9 Effective Alternatives to Spravato for Depression

Maybe your insurance denied Spravato. Maybe the twice-weekly clinic visits don't fit your life, or the cost feels out of reach even with coverage. Or maybe you've started Spravato and it isn't doing what you hoped. Whatever brought you here, you're weighing options, and the choices can feel overwhelming.

You're not alone in this. More than half of people with depression didn't reach remission after their first antidepressant in the National Institute of Mental Health's STAR*D study, and one-third still hadn't after four rounds of treatment. When standard options run out, looking past Spravato is a reasonable next step.

The short answer: Several evidence-based alternatives to Spravato exist, including IV and at-home ketamine, TMS, ECT, and newer oral medications. The right one depends on your priorities around speed, cost, convenience, and insurance coverage.

What Is Spravato?

Spravato is the brand name for esketamine, a nasal spray derived from ketamine. It uses one purified part of the ketamine molecule, while IV and oral ketamine use the full molecule. Spravato is related to ketamine, but it is not the same treatment, and how Spravato works differs in some ways from racemic ketamine.

In March 2019, the FDA approved it for treatment-resistant depression, then expanded its use in 2020 for depression with acute suicidal thoughts. The current FDA label no longer requires taking an oral antidepressant at the same time.

Spravato is available only through a federal safety program, the Spravato REMS (Risk Evaluation and Mitigation Strategy). You can't take it at home. Every dose is self-administered in a certified clinic under direct observation, followed by at least two hours of monitoring. You can't drive until the next day after restful sleep. During the first four weeks, that means two clinic visits per week.

Like other ketamine-based treatments, Spravato works through a different brain pathway than traditional antidepressants, which is part of why many people notice a shift within days or weeks rather than months.

The 9 Alternatives

These range from other forms of ketamine and newer oral medications to brain stimulation, established antidepressants, and investigational options. Each works differently, so the right one depends less on which is "best" and more on which fits your life and your priorities.

1. IV Ketamine

IV ketamine uses the full ketamine molecule, delivered directly into your bloodstream, usually over six infusions across two to three weeks. It acts on the same brain pathway as Spravato rather than one purified part of it.

If you're looking at IV ketamine, speed is usually part of the appeal. Across randomized trials in depression, response rates run 50 to 70%. One randomized trial found a 64% response rate for ketamine versus 28% for the control group after a single infusion. A meta-analysis covering 1,877 participants across 24 trials found IV ketamine outperformed Spravato on response and remission. In practice, the two are comparable on efficacy, and the real difference is access, which the spravato vs ketamine comparison covers in depth.

Relief can arrive within two to four hours and typically lasts three to seven days per infusion. Access is the tradeoff. IV ketamine lacks FDA approval for psychiatric use, so insurance rarely covers it for depression, and you need a clinic for every session.

2. Oral and Sublingual Ketamine

Oral or sublingual ketamine is taken by mouth or dissolved under the tongue. It's the same mechanism as IV ketamine, delivered through a lower-cost, off-label route that telehealth has made far more accessible.

For many people, the appeal is practical: fewer clinic barriers, lower cost, and treatment that can fit more easily into real life. A study of telehealth ketamine reported a 62.8% response rate and 32.6% remission rate, with adverse reactions in just 3.8% of people. A separate study found a 60% response rate after four weeks.

Onset is slower than IV because the body absorbs less of it when taken by mouth, but improvement can still begin within days. You can do this at home with clinical monitoring, and no REMS-certified facility is required.

3. Auvelity (Dextromethorphan-Bupropion)

Auvelity is an oral tablet the FDA approved in 2022 for major depressive disorder (MDD), the first oral medication in decades to act on the same glutamate system in the brain as ketamine and Spravato. Its dextromethorphan component works on that pathway, while the bupropion component raises dextromethorphan levels in the blood so the effect lasts.

Unlike Spravato, you take it at home as a daily tablet, with no clinic visit, no monitoring period, and no driving restriction.

In its phase 3 trial, improvement showed up as early as one to two weeks, faster than most traditional antidepressants though not as fast as ketamine. It is also approved for major depression broadly, not only treatment-resistant cases, so it can be an option earlier in the process.

4. Transcranial Magnetic Stimulation (TMS)

TMS uses a magnetic coil held against your scalp to stimulate underactive brain regions involved in mood, with no surgery or sedation. A typical course runs five days a week for four to six weeks.

TMS can be a good fit if you want something non-medication-based and can manage frequent visits for a few weeks. The American Psychiatric Association reports that roughly 1 in 2 people respond and 1 in 3 reach remission. Harvard Health puts response rates at 50 to 70%.

TMS benefits can last more than a year after treatment ends, and it is FDA-cleared for treatment-resistant depression. Benefits build gradually rather than in hours, but there are no driving restrictions and no memory effects.

5. Electroconvulsive Therapy (ECT)

ECT is the most potent antidepressant treatment available. Electrical currents pass through the brain under general anesthesia to trigger a brief, controlled seizure.

It's reserved for severe, treatment-resistant, or life-threatening depression, usually six to twelve sessions given three times a week. ECT can sound frightening, especially when you're already exhausted by depression, but modern ECT is done under anesthesia and is often considered when other options haven't been enough.

ECT has the highest efficacy numbers of any option here: 70 to 80% response and 50 to 60% remission in people with treatment-resistant depression, though community settings show lower remission, around 30 to 47%.

Memory impairment is the most common side effect, reported in 22 to 79% of people. It's usually worst right after treatment and improves over time, and some ECT techniques can reduce it. ECT is FDA-cleared and covered by most plans, including Medicare and Medicaid.

6. Monoamine Oxidase Inhibitors (MAOIs)

MAOIs are older antidepressants, but they are not automatically a step backward. If you've tried several newer medications and still feel stuck, your clinician may bring up tranylcypromine, phenelzine, isocarboxazid, or the selegiline patch. These medications block the enzyme that breaks down serotonin, norepinephrine, and dopamine, which raises the levels of these mood-regulating chemicals.

Because they are FDA-approved medications, coverage may be more straightforward than it is for off-label treatments, depending on your plan.

MAOIs come with real safety requirements. They require a strict diet that avoids tyramine-rich foods like aged cheeses, cured meats, and certain wines, because combining them can raise blood pressure dangerously.

They also can't be taken with SSRIs. The diet rules can feel intimidating at first, but for some people who have exhausted newer medications, MAOIs are still worth considering, and the selegiline patch may carry fewer dietary restrictions.

7. Augmentation With Lithium or Atypical Antipsychotics

If an antidepressant has helped a little but not enough, you may not need to start over. Sometimes the next step is adding a second medication to build on what's already partly working. The two main options are lithium, a mood stabilizer, or an atypical antipsychotic such as aripiprazole or quetiapine.

A systematic review found both strategies likely beneficial in treatment-resistant depression, with no significant difference between them. Lithium is less expensive, possibly more effective, and lowers suicide risk, though it requires regular blood monitoring for toxicity.

Even with augmentation, overall remission rates in treatment-resistant cases stay modest. Augmentation is worth discussing, but it isn't a guaranteed fix.

8. Psilocybin (Investigational)

Psilocybin is a psychedelic compound from certain mushrooms, studied in controlled clinical settings with psychotherapy support. It works through the serotonin system and is thought to promote neuroplasticity and loosen rigid negative thought patterns.

If you're drawn to psilocybin, the door is not fully open yet. The early data is mixed but promising. A pilot trial reported a 43% combined response and remission rate. A Phase 2b trial found 29% remission at the 25 mg dose versus 8% at a low control dose.

Improvements have been measurable after one session. Psilocybin remains investigational and is not FDA-approved for depression, available mostly through clinical trials. If you're choosing between the two, psilocybin and ketamine differ meaningfully in access and evidence.

9. Zuranolone (Zurzuvae)

Zuranolone stands out for two reasons: it's taken by mouth, and it works on a short timeline. It's an oral capsule taken as a 14-day course.

It works on the GABA system, a calming chemical system in the brain, which sets it apart from both serotonin-based antidepressants and ketamine. In postpartum depression, it begins working within three days.

If your depression is postpartum, this may be directly relevant. If not, it's understandable to feel frustrated that a faster oral option doesn't extend more broadly yet. Zuranolone is FDA-approved for postpartum depression only. It isn't currently available for treatment-resistant depression more broadly.

How the Options Compare

Insurance coverage, speed, and cost differ sharply across these options. The table below focuses on the treatments most directly comparable to Spravato on speed, coverage, and cost. In real life, the treatment that works fastest may not be the one your insurance wants to cover.

Two independent cost analyses found Spravato expensive relative to alternatives. One evidence report judged its price high compared with its health benefit, and a separate cost analysis found ECT delivered more benefit at lower cost.

Which One Might Fit Your Situation

There's no universally right choice here. Your best fit depends on what matters most to you right now.

• If speed is your priority, ketamine-based treatments work fastest. IV ketamine can bring relief in hours, and at-home sublingual ketamine often works within days. ECT and TMS take weeks.
• If insurance coverage is the deciding factor, FDA-approved or FDA-cleared options such as Spravato, TMS, and ECT may be easier to pursue through insurance than off-label IV ketamine, which is rarely covered for depression. Plan criteria still matter.
• If durability matters more than speed, TMS responders average more than a year of benefit after a completed course. Ketamine treatments work faster but generally need maintenance dosing.
• If you have severe or life-threatening depression, ECT has the highest response and remission rates and is often the right call when other options haven't been enough.

Most people are weighing more than one of these at once, and the right answer often comes down to which tradeoff you can live with.

Why the Therapeutic Approach Matters

Comparing these treatments also means looking at what surrounds the medication. Some Spravato and IV ketamine programs focus mainly on medication administration rather than structured integration therapy.

Ketamine appears to promote neuroplasticity, which may make your brain more capable of forming new patterns. The medication opens a door; therapy can help you walk through it. Evidence on integration is still mixed. A 2025 study found no additional benefit from adding psychotherapy. The field is developing, and for many people the integration work can help the change last.

How Innerwell's At-Home Ketamine Therapy Works

For people who want ketamine therapy without the clinic, Innerwell offers an at-home model. You take medication at home with licensed therapeutic support built into every step. This isn't ketamine dropped off with minimal supervision, and it isn't a REMS clinic either. It's clinician-guided at-home ketamine therapy with preparation, integration, and ongoing monitoring built into care.

The process:

1. Evaluation: A virtual psychiatric assessment determines whether ketamine therapy is a safe fit, including a review of your medical history, current medications, past treatment responses, and goals.
2. Delivery: Sublingual ketamine tablets ship securely to your door through a licensed pharmacy, with precise dosing instructions and no IV clinic, REMS facility, or two-hour monitored waiting room.
3. Preparation and integration: You work with licensed psychotherapists before treatment to set intentions and afterward to process what came up, which can help translate the experience into longer-term change.
4. Ongoing monitoring: Your care team tracks your mood, symptoms, and progress through telehealth, then adjusts your plan as you go.

Every part of this is handled by licensed clinicians: psychiatric providers and psychotherapists who hold Master's or Doctoral degrees, not unlicensed guides.

Pricing: Foundation is $599 ($75/treatment) with insurance or $998 ($125/treatment) self-pay. Extended is $1,299 ($54/treatment) with insurance or $1,999 ($83/treatment) self-pay. Insurance coverage is available in California and New York, with self-pay available elsewhere.

Program outcomes: People in Innerwell's program have seen a 69% reduction in depression symptoms after 10 weeks, a 60% reduction in anxiety symptoms after 10 weeks, and 87% see improvement within 4 weeks, alongside a 4.7 out of 5 star average patient rating.

Ketamine use for depression is off-label. The FDA has approved ketamine as an anesthetic, not for psychiatric conditions specifically.

Ketamine may not be appropriate for people with uncontrolled hypertension, a history of psychosis, unstable heart disease, active substance-use disorder, or pregnancy. Those are some of the reasons Innerwell's clinical team reviews your medical history and eligibility before treatment. Ketamine therapy isn't right for everyone, and a careful provider should tell you that upfront.

Take our free assessment to see if ketamine therapy might be right for you.

Frequently Asked Questions

Is at-home ketamine therapy as effective as going to a clinic?

Real-world data is encouraging. Studies of at-home sublingual ketamine, taken with telehealth monitoring, report response rates in line with clinic-administered ketamine, and serious side effects are uncommon. You don't give up effectiveness. What changes is the logistics: no twice-weekly clinic trips and no two-hour monitored waiting room. For a lot of people, being in their own space makes the experience feel safer. Even at home, treatment stays clinically supervised, not something you do on your own.

Can I switch to a different option if I've already tried Spravato?

Yes. Trying Spravato doesn't lock you into it, and not responding to it doesn't mean nothing else will work. Because these treatments act on the brain in different ways, people who don't respond to one can still respond to another. The move is worth making with a clinician who can look at your full history, current medications, and how you responded to Spravato, then plan the transition so it's safe and unhurried. You don't have to start from zero.

What if the alternative I try doesn't work either?

That fear makes sense, especially if you've already cycled through treatments that let you down. No single option works for everyone. But running out of treatments that have worked so far isn't the same as running out of options. Different treatments reach depression through different pathways, so a new approach can help even when others haven't. What matters most is a care team that tracks how you're doing and adjusts the plan, rather than leaving you to figure it out alone.