What is the augmentation strategy for depression?

October 7, 2025 •

5 min read

According to the STAR*D trial, up to two-thirds of patients with major depressive disorder may not achieve full remission with their initial antidepressant treatment. This is where the augmentation strategy for depression becomes a crucial next step, involving the addition of a second medication to an existing antidepressant to boost its effectiveness.

Quick Summary

The augmentation strategy for depression involves adding a second medication to an antidepressant that hasn't achieved full symptom remission. This approach is used for treatment-resistant depression to enhance efficacy, often utilizing atypical antipsychotics, lithium, or thyroid hormones.

Key Points

Definition: Augmentation is the strategy of adding a second medication to an existing antidepressant to improve treatment response, typically used for treatment-resistant depression.
Common Agents: Atypical antipsychotics (aripiprazole, quetiapine), mood stabilizers (lithium), thyroid hormones, and other antidepressants (bupropion) are frequently used as augmenting agents.
Timing: This strategy is usually considered after a patient has had an inadequate or partial response to one or more trials of antidepressant monotherapy.
Mechanism: Augmentation works by modulating different neurotransmitter systems (e.g., dopamine, serotonin) to achieve a more comprehensive and robust therapeutic effect.
Comparison to Switching: Unlike switching, augmentation retains the benefits of the original medication while adding a new one, which can be advantageous for partial responders.
Side Effects: Using multiple medications can increase the risk of side effects, such as metabolic changes with antipsychotics or toxicity with lithium, requiring close medical supervision.
Personalized Care: An individualized treatment plan is essential, and augmentation may be combined with other therapies like psychotherapy for the best results.

Understanding the Augmentation Strategy

When a patient with major depressive disorder (MDD) fails to achieve full symptom relief after an adequate trial of a single antidepressant medication, clinicians may consider several options. One of the most common and evidence-based approaches for treatment-resistant depression (TRD) is the augmentation strategy. Augmentation involves adding a second drug to the primary antidepressant rather than replacing it entirely, with the goal of enhancing or accelerating the therapeutic response. This is distinct from a 'combination strategy,' which typically involves combining two or more drugs that are both considered antidepressants, or a 'switching strategy,' where the original medication is discontinued and a new one is started.

The rationale behind augmentation is to target multiple neurotransmitter systems that may be involved in the complex pathophysiology of depression. For example, while many first-line antidepressants primarily focus on serotonin pathways, adding an agent that modulates dopamine or norepinephrine can provide a more comprehensive treatment effect. This approach acknowledges that different individuals may have different neurobiological underpinnings to their depression, and a single drug may not be sufficient to address all of them.

Common Augmenting Agents

Numerous agents have been studied and are used in clinical practice to augment antidepressant therapy. The choice of agent depends on several factors, including the patient's specific symptoms, potential side effects, and existing health conditions.

Atypical Antipsychotics

Aripiprazole (Abilify): Aripiprazole is a partial agonist of dopamine D2 and serotonin 5-HT1A receptors, and an antagonist of serotonin 5-HT2A receptors, providing a unique pharmacological profile. It has received FDA approval for adjunctive treatment of MDD and has shown significant efficacy in clinical trials, including in older adults with TRD.
Quetiapine (Seroquel): This agent blocks multiple receptors, including dopamine, serotonin, and adrenergic receptors, which is thought to contribute to its antidepressant effects. Extended-release quetiapine has FDA approval for adjunctive use in MDD.
Brexpiprazole (Rexulti): Similar to aripiprazole, brexpiprazole is a partial agonist of D2 and 5-HT1A receptors and an antagonist of 5-HT2A receptors, and it also holds FDA approval for adjunctive MDD treatment.

Mood Stabilizers and Hormones

Lithium: One of the most documented augmentation strategies for TRD, lithium enhances serotonin transmission and is particularly effective for patients with severe depression or a history of suicidal ideation. Its use requires careful blood level monitoring to manage side effects and prevent toxicity.
Thyroid Hormones: Triiodothyronine (T3) or levothyroxine (T4) can be added to an antidepressant regimen, especially in patients with subclinical hypothyroidism or other indications. This is a well-established strategy for potentiating antidepressant effects.

Other Pharmacological Agents

Bupropion (Wellbutrin): As a norepinephrine and dopamine reuptake inhibitor, bupropion can be combined with SSRIs to target different neurotransmitter systems. It may also help counteract some SSRI side effects, such as sexual dysfunction.
Buspirone (Buspar): This partial 5-HT1A receptor agonist can be added to an SSRI to enhance serotonergic activity, though evidence for its efficacy as an augmenting agent is mixed.
Ketamine/Esketamine: These newer agents act on the N-methyl-D-aspartate (NMDA) receptor system and can produce a rapid antidepressant effect in TRD. Intranasal esketamine is FDA-approved for TRD, and intravenous ketamine is used off-label in specialized clinics.

Augmentation vs. Switching: A Clinical Decision

The choice between augmenting a current antidepressant and switching to a new one is a key decision in managing TRD. The right approach is often individualized based on the patient's response and tolerability of the initial medication. Augmentation is often favored in patients who have had a partial but insufficient response to their initial treatment, as it maintains the therapeutic gains already achieved. Switching is typically considered when there has been a minimal or no response, or if side effects from the current medication are intolerable.


Feature	Augmentation Strategy	Switching Strategy
Core Action	Adds a second medication to the existing antidepressant.	Discontinues the existing antidepressant and starts a new one.
Timing	Often used after a partial response to the first antidepressant trial.	May be used after minimal or no response to a first trial, or due to intolerable side effects.
Therapeutic Advantage	Builds on existing therapeutic gains; potentially faster effect onset than a full switch.	Targets a new mechanism of action; may be more effective if the first mechanism was ineffective.
Risk/Drawbacks	Risk of increased side effects, drug interactions, and higher cost due to multiple medications.	Risk of withdrawal symptoms and potential loss of any therapeutic benefit from the first medication; requires careful cross-tapering.
Patient Preference	Can feel less disruptive as the existing medication is continued.	May involve a period of medication instability, but offers a fresh start if the initial agent was problematic.

Potential Side Effects and Management

Augmentation strategies, particularly with atypical antipsychotics, can introduce additional side effects. These can include weight gain, metabolic changes (such as elevated blood glucose or lipids), and movement-related issues like akathisia (inner restlessness). Lithium, while effective, requires blood monitoring due to its narrow therapeutic window and potential for renal and thyroid side effects. Clinicians must balance the potential for enhanced efficacy with the increased risk of adverse events and the burden of managing multiple medications.

Importance of an Individualized Approach

For many patients, especially those with TRD, the optimal treatment plan is not a one-size-fits-all solution but a personalized strategy. A comprehensive treatment approach may also involve non-pharmacological interventions, such as cognitive-behavioral therapy (CBT), electroconvulsive therapy (ECT), or transcranial magnetic stimulation (TMS). A detailed discussion with a healthcare provider is essential to weigh the benefits and risks of any treatment path.

Conclusion

The augmentation strategy for depression is a critical tool for clinicians managing patients who have not fully responded to initial antidepressant monotherapy. By adding a second agent with a different mechanism of action, this approach aims to increase the likelihood of remission and improve a patient's overall quality of life. Common augmenting agents include atypical antipsychotics like aripiprazole and quetiapine, mood stabilizers such as lithium, and other medications like bupropion and ketamine. While effective, augmentation involves careful consideration of potential side effects and requires close monitoring by a healthcare professional. Ultimately, the decision to augment or switch is a shared one between the patient and provider, tailored to individual needs and treatment history to achieve the best possible outcome.

An excellent resource for more information is the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines, which provide evidence-based recommendations on augmentation and other depression treatment strategies.

Frequently Asked Questions

Augmentation involves adding a non-antidepressant medication (like an antipsychotic or mood stabilizer) to an existing antidepressant. Combination therapy typically refers to using two different antidepressant medications together.

Augmentation is considered when a patient has not achieved a full therapeutic response, or has had a partial response, after an adequate trial of a single antidepressant (monotherapy). It is a key strategy for managing treatment-resistant depression.

Common augmenting agents include atypical antipsychotics (e.g., aripiprazole, quetiapine), lithium, thyroid hormones (T3/T4), and other antidepressants with different mechanisms of action, like bupropion.

No. Augmentation must be done under the careful supervision of a healthcare provider. Combining medications increases the risk of side effects and drug interactions, and requires professional monitoring to ensure safety and effectiveness.

This depends on the individual case. Some studies show augmentation with specific agents like aripiprazole can be more effective than switching for some patients, especially those who had a partial response. For others, particularly those with no initial response, switching may be a better option.

Yes. While the term primarily refers to medication, non-pharmacological methods like psychotherapy (e.g., CBT), electroconvulsive therapy (ECT), or transcranial magnetic stimulation (TMS) can also be used to augment antidepressant treatment.

Atypical antipsychotics can cause side effects such as weight gain, metabolic issues (elevated glucose and lipids), and movement disorders like akathisia. Close monitoring is required to manage these risks.

The onset of a clinical response can vary. Some augmentation agents, like aripiprazole, may show initial benefits within weeks, while others can take longer. Your doctor will monitor your progress to assess the effectiveness.