You've been on an antidepressant for months. It helped — sort of. Your depression didn't vanish, but it didn't stay completely the same either. You're at 40% better when you were hoping for 90%. Your provider says the medication is "working" because your scores improved. But you still can't fully engage with your life, still struggle to feel genuine pleasure, still drag yourself through most days.

This experience — a partial response to an antidepressant — is extremely common. It affects millions of Americans and a significant number of patients right here in Southeast Idaho. And it points toward one of the most important, most underutilized areas of psychiatric medicine: augmentation therapy for treatment-resistant depression.

This post covers what augmentation means, what options have the strongest evidence, and how a systematic augmentation strategy can transform a partial antidepressant response into something that actually resembles remission.

Antidepressant augmentation means adding a second medication (or a non-pharmacological intervention) to a partially effective antidepressant to boost or complete its effect — rather than abandoning the original medication entirely.

This approach is supported by a critical insight from the STAR*D trial: even patients who don't achieve remission with a first antidepressant have a better chance of achieving remission by augmenting the initial medication than by switching to a new one outright.

The logic is that if an antidepressant is producing some benefit, its core mechanism may be relevant for that patient's neurobiology — what's missing is an additional pharmacological action that addresses a different pathway.

Three atypical antipsychotics carry specific FDA approval as adjunctive treatments for MDD:

Aripiprazole (Abilify) Partial dopamine agonist, serotonin modulator. Addresses the dopaminergic hypoactivity that SSRIs don't target. Multiple large RCTs with a number-needed-to-treat (NNT) of approximately 9 for response over placebo augmentation. Generally well-tolerated; common side effects include restlessness (akathisia) and weight gain. Start low (2 mg) and titrate slowly.

Quetiapine (Seroquel XR) Broad receptor binding including D2, 5-HT2A, histamine H1, and alpha-adrenergic receptors. Strong sedative component. Particularly helpful when anxiety, insomnia, and agitation accompany depression. Weight gain and metabolic effects are significant concerns for long-term use.

Brexpiprazole (Rexulti) Similar to aripiprazole but with a potentially better-tolerated akathisia profile. FDA-approved based on phase III trials; considered a next-generation option. Favorable side effect profile; weight gain possible but generally modest.

Lithium augmentation of antidepressants is one of the oldest and best-supported augmentation strategies in psychiatry, with evidence dating to the 1980s. It is particularly well-supported for patients with recurrent depression and may have specific value in patients with TRD who haven't responded to atypical antipsychotic augmentation.

Lithium acts on multiple intracellular signaling pathways and has neuroprotective and antisuicidal properties independent of its mood-stabilizing effects. It also increases serotonergic transmission by enhancing the sensitivity of serotonin receptors.

Clinical notes:

• Requires careful monitoring: serum lithium levels, kidney function (creatinine, eGFR), and thyroid function
• Narrow therapeutic window: therapeutic range for augmentation is generally 0.6–0.8 mEq/L
• Drug interactions are important: NSAIDs and ACE inhibitors can raise lithium levels
• Particularly underused in younger patients due to monitoring requirements, though monitoring is manageable

Triiodothyronine (T3 / liothyronine) has been used as an antidepressant augmentation agent since the 1970s. T3 directly affects brain function, modulating serotonin receptor sensitivity and beta-adrenergic receptor density. It may also address subclinical thyroid insufficiency that perpetuates depression, even in patients with "normal" TSH.

STAR*D found T3 augmentation comparable to lithium augmentation in remission rates with a better tolerability profile. Particularly worth considering when thyroid labs reveal suboptimal free T3 or subclinical hypothyroidism. Typical doses: 25–50 mcg daily.

Bupropion (Wellbutrin) works on norepinephrine and dopamine — mechanisms not addressed by SSRIs — making it a logical augmenter in SSRI partial responders. STAR*D level 2 data supports bupropion augmentation. It is also a practical option when sexual dysfunction from SSRIs is a concern, as bupropion can mitigate this side effect.

The combination of an SSRI or SNRI with mirtazapine — colloquially called "California Rocket Fuel" — has been used clinically for decades. Mirtazapine blocks alpha-2 autoreceptors (increasing norepinephrine and serotonin release) and blocks 5-HT2 and 5-HT3 receptors. Combined with an SSRI's serotonin reuptake inhibition, this creates a multi-pronged serotonergic and noradrenergic effect. Particularly useful when insomnia and poor appetite are prominent features.

As detailed elsewhere on this blog, ketamine and esketamine can be viewed as augmentation strategies when added to ongoing antidepressant therapy. In fact, the FDA-approved labeling for Spravato specifies use in conjunction with an oral antidepressant — explicitly as augmentation.

The combination of ongoing antidepressant + ketamine/esketamine may also improve the durability of ketamine's antidepressant effects.

At Roth Family Medicine and Mental Health, we approach TRD augmentation systematically:

1. Confirm the diagnosis: Is this truly MDD, or has a bipolar spectrum condition, ADHD, trauma-related disorder, or personality disorder been missed?
2. Rule out physiological contributors: Thyroid, inflammatory markers, nutritional status, hormones. These should be addressed first or concurrently.
3. Confirm prior trials were adequate: Dose and duration are frequently subtherapeutic in real-world practice.
4. Select augmentation based on clinical phenotype:
   • High anxiety + insomnia → quetiapine or mirtazapine augmentation
   • Low motivation + cognitive dulling → aripiprazole or bupropion
   • Recurrent depression + suicidality → lithium
   • Suboptimal thyroid function → T3 augmentation
   • Rapid relief needed → ketamine/esketamine
5. Monitor systematically using validated rating scales, not just clinical impression
6. Consider TMS if 2–3 augmentation strategies have failed

How many augmentation strategies should I try before moving to ketamine or TMS? There's no universal number. Most TRD treatment algorithms suggest 2–3 augmentation trials before escalating to neuromodulation or ketamine, but patients with severe functional impairment or suicidality may warrant earlier escalation. This is a conversation to have with your provider.

Can I be on an antidepressant and receive ketamine at the same time? Yes, and for many patients this is the recommended approach. Some antidepressant medications may slightly attenuate ketamine's effects (e.g., benzodiazepines), while others may enhance durability.

Are atypical antipsychotics safe long-term? They can be used long-term under appropriate monitoring. Metabolic monitoring (weight, blood glucose, lipids) is important. Not every patient needs lifelong augmentation — some can taper after sustained remission.

Is lithium still used in 2025? Absolutely. Despite being decades old, lithium remains one of the most evidence-backed augmentation and mood-stabilizing agents in psychiatry, with the added benefit of robust antisuicidal data that few other medications match.

1. Rush AJ, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905–1917.
2. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder. Am J Psychiatry. 2009;166(9):980–991.
3. Bauer M, et al. Lithium augmentation therapy in refractory depression. Can J Psychiatry. 2014;59(12):657–665.
4. Trivedi MH, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243–1252.

Medical Disclaimer: This content is for educational purposes only and does not constitute medical advice. All treatment decisions should be made in consultation with a qualified healthcare provider.

Kyle Roth, FNP-BC, APRN, MSN, MHA | Roth Family Medicine and Mental Health | Pocatello, Idaho | (208)-904-4705 | www.rothfamilymed.com