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In the United States, major depression is one of the most common mental disorders, with 21 million adults experiencing at least one major depressive episode in 2021, representing 8.3% of all US adults. Despite the availability of effective antidepressant medications, many patients being treated for major depressive disorder experience modest response and remission rates. Response is marked by a 50% or greater reduction in symptoms from baseline. While remission is characterized by symptom-free status and a return to normal functioning, it is estimated that less than one-third of patients achieve remission during the first round of treatments with antidepressant medications. The remaining patients are known as partial responders. These are patients with inadequate antidepressive treatment response, typically showing symptom improvement between 25% to 49% from baseline. Even for patients who have achieved remission, residual symptoms such as low mood, anxiety, insomnia, irritability, and guilt may persist. These residual symptoms may be troublesome enough to significantly impact their quality of life.

Partial responders represent a patient population in need of additional treatment support from providers. Achieving response and remission are important outcomes for patients on antidepressant treatment. The absence of remission and residual symptoms is linked to higher risks of relapse and recurrence, increased healthcare resource utilization, elevated rates of chronic illness, and diminished quality of life.  

For partial responders, most treatment guidelines recommend switching to a different antidepressant or adjunctive use of another medication, either another antidepressant or a non-antidepressive agent. The STAR*D trial demonstrated that adjunctive medication strategy may expedite the response to antidepressant therapy and provide faster relief from residual symptoms compared with multiple trials of antidepressant monotherapy. One potential add-on therapy is bupropion, a norepinephrine and dopamine reuptake inhibitor. Bupropion sustained release has shown modest improvements in depressive symptoms when combined with serotonin reuptake inhibitor antidepressants. Common side effects associated with bupropion include headaches, weight loss, dry mouth, insomnia, dizziness, constipation, and a fast heartbeat. Patients with history of seizure disorders should be aware of the seizure risks associated with bupropion as it is contraindicated in this population. According to the VAST-D trial, bupropion is at least as effective as switching agents, but may be less effective than other adjunctive agents.  

Esketamine may be beneficial as an adjunctive agent to an oral antidepressant in patients with treatment-resistant depression, particularly in patients with suicidal ideation who have failed adequate trials of two separate antidepressant medications. In the Transform-2 study—a randomized double-blind trial consisting of 3 short-term clinical trials over 28 days—esketamine showed improvement in depressive symptoms compared to placebo when administered alongside an oral antidepressant. More common side effects associated with esketamine include nausea, dissociation, dizziness, vertigo, diminished tactile sensations, sedation, and tingling sensations in the extremities. Antidepressive add-on medications may expose patients to potentially serious but rare conditions such as serotonin syndrome, a marked decrease in blood sodium levels, and suicidal ideation.  

Second-generation antipsychotics may be useful as adjunctive therapy and major depressive disorder treatment. These medications work by blocking D2 dopamine receptors as well as the 5-HT2a subtype of serotonin receptor. The VAST-D trial showed this strategy to be more beneficial than switching to a different antidepressant. Second-generation antipsychotics to receive FDA approval for adjunctive treatment for major depressive disorder include aripiprazole, quetiapine, extended release cariprazine, and brexpiprazole.

Adverse events with second-generation antipsychotics may include metabolic abnormalities and motor- related extrapyramidal symptoms like akathisia or restlessness, and dystonia or involuntary muscle movements.  

It is important to note that adding psychotherapy to the use of medications may have modest and synergistic benefits in patients compared to use of either medication or psychotherapy alone.  

The goal of major depression treatment is remission. Distinguishing partial response from remission requires clinicians to continuously monitor patients for residual depression symptoms. Clinicians can educate patients about recognizing residual symptoms early on, and consistently following up with patients after office visits may help to improve adherence to treatment and patient outcomes.