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Depression
Switching or Augmenting in MDD: Approaching the Next Step When First-line Treatments Fall Short

Released: August 05, 2025

Joseph F. Goldberg
Joseph F. Goldberg, MD
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Key Takeaways
  • Always reassess major depressive disorder diagnosis, comorbidities, and adherence before concluding a treatment has failed.
  • Favor augmentation when there is partial response (>25% improvement) and switching when improvement is minimal
  • Patient preference and symptom-specific strategies are central to optimizing outcomes

Healthcare professionals who treat major depressive disorder (MDD) often wrestle with patients’ incomplete responses to pharmacotherapies, posing vexing questions about the best “next” strategies to pursue. Deciding whether to switch to a new medication or retain and augment an existing one remains an age-old question in clinical psychopharmacology. Although some studies suggest that there is no universal “best” next treatment option after poor response, deciding on successive interventions is nonarbitrary and hinges on basic principles involving efficacy, tolerability, pharmacokinetics, phenomenology, and patient preference 

Is the diagnosis correct? Whether the diagnosis of MDD is correct or not is perhaps the most fundamental question. MDD carries a wide differential diagnosis that includes bipolar depression, psychotic depression, MDD with mixed features, substance-induced mood disorders, depression secondary to another (nonpsychiatric) medical condition, negative symptoms of schizophrenia, and adjustment disorder with depressed mood, among others. Rigorous reevaluation of a presumptive diagnosis is never an unwise initial step.

Are there untreated comorbid conditions? Depression is unlikely to improve in the face of untreated alcohol or other substance use disorders, undertreated anxiety disorders, unaddressed significant trauma histories, untreated comorbid personality disorders, or other problems that may need prioritized treatment before progress can be made to treat MDD.

Has treatment adherence been adequate? More than one half of patients with MDD are poorly adherent to prescribed antidepressants, making it difficult to judge whether the allegedly unsuccessful medication trials have actually failed (inadequate efforts) rather than being negative (truly ineffective).

Has there been a partial response? As a rule of thumb, augmentation is considered appropriate when there has been at least a partial response (technically defined as >25% improvement from baseline using a standard measure of depression symptom severity, such as the PHQ-9), after a 4-week to 6-week trial. Discontinuation and switching pharmacotherapies are favored if there has been <25% improvement.

Were the medication trials appropriate and adequate? Difficult-to-treat or chronic forms of MDD sometimes require longer than the oft-cited 4-week to 6-week period for judging treatment response. In the STAR*D trial, for example, most patients with either chronic or anxious depression did not respond until later than 6 weeks of treatment initiation. Likewise, subtherapeutic dosing counts as a common reason for unsuccessful treatment outcomes.

How many trials have been unsuccessful in the current episode, and what is the degree of treatment resistance? Few interventions are evidence based specifically for treatment-resistant depression (TRD), but those that are typically warrant consideration sooner rather than later. Intranasal esketamine and olanzapine-fluoxetine combination are the only 2 FDA-approved pharmacotherapies for TRD (identified when at least 2 adequate medication trials result in inadequate or nonresponsive outcomes), whereas repetitive transcranial magnetic stimulation (rTMS) and vagus nerve stimulation are the only 2 device-based and FDA-cleared treatments for TRD. Electroconvulsive therapy, a technology predating FDA regulatory oversight, still remains a gold-standard intervention in highly severe TRD. Inadequate response to multiple adequate pharmacotherapy trials often favors retaining and building on existing partial benefits rather than going back to the drawing board to start anew.

Are there particular target symptoms or symptom constellations that point to value for a particular intervention? Considering the role of the particular medications or their presumed mechanisms of action is the polestar. For example, lithium may be added to traditional antidepressants to reduce impulsivity around acting on suicidal thoughts, prodopaminergic medications in case of low motivation or inattention, or serotonergic agents when marked anxious features are present.

Can pharmacogenetics help? In a word, not so much. Pharmacogenetic testing does not identify medicines that will work better than others, but it points to medicines that may be less effective or have a greater adverse effect burden because of differences in metabolism. 

When might psychotherapy be the best augmentation? Perhaps surprising to some, most studies comparing pharmacotherapy with psychotherapy for MDD show few outcome differences. That said, psychotherapy is often regarded as a preferred treatment when there are obvious psychological or psychosocial components related to depression, such as interpersonal triggers or cognitive distortions about themselves or their surrounding world, whereas pharmacotherapies tend to be favored in more moderate to severe forms of depression, particularly involving significant vegetative signs, marked anhedonia, or suicidal thinking.

What is the patient’s own preference? Patient preference in choosing among viable options (switching, augmentation, and psychotherapy) not only fosters patient empowerment but is also a known contributor to better MDD outcomes.

New and Emerging Augmentation Agents
Newer, more metabolically neutral second-generation antipsychotics (SGAs) with antidepressant properties continue to garner attention for both efficacy and better tolerability than older second-generation antipsychotics.  Compounds such as cariprazine and lumateperone are evidence-based examples. Novel “pipeline” agents include the orexin-2 receptor antagonist seltorexant, which can be especially helpful targeting sleep as a residual depression symptom. Kappa opioid receptor antagonists (KORs) such as aticaprant offer another novel strategy still in development for augmentation treatment in MDD. Yet another novel drug class includes positive allosteric modulators (PAMs) of a particular type of ionotropic glutamate receptors known as AMPA receptors, for which the investigational drug NBI-1065845 has shown promise. Another novel class of drugs known as trace amine associated receptor-1 (TAAR-1) agonists (eg, ulotaront) modulates monoaminergic and glutamatergic neurotransmission and has shown promising, although mixed, results in MDD studies. Finally, psychedelics continue to draw attention in TRD, with agents such as psylocibin and CYB003 actively in the midst of phase III trials.

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When selecting a next-step treatment for MDD, how consistently do you facilitate shared decision-making by incorporating patient preference into the final decision among switching, augmentation, or psychotherapy options?

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