Treatment-Resistant Depression: Augmentation and Advanced Therapies That Actually Work

When antidepressants don’t work, it’s not because you’re weak or failing. It’s because depression isn’t one disease-it’s many. About 30 to 40% of people with major depression don’t get relief after trying two different antidepressants. This is called treatment-resistant depression, or TRD. And if you’re one of them, you’re not alone. But you might feel like you’re out of options. You’re not.

What Makes Depression Resistant?

TRD isn’t a diagnosis you get from a quick checklist. It’s a label that comes after real, adequate trials. That means taking the right dose for long enough-usually 6 to 8 weeks-without improvement. Many people stop too soon because side effects kick in, or they think it’s not working fast enough. But if you’ve tried two different classes of antidepressants-like an SSRI and an SNRI-and still feel stuck, that’s when you enter the TRD zone.

It’s not just about medication. Underlying issues like chronic stress, trauma, thyroid problems, or even inflammation can block antidepressants from doing their job. Some people have high levels of inflammatory markers in their blood, which studies show can make depression harder to treat. One 2022 study found that adding an anti-inflammatory drug called infliximab helped people with high inflammation, leading to a 30.5% remission rate versus just 13.7% in the placebo group.

Augmentation: Adding Something to Make It Work

Augmentation means sticking with your current antidepressant and adding something else to boost its effect. This avoids the risk of stopping what’s already working, even if it’s only partially helping.

The FDA has approved five augmentation options specifically for TRD:

Aripiprazole (Abilify) - 2 to 15 mg/day. Works well for people who struggle with fatigue or low motivation. Side effects? Restlessness (akathisia) in up to 25% of users.
Brexpiprazole (Rexulti) - 0.5 to 3 mg/day. Similar to aripiprazole but often better tolerated. Less likely to cause shaking or jitteriness.
Quetiapine extended-release (Seroquel XR) - 150 to 300 mg/day. Helps with sleep and anxiety, but weight gain and drowsiness are common. One study showed 48% response rates when added to SSRIs.
Olanzapine-fluoxetine (Symbyax) - a combo pill. Effective but can cause significant weight gain-up to 5-7% of body weight in some cases.
Lithium - not FDA-approved for this use, but widely used off-label. Requires blood tests every few months. Target level: 0.3 to 0.6 mEq/L. Too low? No effect. Too high? Dangerous.

A 2022 analysis of 65 studies found that liothyronine (a thyroid hormone), nortriptyline, and lithium all had strong results. But not all augmentations are created equal. Ziprasidone and cariprazine had higher dropout rates because of side effects. Aripiprazole had the best balance of effectiveness and tolerability in real-world use.

And then there’s bupropion. It’s not FDA-approved for augmentation, but the VAST-D trial showed it worked almost as well as aripiprazole-21.3% remission rate-and it’s often chosen for people with sexual side effects or extreme fatigue from other antidepressants.

Patient receiving rTMS therapy in clinic, with glowing mood progress chart nearby.

When Augmentation Isn’t Enough: Advanced Therapies

If you’ve tried two or three augmentation strategies and still feel the same, it’s time to think beyond pills.

Repetitive Transcranial Magnetic Stimulation (rTMS) is one of the most reliable next steps. It uses magnetic pulses to stimulate areas of the brain involved in mood. No anesthesia. No memory loss. No hospital stay. You sit in a chair for 20 to 40 minutes, five days a week, for four to six weeks. Over 50 clinical trials show a 50-55% response rate and 30-35% remission rate in TRD patients. It’s covered by most insurance plans in the U.S. and Canada now.

Esketamine nasal spray (Spravato) is the first rapid-acting antidepressant approved by the FDA. You get it in a certified clinic, under supervision, because it can cause dissociation-feeling detached from your body or surroundings. In one trial, 70.3% of people responded within four weeks, compared to 47.5% on placebo. The effect can kick in within hours. But it’s expensive, requires ongoing clinic visits, and isn’t meant to be used alone-it’s always paired with an oral antidepressant.

Electroconvulsive Therapy (ECT) is still the gold standard for severe, life-threatening depression. It’s effective in up to 70-80% of TRD cases. But many people avoid it because of the stigma and fear of memory loss. Modern ECT is much safer than in the past, with shorter treatments and better anesthesia. Still, rTMS is often preferred for its lack of cognitive side effects.

Deep Brain Stimulation (DBS) is experimental but promising. Tiny electrodes are surgically implanted in the brain, targeting the subcallosal cingulate cortex. One small 2017 study found 92% of patients responded after two years. But it’s invasive, expensive, and only available in research centers. Not a first-line option-but for those who’ve tried everything else, it’s a lifeline.

What’s on the Horizon?

Science is moving fast. Psilocybin-the active compound in magic mushrooms-is showing incredible results. A 2020 JAMA Psychiatry trial with 24 people found a 71% response rate after just two doses, compared to 9.4% in the placebo group. It’s not legal yet, but Phase 3 trials are underway. Many experts believe it could be approved within the next few years.

Other emerging options include:

Modafinil - a wakefulness agent that boosts energy and focus. Works best for people with severe fatigue.
Lisdexamfetamine - a stimulant used for ADHD, but studies show it helps with motivation and anhedonia in TRD.
Anti-inflammatory drugs - like infliximab or celecoxib - for people with high CRP levels.

The future of TRD treatment is personalized. Not everyone needs the same thing. Blood tests for inflammation, genetic markers for drug metabolism, even brain scans may soon help doctors pick the right treatment faster.

Person at therapeutic crossroads with paths to esketamine, psilocybin, DBS, and rTMS.

What Works Best for You?

There’s no single answer. But here’s a simple way to think about it:

If you’re fatigued and unmotivated → try bupropion or modafinil.
If you’re anxious and sleepless → quetiapine or brexpiprazole.
If you need fast relief → esketamine.
If you want something non-drug → rTMS.
If you’ve tried everything and still feel hopeless → talk to a specialist about DBS or psilocybin trials.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) recommends matching treatment to your symptoms, side effect history, and lifestyle. Want to avoid weight gain? Skip olanzapine. Hate daily pills? rTMS might be better. Need quick results? Esketamine.

Real-world data from the EU-NEURD registry shows that only 28.4% of TRD patients reach full remission with standard treatments. That means over 70% still struggle. But that doesn’t mean hope is gone. It means we need to keep trying-smartly.

What to Do Next

If you’ve been stuck for months or years:

Confirm your diagnosis. Is it really depression? Or could it be bipolar disorder, PTSD, or a medical condition?
Review your past treatments. Were doses high enough? Were they taken long enough?
Ask for a referral to a mood disorder clinic. These specialists see TRD every day.
Request a blood test for thyroid function and inflammation (hs-CRP).
Discuss rTMS or esketamine with your doctor. Insurance often covers them now.
Consider therapy. CBT has an effect size of 1.58 in TRD-stronger than most medications.

TRD isn’t a dead end. It’s a signal that your brain needs a different kind of help. The tools are here. You just need to ask for them.

What counts as an adequate trial for antidepressants?

An adequate trial means taking a standard dose (like 20 mg of sertraline or 150 mg of venlafaxine) for at least 6 to 8 weeks. Many people give up too early because they don’t feel better in the first week or two. But antidepressants take time. If you didn’t reach the full dose or stopped before 6 weeks, it doesn’t count as a true trial.

Can I take multiple augmentation agents at once?

It’s possible, but risky. Combining two antipsychotics or adding lithium with an SSRI and an SNRI increases side effects without clear proof of better results. Most guidelines recommend trying one augmentation at a time. If one doesn’t work after 6 to 8 weeks, then move to the next. More isn’t always better.

Is esketamine safe for long-term use?

Esketamine is approved for maintenance use, but long-term safety data is still limited. The biggest concerns are dissociation during dosing and potential for abuse. It’s only given in certified clinics under supervision. Most people use it for 8 to 12 weeks, then taper off if they respond. It’s not meant to be a lifelong solution-it’s a bridge to recovery.

Does rTMS hurt?

No, it doesn’t hurt. You’ll feel a tapping or knocking sensation on your scalp during treatment. Some people get mild headaches or scalp discomfort, especially at first. These usually fade after a few sessions. No needles. No anesthesia. No recovery time. You can drive yourself home afterward.

Why aren’t psilocybin and other psychedelics available yet?

Psilocybin is still in clinical trials. While results are strong-71% response in one study-it’s not yet approved by Health Canada or the FDA. Regulatory approval requires larger trials, long-term safety data, and standardized dosing protocols. But it’s likely to become available within the next 2 to 5 years, especially for TRD.

Can therapy help if medications failed?

Yes. Cognitive behavioral therapy (CBT) has been shown to be as effective as medication for some people with TRD. It helps rewire negative thought patterns and build coping skills. When combined with medication, it boosts remission rates. Even if you’ve tried therapy before, it’s worth trying again with a therapist who specializes in treatment-resistant depression.