Treatment-Resistant Depression

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What I bring

I have worked on ketamine for treatment-resistant depression since my residency training at Emory. In 2014 I published one of the first descriptions of subanesthetic ketamine given as pre-treatment before ECT — distinct from the prior literature, which had used ketamine as the anesthetic agent during ECT. (Sultan RS, Riva-Posse P, Garlow SJ, Schwartz AC. Psychosomatics. 2014;55(4):396–399.)

That paper is a single case report, and I'll describe it as one: a 52-year-old man with four years of treatment-resistant depression and catatonic features whose Hamilton score fell from 34 to 22 within 24 hours of a 0.5 mg/kg infusion, then to 7 at four weeks following a course of ECT. Multiple interventions were started concurrently, so the effect cannot be cleanly attributed to ketamine alone — the paper says so explicitly. It was a proof of concept, not evidence of efficacy.

I mention it because it is where my interest in this started, not because one case establishes anything.

Also: neuromodulation training at Emory, and Assistant Professor of Clinical Psychiatry at Columbia.

Most people arriving at this page have been depressed for years and have concluded they're the exception nothing works for. Usually they're not.

First: is it actually resistant?

The formal definition is two or more adequate antidepressant trials in the current episode without remission. Adequate carries the weight — a therapeutic dose, sustained six to eight weeks.

Apply that honestly and a large share of "treatment-resistant" histories turn out to be:

Inadequate trials. Four weeks at a starting dose. Three medications tried in six months, none long enough. Stopped at the first side effect without a dose adjustment attempt.

Wrong diagnosis. In rough order of frequency:

• Bipolar disorder — depression that doesn't respond to antidepressants, or responds then destabilizes, should prompt a careful bipolar screen. Average diagnostic delay is six to ten years.
• ADHD — a lifetime of unexplained underperformance produces depression that is a reasonable response to circumstances. Antidepressants don't fix the circumstances.
• PTSD — trauma-related depression that hasn't been identified as such.
• Autism — late-identified autistic adults are frequently treated for depression for years first.

Untreated contributors. Active alcohol or cannabis use. Sleep apnea. Hypothyroidism. Chronic pain. An unaddressed life situation that no medication can resolve.

No psychotherapy. A surprising number of TRD referrals have never had an adequate course of evidence-based psychotherapy. That is not treatment resistance.

I work through all of this before escalating. It is unglamorous and it is where most of the wins are.

When it is genuinely resistant

Augmentation — adding to rather than replacing:

• Lithium — long-established evidence, underused, and the only psychiatric medication with a demonstrated anti-suicide effect. Requires level and renal/thyroid monitoring.
• Thyroid hormone (T3) — evidence from STAR*D, well tolerated.
• Atypical antipsychotics — aripiprazole, quetiapine, brexpiprazole, cariprazine all carry TRD augmentation indications. Effective, with real metabolic and movement-disorder costs. As the author of a 440-cited study on antipsychotic prescribing, I use these with explicit stopping rules rather than indefinitely.

Switching class — where the first agents shared a mechanism.

Esketamine (Spravato) — FDA-approved for TRD in 2019. Intranasal, administered in a certified setting under a REMS program with two hours of post-dose monitoring. Rapid onset, sometimes within hours, which matters where risk is high.

Intravenous ketamine — off-label, substantial supporting evidence, rapid antidepressant effect. Durability is the open question; it generally requires a maintenance strategy.

Ketamine combined with ECT. Where my own published work began, in a 2014 case report. The evidence base since remains thin and this is not a routine outpatient intervention. Where it's indicated I coordinate referral to a center that provides it.

TMS — FDA-cleared, non-invasive, typically about 30 sessions over six weeks. No systemic side effects, no anesthesia, no cognitive effects. Reasonable evidence, and a good fit for people who can't tolerate medication.

ECT — the most effective treatment available for severe depression, particularly with psychotic features or catatonia, with response rates well above anything else. Cognitive side effects are real and mostly transient, and modern unilateral ultra-brief pulse technique has substantially reduced them. It remains stigmatized far out of proportion to its risk profile, and for the sickest patients it is often the right answer.

How I work

Visit 1 (90 min). Full re-evaluation from the beginning — I don't inherit the existing diagnosis. Complete treatment history with doses and durations. Systematic differential.

Then a written sequence. What to try, in what order, with defined trial durations and decision points, so nobody is guessing at month four whether something is working.

Neuromodulation referral where indicated. I'll tell you when TMS or ECT is the right next step and coordinate the referral rather than continuing to cycle medications.

Related

Depression · Bipolar · Medication management · Second opinions · ADHD · PTSD

When Depression Becomes an Emergency

Depression that has resisted treatment for years carries elevated suicide risk precisely because it has gone on so long. If you are not in immediate crisis but are having suicidal thoughts, that warrants same-day or next-day psychiatric evaluation — not a wait-and-see approach.

Frequently Asked Questions

What is treatment-resistant depression?

Failure to achieve remission after two or more adequate antidepressant trials in the current episode, where adequate means a therapeutic dose sustained for six to eight weeks. Trials that were too short or too low-dose don't count toward the definition.

How do I know if my depression is truly treatment-resistant?

Review the actual doses and durations of each trial, and confirm the diagnosis. Undiagnosed bipolar disorder, ADHD, PTSD, sleep apnea, and active substance use are common findings in apparent treatment resistance and change the treatment entirely.

Does ketamine work for depression?

Both intravenous ketamine and intranasal esketamine produce rapid antidepressant effects in treatment-resistant depression, sometimes within hours. Esketamine is FDA-approved under a REMS program requiring administration in a certified setting. The main open question is durability, which generally requires a maintenance plan.

Is TMS effective for depression?

Yes. Transcranial magnetic stimulation is FDA-cleared for treatment-resistant depression, typically involving about 30 sessions over six weeks. It has no systemic side effects and requires no anesthesia, which makes it a good option for people who can't tolerate medication.

Is ECT still used?

Yes, and it remains the most effective treatment available for severe depression, particularly with psychotic features or catatonia. Cognitive side effects are real and largely transient, and modern technique has substantially reduced them. It is stigmatized well out of proportion to its actual risk profile.

What is lithium augmentation?

Adding lithium to an existing antidepressant. It has long-standing evidence in treatment-resistant depression, is substantially underused, and is the only psychiatric medication with a demonstrated anti-suicide effect. It requires blood level, kidney, and thyroid monitoring.