Alternatives to Esketamine: Complete Guide

You were told Spravato could help when nothing else had. Maybe it did, or maybe the twice-weekly clinic visits, the two-hour monitoring sessions, and the insurance battles made treatment unsustainable. Or maybe you're still weighing whether to start at all, and you want to know what else is out there before committing to a treatment that requires arranged transportation home every single time.

You're not the only one asking. Roughly one in three people with treatment-resistant depression (TRD) don't respond to standard antidepressants, and for many of them, Spravato's logistics create barriers that have nothing to do with whether the drug works.

The bottom line: Several alternatives to esketamine exist, including IV ketamine, sublingual ketamine, Auvelity (an oral medication that targets the same brain pathway), transcranial magnetic stimulation (TMS), and electroconvulsive therapy (ECT). Each comes with different tradeoffs in efficacy, cost, convenience, and insurance coverage. Your best option depends on what specifically isn't working about esketamine for you.

What Is Esketamine (Spravato)?

Spravato is a prescription nasal spray containing esketamine, one form of ketamine. The FDA approved it in 2019 for treatment-resistant depression in adults, and in January 2025 it became the first FDA-approved TRD treatment that can be used on its own. Spravato works on a different brain pathway than traditional antidepressants, which is why effects can show up within hours rather than weeks.

The catch is access. Spravato can only be administered in a healthcare setting certified under the Risk Evaluation and Mitigation Strategy (REMS) program, with mandatory monitoring after every dose. Home use is not permitted.

Why People Look for Alternatives

Side effects push some people away. Dissociation occurs in 41% of people, and the FDA label carries boxed warnings for sedation, dissociation, respiratory depression, and abuse potential. If altered states feel distressing or you have a trauma history, those side effects can make Spravato a poor fit regardless of how well it might work.

Cost is another barrier. Annual drug costs alone can run from roughly $18,000 to over $45,000 in the first year. Even with insurance, prior authorization denials are common enough that the American Psychiatric Association has flagged reimbursement barriers as a systemic concern.

Time also adds up. Four weeks of induction can consume eight half-days in treatment logistics, before maintenance dosing even begins.

What Are the Main Alternatives?

The options can start to blur together fast. Some are other forms of ketamine, others use brain stimulation, and a third group works through medications. You don't need the "best" option on paper. You need one whose tradeoffs fit your life.

1. IV Racemic Ketamine

If you want the ketamine option with the strongest evidence behind it, IV racemic ketamine is usually where people look first. Racemic ketamine contains two forms of ketamine, while Spravato contains one. It's administered as a 40-minute infusion at specialized clinics and is used off-label for depression.

The evidence is strong. A 2024 meta-analysis found response rates of 35 to 55% and remission rates of 25 to 35%. The most rigorous direct comparison was a 2025 meta-analysis of eight head-to-head studies including 978 patients, which found no statistically significant difference in response or remission between IV ketamine and intranasal esketamine.

Real-world data from McLean Hospital (153 patients) showed IV ketamine produced a 49% reduction in depression scores versus about 40% for esketamine, and reached statistical significance after just one treatment compared to two for esketamine.

The tradeoff is practical: IV ketamine isn't FDA-approved for depression and is usually paid out of pocket.

2. Sublingual Ketamine

If the hardest part of Spravato is the clinic burden, sublingual ketamine is often the alternative people look at next. Sublingual (under-the-tongue) ketamine tablets use compounded preparations of racemic ketamine. A prospective review of 60 patients found roughly 50% improved after four weeks, and about 60% improved among those who completed a full 12-session course. A separate study found nearly 50% of people cut their depression scores in half after three doses.

Convenience is the appeal. Oral ketamine can be taken at home with telehealth supervision. No clinic schedule, no arranged transportation home.

The evidence base is thinner than for IV ketamine. The FDA has also issued a safety alert about compounded ketamine used at home without REMS safeguards. That warning applies to compounded ketamine used without clinical supervision, not to programs with licensed prescribers and ongoing monitoring. Provider quality matters here.

3. Auvelity (Dextromethorphan-Bupropion)

If you want an oral option that works on the same brain pathway as ketamine, Auvelity is the closest pharmacological cousin to esketamine. It was developed as an oral alternative to ketamine for people who couldn't tolerate the monitoring requirements. The FDA approved it in 2022 for major depressive disorder. That made it the first oral medication with an NMDA-receptor mechanism approved for depression.

It's taken twice daily as a pill, broadly covered by insurance, and avoids the dissociation, monitoring requirements, and clinic visits of esketamine. Trial data showed faster onset than standard antidepressants. Effects often appear within one to two weeks.

The downsides are real. Auvelity hasn't been compared head-to-head with ketamine or esketamine in randomized trials, so the relative efficacy is unknown. Side effects include dizziness, nausea, and headache, with a small seizure risk from the bupropion component. If you want the convenience of a pill that targets the ketamine pathway, Auvelity vs ketamine offers a closer look at how they compare.

4. Repetitive TMS

If dissociation, sedation, or driving restrictions are what make ketamine-based treatment feel like the wrong fit, TMS may feel more manageable. Transcranial magnetic stimulation uses magnetic fields to stimulate brain regions associated with mood. No anesthesia, no controlled substance, no dissociation. You can drive home immediately. The National Institute of Mental Health (NIMH) confirms strong clinical evidence for its effectiveness when medications haven't worked.

A network meta-analysis of treatments for treatment-resistant depression found TMS response rates comparable to both electroconvulsive therapy (ECT) and ketamine, with no statistically significant differences between active treatments. For many people, the appeal is that it works without psychoactive effects.

TMS appears to have the most favorable safety profile among the options here. Published safety reviews of repetitive TMS (rTMS) report low seizure risk when expert guidelines are followed, and most side effects are limited to mild headache or scalp discomfort.

The main limitation is time. Standard protocols require daily visits, five per week, for four to six weeks. Newer accelerated protocols are closing that gap; the FDA cleared a six-day accelerated deep TMS protocol in September 2025. Some major insurance plans cover TMS.

5. ECT (Electroconvulsive Therapy)

If you need the treatment with the highest odds of remission, ECT is usually the option people consider most seriously. ECT remains what the NIMH calls the "gold standard" for treatment-resistant depression, with remission rates of 60 to 80%. Those rates are higher than reported for the other options here.

ECT requires general anesthesia and is typically administered two to three times per week for three to four weeks. It's broadly covered by insurance and is most often considered when other options, including ketamine and TMS, haven't worked, or when psychotic features are present.

The cognitive tradeoff is real. Memory impairment is common and can persist for months.

For severe TRD where even ECT hasn't worked, vagal nerve stimulation (VNS) and deep brain stimulation (DBS) exist as device-based options. Clinicians rarely consider them first, but they're worth knowing about if you've exhausted the other paths.

6. Medication Augmentation

If you're not ready for a device-based or ketamine-based treatment, that's a reasonable place to be. Several FDA-approved oral medications can be added to antidepressants when they aren't working alone. Atypical antipsychotics like aripiprazole, quetiapine, and brexpiprazole are the most common. They take weeks rather than hours, but they're oral, widely available, and covered by insurance.

The most direct head-to-head evidence comes from the 2023 ESCAPE-TRD trial, which compared esketamine plus an SSRI/SNRI against extended-release quetiapine plus an SSRI/SNRI in 676 adults with TRD. At eight weeks, 27.1% of the esketamine group were in remission compared with 17.6% of the quetiapine group, and esketamine maintained an advantage at 32 weeks. For someone choosing between augmentation and esketamine, this is the most rigorous evidence available.

Lithium augmentation has decades of evidence behind it, but it asks more of you in return: regular blood monitoring, plus thyroid and kidney risks. A network meta-analysis found ketamine superior to lithium for both response and remission in TRD. Lumateperone (Caplyta) was approved in November 2025 as an add-on for depression with a cleaner metabolic profile than older options, though it's approved for major depressive disorder broadly, not TRD specifically. If SSRIs alone haven't worked for you, SSRI alternatives covers that broader decision in more depth.

For completeness, psilocybin and other classic psychedelics have FDA breakthrough designations for depression and are in late-stage trials, but they aren't currently available outside research settings.

How to Compare What Matters for Your Decision

If you're feeling torn, that makes sense. None of these options is perfect, and you get to decide which tradeoff matters most right now.

If cost and the clinic schedule were the main problems with Spravato, sublingual ketamine or TMS may be worth considering. If dissociation was intolerable, TMS offers comparable efficacy with no psychoactive effects at all. If you want a pill that targets the ketamine pathway without dissociation or clinic visits, Auvelity is worth discussing with a prescriber. If you need the highest possible chance of remission and can accept cognitive risks, ECT's 60 to 80% remission rate is unmatched.

If you want the rapid onset of ketamine with the convenience of at-home treatment and the support of licensed clinicians, sublingual ketamine paired with integration therapy may balance those priorities.

Why Therapeutic Support Matters

If you've already been through a lot, this part matters.

Ketamine promotes neuroplasticity, meaning your brain becomes briefly more capable of forming new patterns and connections. But that window is most valuable when you use it intentionally. The medication opens a door; therapy helps you walk through it.

Without therapeutic support, the effects of ketamine tend not to last as long. With it, the insights that surface during treatment can translate into changes that hold after the dosing window closes. That's why provider quality matters, and why a program that builds in preparation and integration is meaningfully different from one that just hands you the medication.

How Innerwell's At-Home Ketamine Therapy Works

Innerwell offers at-home sublingual ketamine therapy paired with licensed psychiatric providers and licensed therapeutic support. This isn't ketamine dropped off with minimal supervision. You work with Master's- or Doctoral-level therapists who provide preparation before treatment and integration afterward, so the experience can translate into lasting change. The goal is a treatment you can realistically stay with long enough to give it a chance to work.

The process:

1. Evaluation: A psychiatric assessment determines whether ketamine therapy is appropriate for you, including a review of your treatment history and current symptoms.
2. Delivery: Sublingual ketamine tablets are prescribed and shipped to your home. No clinic visits, no arranged transportation, no two-hour monitoring windows.
3. Preparation and integration: Therapy sessions before and after each ketamine experience give you space to set intentions, process what comes up, and build on the insights that emerge.
4. Ongoing monitoring: Your clinical team tracks your progress and adjusts the treatment plan based on how you respond.

Pricing: With insurance, sessions cost $54 to $75 each. Self-pay ranges from $83 to $125 per session, a fraction of the $590 to $895 per-session drug cost for Spravato alone.

Program outcomes: 69% of people in Innerwell's program see a reduction in depression symptoms after 10 weeks. 60% see a reduction in anxiety symptoms. 87% improve within four weeks. The average rating is 4.7 out of 5.

Take our free assessment to see if ketamine therapy might be a good fit for you.

Frequently Asked Questions

Will my insurance cover any of these alternatives?

Coverage varies widely by formulation. Spravato has the broadest commercial and Medicare coverage among ketamine-based options. TMS and ECT are also broadly covered, with TMS typically requiring documentation of prior antidepressant trials. IV ketamine and compounded sublingual ketamine are usually paid out of pocket, though some at-home programs have insurance partnerships that bring per-session costs into the $54 to $125 range. Auvelity and oral augmentation medications like quetiapine are typically covered like other prescription medications, though formulary placement varies by plan.

What if Spravato worked at first but stopped working?

This is common enough that researchers have studied it. Diminishing antidepressant effect during esketamine treatment can stem from several causes, and the usual next steps are dose or frequency adjustments first. If those don't restore the response, switching to a different TRD strategy (TMS, ECT, or another ketamine formulation) is reasonable. Have this conversation with your prescriber before stopping treatment, since unstructured discontinuation can lead to symptoms returning faster than expected.

Can I switch from Spravato to another form of ketamine?

Yes. Peer-reviewed literature has documented transitioning between ketamine formulations while maintaining antidepressant response. Specialists generally recommend having a clear plan for what comes next before stopping any ketamine treatment, because the absence of a plan can lead to symptom return. A clinician can walk you through Spravato vs ketamine and map out a transition.

How long do people typically stay on ketamine therapy?

Most protocols start with an induction phase of six to eight doses over four to eight weeks, followed by maintenance dosing that varies by individual response. Some people maintain benefits with monthly or bi-weekly dosing; others taper off after several months once gains have stabilized through integration work. What matters is matching the schedule to your symptom trajectory rather than following a fixed protocol indefinitely.