Major Depressive Disorder (MDD) is a prevalent illness that is frequently associated with significant disability, morbidity, and mortality. Results from the 2003 National Comorbidity Replication study found that the lifetime prevalence of MDD among American adults is 16.2%, ranking it among the most common and costly medical illnesses.1
Despite the development and availability of numerous treatment options for MDD, studies have shown that antidepressant monotherapy yields only modest rates of response and remission. For example, a metaanalysis2
of all double-blind placebo-controlled studies of antidepressants published since 1980 revealed response rates of 53% for antidepressants and 36% for placebo (absolute difference in response rate of 16.8%). Similarly, Petersen et al3
report remission rates as low as 20% to 23% following each successive treatment among patients with MDD enrolled in one of two academically affiliated, depression-specialty clinics. In fact, only about. 50% of all patients enrolled ultimately achieved full remission of their depression. Similarly, only about one in three patients with MDD experienced a remission of their depression following treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram during the first level of the large, multicenter, Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial.4
Clearly, there is an urgent need to develop safer, better-tolerated, and more effective treatments for MDD.
There are three major “paths” towards the development of novel pharmacotherapeutic strategies for MDD (Table I).5
The first, approach involves developing new antidepressants to be used as monotherapy. A second approach involves combining pharmacologic agents, including established treatments (ie, established antidepressants), existing but not established agents, and new or novel agents. Finally, a third approach involves identifying subpopulations of depressed patients who are more likely to experience the benefits of a given (existing) treatment versus placebo, or versus a second treatment. Attempts have been made to identify such “subpopulations,” specifically by testing whether a given biological clinical marker also serves as a moderator, mediator (correlate), or predictor of clinical improvement following the treatment of MDD with standard, first-line antidepressants. A predictor
of treatment (efficacy) outcome can involve factors (whether clinical or biologic), the presence or magnitude of which influences the likelihood of a particular outcome occurring during treatment. Efficacy outcomes in MDD commonly include either the resolution of depressive symptoms during treatment (the magnitude of reduction in depressive symptoms), the rapidity of response (the time course of symptom reduction), the attainment of a treatment response, or the attainment of symptom remission.
Common pathways towards the development of more effective pharmacologic strategies for Major Depressive Disorder (MDD).
Differential predictors or moderators of efficacy outcome are a special subcategory of outcome predictors. Moderators of outcome involve factors (clinical or biologic), the presence or magnitude of which at baseline (immediately before treatment is initiated) influences the relative likelihood of a particular outcome occurring following treatment with one versus another agent. Thus, moderators of response can help predict differential efficacy between two or more treatments for MDD (for example, patients who present with a given moderator are more likely to respond to treatment with one antidepressant versus another than patients who do not present with that, given moderator).
Mediators of efficacy outcome (sometimes also referred to as correlates) are measurable changes (usually biologic) that occur during treatment and correlate with treatment outcome. These changes can either precede (in which case they may also predict outcome - “predictive mediators”), or temporally coincide with treatment outcome (“simple mediators”). Differential mediators of outcome are also possible (changes that predict or correlate with an event, following treatment with one agent but not another). Figure 1 provides an overview regarding the combinations pertaining to mediators, moderators, and predictors of efficacy outcome in MDD. Table II outlines potential clinical, scientific, and treatment-development implications that may derive by identifying mediators, moderators, and predictors of efficacy outcome in MDD.
Potential clinical, scientific and treatment development applications of predictors, moderators and mediators of treatment outcome in Major Depressive Disorder.
In the following paragraphs, we will attempt to summarize the literature focusing on several major areas (“leads”) where preliminary evidence exists regarding clinical and biologic moderators, mediators, and predictors of symptom improvement in MDD. In the first section, we will focus on clinical variables while, in the second section, on biological variables.