Treatment of Major Depressive Disorder Must Include Focus on "Residual" Symptoms

A review in the American Journal of Medicine suggests that sustained remission of major depressive disorder (MDD) requires treatment of all symptoms until they are undetectable, and makes a case for linking symptoms with malfunctioning brain circuits and neurotransmitters to find a targeted approach for treating residual symptoms.

The authors note that dealing with “residual” symptoms, which can include anxiety and insomnia, among others, is not a trivial issue. Failing to treat these symptoms can lead to continued functional impairment, a higher risk of relapse, a shorter course of well intervals, fewer symptom-free weeks, and increased risk of suicide. Yet, the challenge of identifying and treating residual symptoms is immense. For MDD, which is defined as depressed mood or apathy/loss of interest plus ≥4 additional symptoms, there are more than 60 forms of the condition given the various possible combinations of symptoms.

The review looks at many of those combinations, residual symptoms, current pharmacologic and nonpharmacologic treatments for each, and the latest evidence on the neurobiology behind MDD and its major symptoms. Among the more interesting aspects of the review:

• Significant residual symptoms may predispose patients to recurrence, chronicity, and suicidality. The optimal outcome for patients with major depressive disorder is now considered to be symptomatic remission, a marker of wellness that is critical to return to premorbid level of functioning.
• A literature review that assessed the burden of treatment-resistant depression in the United States concluded that up to 20% of patients with depression are treatment resistant and that annual added societal costs related to treatment-resistant depression are in the range of $29 to $48 billion.
• Common tools that measure MDD treatment do not directly assess functional impairments; the authors examine the Sheehan Disability Scale, a brief patient-rated measure of functional disability in work, social, and family life, and other potential adjuncts to traditional therapeutic measurements.
• The 3 most debilitating MDD symptoms include 1 affective (sad mood), 1 cognitive (concentration problems), and 1 somatic (fatigue) symptom, which suggest the need to monitor all kinds of symptoms of depression rather than focusing on 1 domain or factor score.
• Psychiatric symptoms correlate somewhat with malfunctioning brain circuits, but psychiatric disorders do not correlate well with genotypes, biosignatures, or brain circuits.
• “It is notable that all antidepressants are similarly effective: Approximately one third of patients get better with their first-line therapy,” the researchers indicate. “The challenge is what to do for those patients who do not respond to initial therapy. It is important to treat the residual symptoms by switching to a drug with a different mechanism of action or by adding a second drug with a different mechanism of action…”

Looking ahead, the review authors noted, “Applying neurobiology principles to treatment selections may assist physicians in determining whether to switch antidepressants, add another antidepressant medication, or augment antidepressant therapy with another pharmacologic agent or a nonpharmacologic treatment such as psychotherapy. Throughout a treatment course for major depressive disorder, antidepressant medications must be given for a sufficient duration at a sufficient dose and patients monitored for response to adverse events with treatment and psychiatric and medical comorbidities. Patients with residual symptoms or treatment-resistant depression can achieve complete remission of their symptoms and regain functionality.”