The treatment of MDD is complicated by high rates of residual symptoms (i.e., partial- and non-responders to antidepressant medications) and associated treatment response heterogeneity, which is reflected by modest first-step remission rates. Two types of residual symptoms are commonly described:
- Residual symptoms that are classically depicted as continued manifestations of core depressive symptoms (i.e., impairments in sleep, interest, guilt, energy, cognition, appetite, psychomotor activity, suicidal ideation and depressed mood);
- Residual symptoms that co-occur as nonclassic symptoms of MDD (i.e., anxiety, pain, irritability and cognitive impairments) ().
Commonly occurring residual symptoms in major depressive disorder.
While traditional antidepressants are utilized to target core depressive symptoms, this second class of noncore residual depressive symptoms has limited data regarding antidepressant treatment efficacy and symptom resolution. Regardless of the symptom type, residual depressive symptoms increase the risk for relapse and are associated with psychosocial impairments and a more chronic course of illness [11
Traditional treatment strategies for residual symptoms have included switching to another agent or augmenting the original antidepressant with an additional medication. The STAR
D study revealed that both of these strategies are efficacious and the decision to switch or augment should be based on treatment response, tolerability (i.e., side effects) and patient preference [13
]. A novel strategy with limited evidence, however, is to initiate therapeutic combinations at the onset of treatment to enhance efficacy and hasten time to remission [14
]. Employing switch, augmentation and combination strategies to treat MDD are part of a new initiative to personalize the treatment of MDD such that patients achieve a more complete functional recovery. In fact, the Strategic Plan of the National Institute of Mental Health’s recognizes the need to target and personalize the treatment of individuals with mental illness [15
]. In the plan, Strategy 3.2 aims to ‘expand and deepen the focus to personalize intervention research.’ As a part of this strategy, it is suggested that traditional outcome measures used in clinical efficacy studies be expanded to include functional measures and ‘other indicators of recovery’, which must include targeted symptoms and specific symptom profiles. It is hoped that this more personalized treatment will provide depression and other mental illness patients with more thorough recovery.
The decision to switch versus augment an inadequate existing treatment can be difficult. In general, if a patient has difficulty tolerating a medication or if an adequate dose and duration produces little or no response, switching to a new agent is considered. However, one potential drawback of switching medications is that the initial medication may have required additional time to achieve efficacy. Additionally, for individuals whose depression has responded but residual symptoms have persisted, switching may extend the time it takes to achieve remission. In these settings, augmentation strategies are often preferred. Ideally, augmentation strategies should enhance the action of the initial antidepressant medication, thereby reducing residual symptoms and/or achieving remission. A number of agents are currently used clinically for augmenting primary antidepressants, of which lithium and triiodothyronine (T3
) are most commonly used as first-line augmenting agents [16
]. In fact, Bauer and colleagues found that lithium, when used as an augmentation agent, in the continuation phase of treatment for MDD is effective in preventing relapse [17
]. In addition to these conventional agents, recent studies have shown that nontraditional agents, such as modafinil, can be effective in reducing residual symptoms associated with depression [21
]. While it is important to target augmentation treatments to reduce symptoms of the overall depressive syndrome, a number of augmentation agents are targeted at alleviating specific residual symptoms (e.g., anxiety, insomnia/fatigue and cognitive impairments) and thereby enhancing the efficacy of first-line antidepressants ().
Adjunctive treatment for residual symptoms associated with major depressive disorder.