start of two 12-month maintenance periods. Those taking fluoxetine during the acute and continuation phases continued to receive double-blind treatment with fluoxetine. This study will address several unanswered questions about the long-term treatment of recurrent MDD, such as whether extended maintenance treatment (ie, up to 2 years) lessens the risk for developing future depressive episodes; whether fluoxetine and venlafaxine ER are effective for both short- and long-term treatment of MDD; whether rates of tachyphylaxis differ between anti- depressant classes; and whether the likelihood of depressive recurrence differs according to the time point when treatment is discontinued.