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You've tried antidepressants. Maybe several. The constant pattern of waiting six weeks, adjusting the dose, and waiting again has worn you down. Now you're researching faster options and seeing two names everywhere: Auvelity and ketamine.

Both promise quicker relief than traditional medications. Both target glutamate pathways rather than serotonin. And if you've seen Auvelity described as a "ketamine-like" antidepressant, you're probably wondering: are these really comparable options, or fundamentally different treatments?

The bottom line: These treatments suit different situations. Auvelity offers a convenient daily pill with faster onset than SSRIs, making it a reasonable option for major depressive disorder (MDD) that hasn't been labeled treatment-resistant. Ketamine has stronger evidence for treatment-resistant depression (TRD) specifically, with effects that can begin within hours rather than weeks. Auvelity did not show statistical separation from placebo in treatment-resistant depression trials.

Auvelity combines dextromethorphan (45 mg) and bupropion (105 mg) into an oral tablet you take twice daily at home. The FDA approved it in August 2022 for major depressive disorder in adults.

The medication targets your brain's glutamate system through NMDA receptor antagonism and sigma-1 receptor agonism rather than primarily serotonin pathways. The bupropion component serves mainly to slow dextromethorphan metabolism, keeping levels therapeutic.

How you take it: One tablet in the morning for three days, then add an evening dose from day four onward. No special monitoring required, though standard psychiatric follow-up remains important.

Ketamine therapy uses ketamine, originally developed as an anesthetic, to treat depression through a different pathway than traditional antidepressants. All forms work through NMDA receptor blockade, triggering rapid changes in synaptic function and neuroplasticity.

Ketamine comes in several forms: at-home sublingual ketamine (tablets taken under telehealth supervision), esketamine/Spravato (FDA-approved nasal spray administered in certified clinics with 2+ hour monitoring), and IV ketamine (intravenous infusions at specialty clinics, widely used but off-label).

For most people comparing Auvelity to ketamine, the practical choice is between Auvelity's daily pill and at-home ketamine's supervised sessions.

Let's dive in and explore the key differences between Auvelity and ketamine, so you can make an informed decision on finding your rapid relief option.

Auvelity is sometimes marketed as a "ketamine-like" antidepressant because both affect NMDA receptors. The comparison has some basis—and important limits.

The similarities are real: both work partly through glutamate pathways via NMDA receptor antagonism, both offer faster onset than traditional SSRIs and SNRIs, and both represent alternatives when serotonin-focused medications haven't helped.

But the differences matter more. Auvelity's NMDA effects are weaker and indirect compared to ketamine's direct blockade. Ketamine produces dissociative experiences; Auvelity does not. Ketamine requires monitoring during sessions while Auvelity is taken like any daily pill. And critically, ketamine has FDA approval and robust data for TRD, while Auvelity does not.

Think of it this way: Auvelity is an oral antidepressant with some glutamate activity. Ketamine is a fundamentally different treatment experience that happens to also affect glutamate. The mechanism overlap doesn't make them interchangeable options.

Speed is often the deciding factor, and where these treatments differ most.

Ketamine effects often begin within hours to days of the first session. In clinical trials for esketamine, group-level improvements appeared as early as 24 hours after the first dose. A 2024 JAMA Psychiatry study found clinically meaningful effects by day one, maintained through day 28. At-home ketamine shows similar rapid onset, though timing varies between individuals.

Auvelity shows improvement within 1–2 weeks in clinical trials. That's faster than the several weeks often needed with many SSRIs, but slower than ketamine's hours-to-days timeline.

If you can wait one to two weeks and want the simplicity of a daily pill, Auvelity offers that convenience. If you need relief within days, particularly if you're in acute distress, ketamine delivers faster.

Which Works Better for Treatment-Resistant Depression?

If you've tried multiple antidepressants over the years without adequate relief, this distinction matters most. TRD is typically defined as inadequate response to two or more antidepressants at adequate doses and duration.

The evidence favors ketamine for this population. Esketamine (Spravato) received FDA approval specifically for TRD based on controlled trials demonstrating efficacy. At-home ketamine is used off-label for TRD, with clinical outcomes data showing meaningful improvement. Multiple systematic reviews support ketamine's efficacy in treatment-resistant populations.

Auvelity's picture is different. While positive randomized controlled trials in MDD showed faster onset than placebo and bupropion alone, the medication was tested in TRD and did not demonstrate statistically significant separation from placebo at 6 weeks in an unpublished trial, based on secondary summaries of the sponsor's data. It has no FDA indication for TRD. Dr. Alan Schatzberg noted in APA Psychiatric News that enthusiasm for Auvelity in TRD "needs to be tempered until further clinical experience is gained."

This doesn't mean Auvelity won't help you. For MDD that hasn't been labeled treatment-resistant, it may be a reasonable glutamatergic option with the convenience of oral dosing. But if multiple antidepressants haven't worked, ketamine has demonstrated efficacy for your specific situation, while Auvelity lacks positive published randomized data for TRD populations.

No head-to-head trials compare Auvelity to any form of ketamine directly. Most ketamine studies have relatively small sample sizes compared to traditional antidepressant trials. Long-term comparative data between these approaches don't exist.

Both treatments are relatively new in their current applications: Auvelity approved in 2022, esketamine in 2019, at-home ketamine programs emerging over the past several years. The evidence base is growing but incomplete.

This means your decision involves some uncertainty either way. What we can say with confidence: ketamine has more direct evidence for TRD specifically, while Auvelity has shown faster onset than SSRIs in general MDD populations.

Auvelity: Daily, ongoing use like traditional antidepressants. Most people continue indefinitely if it's working.

Ketamine: Typically involves an initial course of 6–8 sessions over 4–8 weeks, followed by maintenance sessions (weekly to monthly) based on how long benefits last for you. This structure allows many people to eventually reduce frequency rather than taking daily medication indefinitely.

Rather than one being universally "safer," Auvelity and ketamine have different contraindications. Your medical history determines which risks apply to you.

Auvelity: Seizure and Eating Disorder Risks

Auvelity is contraindicated if you have any seizure disorder (bupropion lowers seizure threshold), history of bulimia or anorexia nervosa (increased seizure risk), current or recent MAOI use (within 14 days), or are currently taking another bupropion-containing product like Wellbutrin, Zyban, or Contrave.

Use caution if you have a history of mania or hypomania, angle-closure glaucoma risk, or liver or kidney impairment.

Drug interactions: Strong CYP2D6 inhibitors (like paroxetine, fluoxetine, quinidine) can increase dextromethorphan levels. If you're taking medications metabolized by CYP2D6 (many antidepressants, some beta-blockers), discuss potential interactions.

Common side effects: Dizziness (12.7%), nausea (11.9%), headache (8.8%).

Ketamine: Blood Pressure and Dissociation Considerations

Ketamine is contraindicated if you have uncontrolled high blood pressure, aneurysmal vascular disease, or intracerebral hemorrhage history. It's generally avoided if you have current or past psychotic disorders.

Use caution if you have cardiovascular disease, respiratory depression risk, history of substance use disorder, or current benzodiazepine use (which may reduce ketamine's antidepressant effect).

During treatment: Dissociation (feeling detached from your body), perceptual changes, and blood pressure elevation are common during sessions but typically resolve within 2 hours. For more detail, read about what ketamine feels like.

Discuss with a clinician before either option if you have blood pressure consistently above 140/90, history of mania, hypomania, or bipolar disorder, are taking 4+ psychiatric medications, have history of psychosis or dissociative disorders, have active substance use concerns, or are pregnant or planning pregnancy.

For specific guidance, see our article on driving after ketamine.

Auvelity: Manufacturer copay card available reducing cost to as little as $10/month for eligible commercially insured patients. Prior authorization typically required.

At-home ketamine: Often $54–400/month through programs with insurance partnerships, depending on provider and plan. Coverage varies. Some programs (including Innerwell) have direct insurance partnerships, while others are cash-pay only.

Clinic-based ketamine (IV or esketamine): Esketamine commonly ranges from tens to over a thousand dollars monthly out-of-pocket. Requires documented TRD. IV ketamine is rarely covered.

Note: Medicare and Medicaid beneficiaries cannot use manufacturer copay assistance programs.

Clinic-based ketamine involves transportation, unpaid time off work for 2+ hour visits (twice weekly initially), and childcare during appointments. Some ketamine programs charge separately for psychiatric evaluation, therapy sessions, or integration support. Auvelity carries standard psychiatry follow-up costs.

You have MDD that hasn't been labeled treatment-resistant

You want the simplicity of a daily pill with no monitoring

You have commercial insurance (copay card brings cost to ~$10/month)

Seizure history and eating disorders aren't concerns

You have treatment-resistant depression (two or more antidepressants haven't worked)

You need relief within days rather than weeks

You're willing to commit to sessions rather than daily pills

You want the option to eventually reduce frequency rather than indefinite daily medication

Uncontrolled blood pressure and psychosis history aren't concerns

What if one doesn't work? Response to one doesn't predict response to the other. While both affect NMDA receptors, the mechanisms aren't identical. Many people who don't respond to Auvelity find ketamine effective, and vice versa. Some clinicians use them sequentially, trying Auvelity first given its convenience, then moving to ketamine if response is inadequate.

Could Ketamine Fit Your Situation Better?

At-home ketamine programs vary significantly. Some are essentially medication delivery with minimal support. Others integrate licensed therapeutic guidance throughout treatment.

This matters because ketamine creates a window of neuroplasticity when your brain is more capable of forming new connections. That window is most valuable when paired with therapeutic work. The medication opens a door; therapy helps you walk through it.

Innerwell pairs at-home sublingual ketamine with licensed Master's and Doctoral level psychotherapists, not unlicensed guides. Treatment includes preparation sessions before each dose and integration therapy afterward to help you process what comes up.

Insurance partnerships in California and New York bring costs to $54–75/session (compared to $150–400+ elsewhere). Outcomes data show 69% average reduction in depression symptoms, 60% reduction in anxiety, and 87% reporting improvement within four weeks.

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

No. Auvelity shows effects in 1–2 weeks; ketamine can work within hours to days. Both are faster than traditional SSRIs, but ketamine's onset is significantly more rapid.

Does Auvelity work for treatment-resistant depression?

Current evidence doesn't support Auvelity for TRD. While it's effective for MDD with faster onset than SSRIs, the TRD trial did not show statistical separation from placebo, and it lacks FDA approval for treatment-resistant populations.

Can I switch from ketamine to Auvelity (or vice versa)?

Yes, though this should be done under psychiatric supervision. Some clinicians try Auvelity first given its convenience, then move to ketamine if response is inadequate. Others start with ketamine for TRD, then consider Auvelity for maintenance. Response to one doesn't predict response to the other.

Can I take Auvelity and ketamine together?

Limited reports suggest sequential or combined use may be feasible, but no clinical trials have established safety or efficacy. Potential concerns include overlapping effects on blood pressure, compounded dizziness, and unpredictable interactions. This should only be considered under close psychiatric supervision.

How long do I need to stay on either treatment?

Auvelity is taken daily like other antidepressants, typically long-term. Ketamine usually involves an intensive phase followed by maintenance sessions at less frequent intervals (weekly to monthly) based on how long your response lasts.

They have different risk profiles rather than one being universally safer. Auvelity has absolute contraindications for seizure disorders and eating disorders but requires no monitoring. Ketamine requires blood pressure monitoring and supervision during sessions but has fewer absolute exclusions. Your medical history determines which risks apply to you.

Compare Auvelity and ketamine for depression: which works faster, who each helps most, cost with and without insurance, and key safety differences.

Auvelity vs Ketamine for Depression: Speed, Cost, Safety

Introduction

What Is Auvelity?

What Is Ketamine Therapy?

At a Glance: Auvelity vs Ketamine

Is Auvelity Actually Like Ketamine?

How Fast Does Each Work?

What We Don't Know Yet

How Long Does Treatment Last?

Safety: Different Risk Profiles

Cost Comparison

Making the Decision

Auvelity vs Ketamine for Depression: Speed, Cost, and Safety Compared

If you've tried multiple medications without finding relief, you know the frustration of treatments that promise more than they deliver. You're not alone, and ketamine therapy exists specifically for situations like yours.

Key takeaway: Ketamine helps when other treatments haven't, often working within hours rather than weeks. It operates through brain mechanisms fundamentally different from SSRIs. The medication opens a door; what you do during that window, with integration therapy, determines how lasting those changes become.

What it is: An anesthetic medication repurposed to treat mental health conditions, available as IV infusion, nasal spray (Spravato in clinic), or sublingual tablets (at home)

Strongest evidence: Treatment-resistant depression, with response rates in the 50–70% range; also used for PTSD, anxiety, and chronic pain

Key risks: Transient dissociation, blood pressure elevation, not appropriate for those with uncontrolled hypertension, psychosis, or active substance use disorder

Typical cost: $54–125/session (at-home programs) vs. $400–800/session (IV clinic)

Ketamine therapy uses ketamine—a medication with decades of established use as an anesthetic—to treat depression, PTSD, anxiety, and other mental health conditions. The FDA approved ketamine as an anesthetic in 1970, and researchers discovered its rapid antidepressant effects around 2000.

What sets ketamine apart from SSRIs and other conventional antidepressants is how it works. Traditional medications primarily target serotonin, norepinephrine, or dopamine systems, building up gradually over weeks before showing effects. Ketamine affects the glutamate system instead. As an NMDA receptor antagonist, it promotes rapid changes in brain connectivity that can help loosen rigid, negative thought patterns. This different mechanism explains why ketamine can work within hours rather than weeks.

Using ketamine for mental health conditions is considered "off-label"—meaning the medication is FDA-approved but not specifically for psychiatric use. (The exception is esketamine nasal spray, marketed as Spravato, which is FDA-approved for treatment-resistant depression.) Off-label prescribing is common and legal in medicine when supported by clinical evidence, and ketamine's psychiatric applications now have substantial research backing them.

Traditional antidepressants gradually adjust serotonin levels over weeks. Ketamine takes a fundamentally different approach: it directly triggers your brain's neuroplasticity mechanisms.

A leading theory is that, at antidepressant doses, ketamine works through a cascade of effects:

Stage 1: Releasing the brake. Ketamine blocks NMDA receptors on inhibitory interneurons. This triggers a glutamate surge, your brain's primary activating signal, that reactivates dormant mood-regulating circuits.

Stage 2: Growth factor release. The glutamate surge triggers release of BDNF (Brain-Derived Neurotrophic Factor), a protein that acts like fertilizer for brain cells, promoting neuron survival and restoring the reduced BDNF levels often seen in depression.

Stage 3: New connections form. New synaptic connections begin forming in brain regions that regulate mood. Research from the National Institute of Mental Health and accumulating clinical evidence show that ketamine induces increases in molecules involved in neuroplasticity, paired with rapid antidepressant effects, though the precise mechanisms in humans are still being clarified.

This cascade explains why effects can appear so quickly compared to traditional antidepressants. But the mechanism reveals something important: ketamine creates a window of heightened plasticity. What happens during that window determines how lasting those changes become.

Ketamine can be administered several ways, each with different characteristics.

IV infusion is the most studied method for psychiatric use. Administered in a clinic over about 40 minutes, it offers precise dosing and 100% bioavailability. Best for initial treatment or complex cases requiring close monitoring. Typical cost: $400–800 per session.

Intranasal esketamine (Spravato) is the only FDA-approved ketamine formulation for treatment-resistant depression. Administered in certified healthcare settings with required monitoring periods. Often has better insurance coverage than other formats.

Sublingual lozenges or tablets dissolve under the tongue and can be used at home with telehealth supervision. Lower bioavailability than IV but more accessible for ongoing treatment. This is the format Innerwell uses.

Intramuscular injection is sometimes used in clinic settings as an alternative to IV when vein access is difficult.

The right route depends on your situation, treatment history, and practical considerations like cost and accessibility. Many people start with one format and transition to another for maintenance.

The strongest evidence supports ketamine for treatment-resistant depression. Clinical trials of IV ketamine and intranasal esketamine report response rates in the 50–70% range and remission in roughly one-third of patients.

Major depressive disorder with acute suicidal ideation or behavior has specific FDA approval for esketamine. The FDA approved this indication in August 2020, recognizing ketamine's potential for acute crisis intervention. Evidence: Strong.

PTSD. Clinical trials show ketamine can significantly reduce PTSD symptoms quickly, though FDA approval for this use hasn't occurred yet. Sample sizes are smaller and protocols vary. Evidence: Promising, still under study.

Anxiety disorders. Evidence is more limited than for depression. Some studies show benefit, particularly when anxiety co-occurs with depression. Evidence: Still under study.

Chronic pain. The strongest evidence involves specific neuropathic syndromes like CRPS (Complex Regional Pain Syndrome), often using different IV protocols than depression treatment. Evidence: Varies by condition.

OCD. Early research suggests ketamine may rapidly reduce obsessive-compulsive symptoms, though effects may be short-lived without maintenance. Evidence: Preliminary.

Clinical trials measure symptom reduction on standardized scales. But what does improvement actually feel like?

People often describe it as the volume turning down. The constant background noise of dread or emptiness doesn't vanish, but it quiets enough to function. You might notice you can get out of bed without the usual negotiation. A conversation with a friend doesn't feel like performing. Things that used to bring pleasure start to register again.

It's closer to remembering what "okay" felt like, not euphoria, but relief. The heaviness lifts enough that you can engage with life and do the work that therapy requires.

Ketamine isn't appropriate for everyone. Many programs treat the following as contraindications or strong cautions:

Uncontrolled hypertension. Ketamine can raise blood pressure. If this applies, work with your care team on blood pressure management first; ketamine may become an option once cardiovascular health is stabilized.

Active psychosis or schizophrenia. Ketamine's dissociative effects can worsen psychotic symptoms. Other treatment approaches, including antipsychotic medications and specialized therapy, are more appropriate.

Unstable bipolar disorder. Risk of triggering manic episodes without proper mood stabilization. Focus on mood stabilization with your current treatment team before considering ketamine.

Active substance use disorder. Ketamine has abuse potential. Addressing substance use first creates a safer foundation for any future ketamine treatment.

Pregnancy. Safety during pregnancy hasn't been established.

Certain cardiac conditions. Recent heart attack, severe heart disease, or aneurysmal vascular disease require careful cardiovascular evaluation.

If any of these apply, other treatment options may be more appropriate. A thorough clinical evaluation screens for these factors before treatment begins, and Innerwell's clinical team can discuss alternative approaches if ketamine isn't the right fit.

Now that you understand who ketamine helps and who should avoid it, you can better assess whether it might fit your situation.

Ketamine therapy may be worth exploring if you've tried two or more antidepressants without adequate relief, or experienced intolerable side effects. It's also worth considering if you've had persistent low mood or anxiety for two or more years despite treatment, if depression, anxiety, or trauma symptoms significantly affect your ability to work, maintain relationships, or care for yourself, or if you experience intrusive memories or emotional numbness that hasn't responded to therapy alone.

Is ketamine right for me? explores this question in more depth.

Rapid relief, often within hours or days rather than weeks

Effective for many people who haven't responded to traditional antidepressants

Can reduce suicidal ideation quickly in crisis situations

Works synergistically with therapy to accelerate breakthroughs

Available in at-home formats that reduce barriers to access

Effects may require maintenance sessions to sustain

Dissociative side effects can be uncomfortable for some people

Ketamine therapy treats depression when other medications haven't worked. Learn how it works, who it helps, risks, and whether it's right for you.

Reflections

Auvelity vs Ketamine for Depression: Speed, Cost, and Safety Compared

Ketamine 101: A Complete Guide to Ketamine Therapy

Ketamine Therapy for Intrusive Thoughts: Complete Guide

Ketamine vs. Psilocybin: Which Psychedelic Therapy Fits You?

Is Ketamine Therapy Safe? Common Concerns Answered

Ketamine Therapy Myths and Facts: What You Should Know

Ketamine Therapy for Aggression: Complete Guide