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From Partial Response to Remission: Choosing the Next Step in Major Depressive Disorder

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Released: August 19, 2026

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Management of major depressive disorder becomes more complex when initial antidepressant treatment improves symptoms but does not achieve remission or functional recovery. This activity reviews practical considerations for deciding when to optimize, switch, or augment treatment based on response, residual symptoms, tolerability, and patient-specific risks. Learners will explore how established and more recently approved adjunctive therapies, along with other evolving treatment options, can support individualized treatment decisions for patients with an inadequate antidepressant response.

Mustafa Husain
Mustafa Husain, MD
MDD Adjunct

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Key Takeaways
  • Partial response is not remission. Persistent anhedonia, cognitive difficulty, and loss of function should trigger structured reassessment rather than passive continuation of a partly effective treatment.
  • Switching is generally most useful when the current antidepressant has produced little benefit or is poorly tolerated; augmentation can preserve gains when response is meaningful but incomplete.
  • The expanding treatment landscape supports more individualized care, but residual symptoms should define the treatment target with efficacy evidence, tolerability, and the patient’s functional goals remaining central to selection.

Why Partial Response Is Not Enough
For patients experiencing major depressive disorder (MDD), the first line of treatment typically includes psychotherapy, selective serotonin reuptake inhibitors, or serotonin–norepinephrine reuptake inhibitors, or a combination of both. However, first-line treatment is not sufficient for many. The STAR*D study highlighted the surprising frequency of low treatment efficacy. The study enrolled adults with nonpsychotic MDD and began everyone on citalopram; participants who did not remit or could not tolerate treatment could move through additional levels that mirrored the next steps available to healthcare professionals (HCPs), including switching antidepressants, augmenting medication, and adding cognitive therapy. After initial treatment, 36.8% achieved remission; among those who proceeded to level 2, 30.6% achieved remission, with remission rates in subsequent levels declining even further. The clinical message is clear: Many patients do not remit with an initial antidepressant.

Even while receiving treatment, many patients still experience anhedonia, fatigue, psychomotor retardation, impaired concentration, anxiety, and sleep disturbances. For HCPs, the challenge lies in addressing these residual symptoms. A patient may report feeling “better” while these continuing symptoms negatively affect work, relationships, or daily functioning. Because residual symptoms predict poorer recovery and greater relapse risk, the goal is not simply a reduction in symptom score; it is remission accompanied by meaningful functional recovery.

After an Inadequate Response: Optimize, Switch, or Augment?
Before labeling a regimen ineffective, HCPs must consider factors that may contribute to inadequate antidepressant response. First, there is a possibility of misdiagnosis, particularly bipolar disorder, which often presents with depressive symptoms but requires a different approach to treatment. Psychiatric comorbidities, such as anxiety, and medical conditions, such as sleep apnea and thyroid disease, may also contribute to inadequate response. Inadequate adherence, dose, or treatment duration can also affect outcomes. In addition, genetic factors may influence medication metabolism and response.

Once these factors have been assessed, the Canadian Network for Mood and Anxiety Treatments guidelines can be used to determine next steps. Lack of meaningful response or poor tolerability generally favors switching. A well-tolerated antidepressant that has produced a partial response generally favors considering augmentation more because it preserves gains while addressing what remains.

Established Atypical Antipsychotic Adjunctives: Effective Options With Familiar Tradeoffs
When patient response indicates that adjunctive treatment may be beneficial, there are many options to from which to choose. Lithium, thyroid hormone (triiodothyronine), and psychotherapy are traditional augmentation strategies that have been used for decades. However, atypical antipsychotics have become a popular choice because of their relatively rapid onset, robust clinical evidence, and mechanisms of action that differ from those of conventional antidepressants. To help determine which option is most appropriate for an individual patient, it is important to consider the specific residual symptoms and adverse event profiles, comorbidities, drug interactions with the current antidepressant, and patient preferences and goals.

Aripiprazole, approved for adjunctive MDD treatment in 2007, has demonstrated success in treating patients with persistent anxiety symptoms in placebo-controlled trials. It may also be useful when an effective adjunct is needed without prominent sedation. Akathisia, restlessness, and insomnia can limit use; however, it is considered a first-line adjunctive option based on its tolerability and substantial efficacy data. Weight and metabolic parameters should still be monitored for potential adverse effects.

Quetiapine XR, approved for adjunctive MDD treatment in 2009, may be attractive when insomnia accompanies an incomplete antidepressant response because of its sedating properties, provided daytime sedation is acceptable. That same characteristic can become a disadvantage for patients with residual fatigue, hypersomnia, or concerns about daytime functioning. Weight gain and other metabolic effects also require consideration.

Brexpiprazole, approved in 2015, provides another well-supported adjunctive option and, like aripiprazole, is considered a first-line adjunctive option based on its efficacy and tolerability profiles. Compared with aripiprazole, it may be associated with less akathisia but can contribute to weight gain. It may therefore be useful when activation or restlessness is a concern, provided the patient’s metabolic risk profile is acceptable.

Olanzapine/fluoxetine is somewhat different because it is a fixed antidepressant/antipsychotic combination indicated for treatment-resistant depression rather than an antipsychotic added to the patient’s existing antidepressant. It has demonstrated efficacy in treatment-resistant depression, but sedation, increased appetite, weight gain, dyslipidemia, and glucose abnormalities can substantially influence patient selection. For patients with obesity, diabetes, or other cardiometabolic risks, these concerns may make alternative strategies more attractive.

Regardless of the adjunct selected, HCPs should monitor weight, blood glucose, and lipid profile and assess emergent adverse effects such as extrapyramidal symptoms and sleep disturbances. Older adults may be more vulnerable to adverse effects and polypharmacy, so treatment should be individualized with preexisting medical conditions considered. In patients with obesity, diabetes, or cardiovascular risk, the metabolic profile of the chosen antipsychotic should also factor into selection.

More Recently Approved Adjunctives: Expanding Options for Individualized Care
More recently approved agents broaden the choices available when established adjuncts are effective in principle but are not an ideal fit for a particular patient’s residual symptoms or adverse effect vulnerabilities. Cariprazine was approved for adjunctive MDD treatment in 2022. In a phase III trial of 751 adults with inadequate antidepressant response, cariprazine at 1.5 mg/day significantly improved Montgomery-Åsberg Depression Rating Scale (MADRS) scores at Week 6 vs placebo, although this was not seen in the higher dose. A subsequent post hoc analysis also found improvement in anhedonia among patients with moderate to severe baseline anhedonia, but this should not be interpreted as a specific indication. Its main adverse effects include akathisia, restlessness, and insomnia.

Lumateperone, approved for adjunctive MDD treatment in 2025, adds an option with a potentially favorable short-term metabolic profile. Two 6-week phase III trials in adults with inadequate response to 1 or 2 antidepressant courses demonstrated significant improvement in depressive symptoms, with placebo-subtracted MADRS differences of approximately 4.5-4.9 points. Exploratory analyses have also suggested improvement in anhedonia. Particularly relevant for patient selection, short-term studies showed relatively small changes in weight and cardiometabolic measures, with low rates of akathisia. This may make lumateperone attractive for patients in whom weight gain, cardiometabolic disease, or movement symptoms make some established adjunctives less desirable. The tradeoff is that dizziness, somnolence, and fatigue can occur, so it may not be the best choice when daytime alertness is already impaired.

Recent comparative evidence reinforces why having these additional options matters. In a 2026 meta-analysis of 22 short-term randomized trials involving 10,962 patients, lumateperone had the largest estimated acute response signal, whereas aripiprazole had the most favorable estimate for all-cause discontinuation. Because these were indirect comparisons rather than head-to-head trials, they do not establish a single superior agent. However, they underscore that adjunctive selection should balance efficacy with the adverse effects most likely to interfere with adherence and functional recovery.

The practical advantage of these newer agents is not simply that they are newer. They expand the range of efficacy and tolerability profiles available to HCPs. With both showing promise in the treatment of anhedonia (and other residual symptoms of depression), cariprazine may offer an option when sedation and metabolic effects are important concerns. Lumateperone may be particularly appealing when metabolic or extrapyramidal effects are priorities, provided sedation is manageable. This broader therapeutic range can make it easier to individualize adjunctive treatment around the needs and vulnerabilities of the patient rather than accept the adverse effect profile of a more limited set of established choices.

Beyond Antipsychotic Augmentation: Other Newer Treatment Pathways
The expanding MDD treatment landscape also includes newer options outside of atypical antipsychotic augmentation. Dextromethorphan-bupropion is an oral antidepressant approved for MDD rather than as an adjunctive therapy. In the phase III GEMINI trial of 327 adults, improvement in depressive symptoms separated from placebo beginning at Week 1, and remission at Week 6 occurred in 39.5% of patients receiving dextromethorphan-bupropion vs 17.3% with placebo. Its relatively rapid onset may make it an option when a switch to a different antidepressant strategy is being considered. Vortioxetine is another antidepressant option and may be particularly relevant when cognitive symptoms remain prominent. Clinical trial and pooled analyses have demonstrated improvement in cognitive measures, with additional post hoc data suggesting benefit for anhedonia.

Ketamine-based treatments offer a different pathway for patients with more difficult-to-treat depression. Intravenous racemic ketamine remains off-label for depression, whereas intranasal esketamine is approved by the FDA for adults with treatment-resistant depression and may now be used either as monotherapy or with an oral antidepressant. In a phase IV trial of 378 adults with treatment-resistant depression, esketamine monotherapy significantly improved MADRS scores at 4 weeks, with improvement separating from placebo approximately 24 hours after the first dose. Its rapid antidepressant effect may be particularly relevant when previous treatment strategies have been inadequate, but administration requires a certified treatment setting because of risks including sedation, dissociation, respiratory depression, and abuse or misuse. Patients must also be monitored for at least 2 hours after each dose under a Risk Evaluation and Mitigation Strategy program.

An important reminder: In addition to pharmacotherapy, patients with depression should also receive psychotherapy, lifestyle modification, and regular suicide risk assessment. The HCP should develop an individualized treatment plan in collaboration with the patient. The ultimate goal of treatment is remission with meaningful functional recovery. Moving from symptom reduction to recovery means revisiting that plan whenever residual symptoms continue to limit what the patient can actually do.

Your Thoughts
When a patient reports that mood has improved but residual symptoms continue to limit daily functioning, what most strongly drives your decision to optimize, switch, or augment treatment?

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When considering adjunctive treatment for a patient with MDD who has had a partial response to an antidepressant, what most strongly influences your choice of adjunctive therapy?

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