Fda approval of johnson & johnson’s ketamine nasal spray for depression treatment

In March 2019, the U.S. Food and Drug Administration (FDA) approved Johnson & Johnson’s ketamine-based nasal spray for depression, marking a significant breakthrough in psychiatric treatment (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). The drug, called Spravato (generic name esketamine), is intended for adults with treatment-resistant depression – patients who have not found relief after trying several other antidepressants (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). This approval is notable as it’s the first new antidepressant mechanism introduced in decades (since the late 1980s, when Prozac and other SSRIs emerged) (Psychiatry.org – FDA Approves Novel Depression Treatment). Spravato’s rapid action and novel approach offer hope to those who have suffered from severe depression with limited treatment options.

• Active ingredient: Spravato’s active compound is esketamine, which is the S-enantiomer of ketamine (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). (Ketamine itself is a mixture of two mirror-image molecules, R- and S-ketamine; esketamine is the more potent of the two in terms of antidepressant effect.) Ketamine has a long history as an anesthetic – it was FDA-approved for anesthesia in 1970 (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA) – and is also known recreationally as “Special K.” Esketamine was specifically developed to harness ketamine’s antidepressant properties while being administered in a controlled way via a nasal spray.
• Mechanism of action: Unlike traditional antidepressants that work on serotonin or other monoamine neurotransmitters, esketamine targets the brain’s glutamate system. It is an NMDA receptor antagonist, which means it temporarily blocks a receptor for the neurotransmitter glutamate. This action is thought to trigger a cascade of events that help restore synaptic connections in brain regions involved in mood (Advisory Panel Recommends FDA Approval of Esketamine, with New Mechanism to Treat Resistant Depression | Brain & Behavior Research Foundation). In simpler terms, esketamine can prompt the brain to form new neural connections and pathways. This is a fundamentally different approach than SSRIs, which gradually increase serotonin levels. As Dr. John Krystal, a Yale psychiatrist and ketamine researcher, explains, “When you take ketamine, it triggers reactions in your cortex that enable brain connections to regrow… It’s the reaction to ketamine, not the presence of ketamine in the body, that constitutes its effects.” (How Ketamine Drug Helps with Depression > News > Yale Medicine) This ability to essentially “rewire” parts of the brain may underlie ketamine’s rapid antidepressant effects.
• How it differs from traditional antidepressants: Traditional antidepressants (like SSRIs and SNRIs) often take 4–6 weeks to have a significant effect on mood, and they work by subtly adjusting brain chemistry over time (for example, by preventing the reuptake of serotonin or norepinephrine). Esketamine, by contrast, can act within hours by directly modulating glutamate, the most abundant excitatory neurotransmitter in the brain (Psychiatry.org – FDA Approves Novel Depression Treatment). This direct and fast mechanism is why esketamine can help patients who don’t respond to other drugs. Additionally, Spravato is delivered as a nasal spray under medical supervision, rather than a pill you take daily. The route (intranasal) allows the drug to absorb quickly. Patients self-administer the spray device under a healthcare provider’s guidance at a clinic, rather than taking the medication at home. This method of administration is part of ensuring safety (more on that in the Risks section). In summary, the ketamine nasal spray represents a novel class of antidepressant: it works on a different neurotransmitter system (glutamate vs. serotonin), it’s fast-acting, and it’s given in a controlled setting as opposed to routine at-home dosing.

Developing a new antidepressant with a novel mechanism was a high priority, given the unmet need in treatment-resistant depression. Here’s an overview of how esketamine nasal spray moved through the FDA approval process:

• Breakthrough status & fast-track: Recognizing early on that esketamine showed promise for severe depression, the FDA granted it Fast Track status and later breakthrough therapy designation (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). These designations, given years before approval, helped expedite development and review. Fast Track and Breakthrough Therapy status are reserved for treatments that address serious conditions and show substantial improvement over existing therapies – in this case, esketamine’s rapid effect for hard-to-treat depression was a key factor.
• Clinical trials: Johnson & Johnson’s Janssen Pharmaceuticals conducted an extensive clinical trial program for esketamine. This included five Phase 3 placebo-controlled studies (along with earlier-phase studies) in patients with treatment-resistant depression (Advisory Panel Recommends FDA Approval of Esketamine, with New Mechanism to Treat Resistant Depression | Brain & Behavior Research Foundation). Across these trials, hundreds of patients received esketamine plus standard oral antidepressants, and their outcomes were compared to those on placebo nasal spray plus antidepressants. The trials measured changes in depression severity, response rates, and safety outcomes (discussed in the next section). Results from these studies formed the basis of the FDA application.
• Advisory committee recommendation: Before approval, the FDA convened an independent advisory panel (the Psychopharmacologic Drugs Advisory Committee) to review the esketamine data. On February 12, 2019, this panel of experts voted 14 to 2 (with one abstention) in favor of approving Spravato, concluding that the benefits for treatment-resistant depression outweighed the risks (). The committee was impressed by the drug’s efficacy for hard-to-treat patients, while acknowledging safety concerns could be managed with restrictions. This positive recommendation was a strong signal, as the FDA often (though not always) follows the advice of its advisory committees.

Fda decision (March 2019): Just a few weeks later, the FDA made its final decision. On March 5, 2019, the FDA officially approved Spravato (esketamine) nasal spray for adults with treatment-resistant depression, to be used in conjunction with an oral antidepressant (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). The requirement to pair it with an oral antidepressant was initially mandated to ensure patients maintain a baseline of standard treatment as the esketamine’s effects wear off between doses. The approval came with a specialized risk management program (REMS). Because of risks like sedation, dissociation, and the potential for abuse, the FDA stipulated that esketamine could only be administered in certified medical settings under supervision (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). Patients cannot take the drug home from the pharmacy. This was an unusual restriction reflecting the seriousness of the side effect profile. FDA Acting Director of Psychiatry Products, Dr. Tiffany Farchione, noted at the time, “There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition…[this approval came after] careful review through the FDA’s drug approval process including a robust discussion with our external advisory committees.” (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA) In short, the FDA approval process for Spravato was swift by antidepressant standards – aided by expedited designations – and involved careful weighing of innovative benefits against safety precautions.

The approval of esketamine was grounded in several key studies that demonstrated its effectiveness, especially for people who hadn’t found relief with existing treatments. Here are some highlights from the clinical trial results:

• Higher response rates: In one major four-week trial, patients with treatment-resistant depression were given either esketamine nasal spray or a placebo nasal spray, in addition to a newly started oral antidepressant (since ethical considerations required that even the placebo group receive some form of therapy). The esketamine group saw a markedly higher response. About 70% of patients on esketamine showed a significant improvement in their depression symptoms (as measured by standard scales), compared to just over 50% of patients in the placebo group (How Ketamine Drug Helps with Depression > News > Yale Medicine). In other words, adding esketamine helped a substantial number of patients who would not have responded to a pill alone. Many of these patients had suffered depression for years and failed multiple prior medications, so a 70% improvement rate was quite encouraging.
• Rapid onset of action: Perhaps the most talked-about aspect of ketamine therapy is how quickly it works. Trials showed that symptom relief can begin within hours to a day after dosing. In the positive short-term study, some antidepressant effect was seen as soon as 24–48 hours after the first dose (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). By comparison, traditional antidepressants typically require several weeks to build up effect. An FDA summary noted that significant improvement in depressive symptoms (and even suicidal thinking) could appear in as little as 4 hours after an esketamine dose (Psychiatry.org – FDA Approves Novel Depression Treatment). This rapid effect is a game-changer for patients in crisis or who are extremely ill. However, it’s worth noting that the esketamine’s effects are not permanent from a single dose – the beneficial effects tend to last days to a couple of weeks, hence the need for ongoing, typically weekly or biweekly dosing during maintenance.
• Efficacy and outcomes: The primary measure in the trials was often the change in a depression rating scale (like the MADRS – Montgomery-Åsberg Depression Rating Scale). In the successful trial, esketamine produced a statistically significant greater improvement in MADRS scores over four weeks compared to placebo (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). Two other short-term trials did not meet their preset criteria for significance on the primary endpoint (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA) – a fact that generated some debate. Even in those studies, there were positive trends, but they weren’t strong enough on the primary measure to be deemed a clear success. Why approve the drug then? The FDA considered the totality of evidence: one robust positive trial, plus supportive results from others and an urgent unmet need. Additionally, a longer-term study (maintenance trial) provided crucial evidence. In this maintenance trial, patients who responded to esketamine in an initial phase were either continued on esketamine or switched to placebo, in addition to their oral antidepressant. The findings were that those who kept receiving esketamine went significantly longer without a relapse of depression than those who were withdrawn off it (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). In fact, continuing esketamine cut the risk of relapse by more than 50% compared to coming off it, demonstrating that esketamine isn’t just a short-lived band-aid; it can help sustain recovery when used over time.
• Suicidality outcomes: An important (and separate) focus of research was whether esketamine could rapidly reduce suicidal ideation. Some trials included patients with acute suicidal thoughts. Esketamine did show the ability to reduce the intensity of suicidal thoughts within hours to days, which is extremely noteworthy (Psychiatry.org – FDA Approves Novel Depression Treatment). However, it did not single-handedly eliminate the risk of suicide — and the FDA made it clear it wasn’t approving the drug as an “anti-suicide” medication (more on this in Future Implications). Still, for clinicians, having a tool that can quickly ameliorate intense despair and suicidal ideation is invaluable while longer-term treatments (or safety measures like hospitalization) take effect.
• Patient outcomes: Many patients in the trials achieved what’s called a “response” (meaning a significant drop in depression rating scores), and a meaningful subset achieved remission, meaning their symptoms became very mild. For example, in one analysis, around 25% of esketamine-treated patients went into remission by 4 weeks, compared to about 7–8% of those on placebo (SPRAVATO® (esketamine) approved in the U.S. as the first and only monotherapy for adults with treatment-resistant depression). These numbers come from a post-hoc analysis in a later study, but they illustrate that a portion of patients were essentially symptom-free after a month of esketamine therapy, a result that is impressive in a treatment-resistant group.

In summary, the clinical trials established that esketamine can provide fast and significant relief for many patients with hard-to-treat depression. Not every study was a home run, but the overall data convinced regulators and experts that the drug’s efficacy was real. The phrase “rapid antidepressant effect” – virtually an oxymoron in psychiatry prior to ketamine – was demonstrated for the first time on a large scale. These results, coupled with decades of smaller studies on ketamine, ushered in a new approach to treating depression.

Like any treatment, Spravato’s introduction came with a balance of benefits and risks. It’s important to understand both sides:

Key benefits:

• Rapid relief of symptoms: The foremost benefit is speed. Esketamine works much faster than conventional antidepressants (Psychiatry.org – FDA Approves Novel Depression Treatment). Patients who are in the depths of depression, especially those with suicidal ideation, may begin to feel relief within a day or even hours. This rapid action can be life-saving in acute situations and can reduce suffering early in treatment. One patient described the difference as “night and day,” noting that after ketamine treatment, “now they have a meaning, a purpose, a value, a path”, whereas before they were stuck in despair (Ketamine ‘saved my life’: Depressed, anxious Floridians turn to unregulated psychedelics).
• Helps when others don’t: Spravato is specifically for treatment-resistant depression, meaning it’s intended for people who did not benefit from at least two prior antidepressants (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). For this population, no other new pharmacological option had been approved in decades. Thus, esketamine offers hope to those who had essentially run out of medication options. In trials, adding esketamine on top of standard treatment significantly improved outcomes where another pill alone likely would have failed (How Ketamine Drug Helps with Depression > News > Yale Medicine).
• Improved depression symptoms: Patients who respond to esketamine often experience a substantial drop in their depression severity. This can translate to improvements in daily functioning – being able to get out of bed, go to work, engage socially, and take care of oneself again. Some patients even achieve full remission of depression symptoms after a course of treatment, essentially getting their life back. While not everyone will achieve remission, the odds are meaningfully improved with esketamine for TRD patients.
• Potential reduction in suicidal thoughts: Although esketamine is not a standalone anti-suicide cure, its fast action on mood can temporarily reduce suicidal ideation in severely depressed individuals (Psychiatry.org – FDA Approves Novel Depression Treatment). This benefit is critical: it provides a window of clarity and hope, buying time for other interventions (like therapy, social support, or hospitalization) to be put in place if needed. No traditional antidepressant has such an immediate effect on suicidal thoughts.
• Novel mechanism: From a scientific perspective, esketamine’s success has validated a new target in depression treatment – something that could benefit patients indirectly as well. It has shifted research toward neuroplasticity and glutamate modulation. For patients, this means the landscape of future treatments is expanding beyond the old serotonin-based drugs.

Risks and side effects:

• Dissociation and sedation: The most distinctive side effects of ketamine (and esketamine) are dissociative reactions – experiences of detachment from reality, sometimes described as out-of-body experiences – and sedation. In clinical trials, many patients (up to about 40-50%) experienced some level of dissociation during the dosing sessions (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). Patients have reported feeling like they are in a dream, seeing colors or hearing sounds differently, or feeling disconnected from their body. These effects are generally short-lived, peaking shortly after the dose and resolving within an hour or two (Advisory Panel Recommends FDA Approval of Esketamine, with New Mechanism to Treat Resistant Depression | Brain & Behavior Research Foundation). Sedation (feeling very drowsy or relaxed to the point of nodding off) is also common (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). Because of these effects, patients must remain under observation for at least two hours after dosing (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). In practice, a Spravato session involves checking in to the clinic, taking the nasal sprays (a dose consists of 2–3 sprays per nostril, depending on required dose), then sitting in a comfortable room while a nurse or doctor monitors blood pressure, heart rate, and how the patient is feeling. The patient cannot drive themselves home afterward – they must arrange a ride or other safe transportation, and they’re advised not to drive or operate heavy machinery until the next day (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA) (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA).
• Elevated blood pressure: Esketamine can cause a temporary spike in blood pressure after dosing (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). For most patients this is mild to moderate, but in some cases it can be significant. Because of this, patients with uncontrolled high blood pressure or certain vascular conditions (aneurysms, etc.) may not be candidates for the treatment, or they need to get those conditions under control first. Blood pressure is measured before and after each dose to ensure safety.
• Other common side effects: In trials, other side effects that often occurred on dosing days included dizziness, nausea, vomiting, headache, numbness or tingling sensations, feelings of anxiety, and a sense of being “drunk” or woozy (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). Most of these effects were transient and resolved the same day. Nausea and vomiting are managed by avoiding food for a few hours before treatment and by having anti-nausea medication on hand if needed. Some people also get a headache or fatigue after sessions.
• Potential for abuse/misuse: Ketamine has a reputation as a recreational drug, and thus there is concern that esketamine could be abused if it were readily available. To mitigate this risk, Spravato was classified as a Schedule III controlled substance (indicating moderate potential for abuse) and placed under the FDA’s REMS (Risk evaluation and mitigation strategy) program (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). Under the REMS, only certified clinics and pharmacies can stock the drug, and it cannot be taken home by patients. The nasal spray devices are single-use and are disposed of at the clinic after administration to prevent diversion. During trials, no serious issues with abuse or dependence emerged under supervised use (Advisory Panel Recommends FDA Approval of Esketamine, with New Mechanism to Treat Resistant Depression | Brain & Behavior Research Foundation), but the risk is taken seriously. Patients are screened for history of substance abuse, and Spravato is not recommended for those with active substance use disorders (especially involving ketamine or PCP). The goal is to ensure this medication is used strictly as a therapeutic tool.
• Black box warnings: Spravato’s label carries a boxed warning, the FDA’s strongest caution. It warns about the risks of sedation, dissociation, and importantly, the risk of suicidal thoughts and behaviors after administration (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). This last part may sound ironic since the drug helps reduce suicidal ideation; however, the warning refers to the possibility that some people might experience drastic mood shifts or distress when the drug wears off (or due to the experience itself). All patients receive a Medication Guide explaining these risks. The warning also underscores the need for monitoring – patients are observed post-dose not just for blood pressure and physical safety, but also for any emergent suicidal thoughts or unusual behaviors.
• Need for supervision and inconvenience: Unlike a typical antidepressant that you take daily at home, Spravato requires clinic visits for every dose (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). In the induction phase, this means two visits per week for the first month, then weekly or every two weeks thereafter for maintenance. Each visit can last 2 to 3 hours (including prep and observation time). This is a significant time commitment for patients, and can interfere with work or daily life. The requirement for supervision is a double-edged sword: it ensures safety, but also limits accessibility and convenience.
• Unknown long-term effects: Ketamine’s antidepressant effect was only discovered in the last couple of decades, and esketamine is the first drug of its kind, so there is still much to learn about long-term use. Some open questions include: How long should a patient stay on esketamine if they respond? Could there be any cognitive effects or tolerance that develops with prolonged use? Ongoing studies and post-marketing surveillance are watching for any signs of memory issues, bladder problems (high-dose recreational ketamine can cause bladder damage, though the doses in depression treatment are much lower), or increased addiction potential over time. So far, the safety data has been generally reassuring, but careful observation continues.
• Pregnancy and other precautions: Esketamine can be harmful to a developing fetus and is not recommended for use during pregnancy (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). Women of childbearing potential are advised to use contraception and avoid getting pregnant while on this treatment. Additionally, because the drug can enter breast milk and the effects on infants are unknown, breastfeeding is not advised during treatment. These are standard precautions for many psychiatric medications, but given esketamine’s novelty, there’s extra caution.

In weighing benefits and risks, experts have noted that Spravato can provide relief where nothing else has, which is a huge benefit, but it must be used judiciously and with careful monitoring. The FDA’s restrictions aim to maximize the benefits (by allowing access to a novel therapy) while controlling the risks (through supervision and patient education). For many patients and providers, this trade-off is worthwhile, but Spravato is not meant to replace traditional treatments—it’s an add-on for specific tough cases, used with respect and caution.

Spravato represents a new tool in the depression treatment toolbox. How does it stack up against existing treatments like SSRIs, SNRIs, or therapies like electroconvulsive therapy? Here’s a comparison on several key fronts:

• Mechanism of action: Conventional antidepressants (SSRIs like fluoxetine/Prozac, sertraline/Zoloft, or SNRIs like venlafaxine/Effexor, duloxetine/Cymbalta) work by modulating monoamine neurotransmitters (serotonin, norepinephrine, dopamine). They gradually increase the availability of these neurotransmitters in synapses. Esketamine, on the other hand, works via the glutamate system. It antagonizes (blocks) NMDA receptors which leads to a surge of glutamate release and stimulates AMPA receptors, thought to spur synaptic plasticity. This means Spravato targets a completely different neurotransmitter pathway than SSRIs/SNRIs (Advisory Panel Recommends FDA Approval of Esketamine, with New Mechanism to Treat Resistant Depression | Brain & Behavior Research Foundation). All the traditional antidepressants from the last 50 years ultimately act on serotonin or related systems (Advisory Panel Recommends FDA Approval of Esketamine, with New Mechanism to Treat Resistant Depression | Brain & Behavior Research Foundation), whereas esketamine is the first to target glutamate – essentially a new frontier in depression biology.
• Onset and speed: SSRIs and SNRIs typically require weeks to show effect. Many patients start to notice some improvements by 2-4 weeks, but full effects may take 6-8 weeks (and some patients need trials of multiple drugs over months). This delay can be dangerous for someone who is acutely suicidal and is frustrating for patients in general. Esketamine’s effects are felt within hours to days (Psychiatry.org – FDA Approves Novel Depression Treatment). No conventional oral antidepressant can rival that speed. The only other rapid treatment in psychiatry for depression is ECT (electroconvulsive therapy), which can lift mood within days to a couple weeks, but ECT is a much more involved procedure (with anesthesia and its own side effects like memory loss). Spravato thus fills a unique niche: fast antidepressant action without the need for a full hospital procedure. However, one must also note that Spravato’s effect can be transient without continued dosing, whereas an SSRI, once it kicks in, is taken daily to maintain effect. They’re used in different ways.
• Administration & convenience: Most existing antidepressants are pills (or sometimes patches) taken at home daily. In contrast, esketamine is administered as a nasal spray in a doctor’s office or clinic under supervision (Psychiatry.org – FDA Approves Novel Depression Treatment). This is inherently less convenient and more resource-intensive. Patients on SSRIs simply fill a prescription and manage their dosing themselves. Patients on Spravato have to schedule medical appointments for every dose. This makes Spravato more analogous to something like IV infusion therapies or procedures. In terms of patient experience, taking a pill is routine and usually without any immediate sensation; taking esketamine can be an experience (due to the acute psychoactive effects). So, while SSRIs are low-key and daily, Spravato is episodic and involves a bit of a mini “event” with each dose.
• Effectiveness: For the average patient with depression, SSRIs/SNRIs have a certain success rate (around 50-60% achieve significant improvement on the first medication trial, and some achieve remission). For patients with treatment-resistant depression, by definition those medications have not worked. At that point, augmentation strategies or switching classes (to a tricyclic antidepressant, MAOI, or adding atypical antipsychotics) are tried – with limited success in many. Esketamine was studied specifically in this resistant group and showed that it can produce improvements where oral drugs alone did not. For example, in a head-to-head sense (from the trial data), esketamine + antidepressant outperformed antidepressant + placebo in TRD patients (How Ketamine Drug Helps with Depression > News > Yale Medicine). It’s not that esketamine will work for everyone either – but it greatly increases the odds of response in this difficult population. Another way to look at it: esketamine offers a chance when SSRIs have failed. It’s not necessarily “better than SSRIs” if you consider a broad population (because many people do respond to SSRIs), but it’s better for those whom SSRIs leave behind.
• Safety and side effects: SSRIs are not free of side effects – common issues include nausea, insomnia or sedation, sexual dysfunction, weight gain, and emotional blunting, among others. However, these side effects are generally ongoing/manageable and don’t require supervision. Esketamine’s side effects (dissociation, blood pressure spikes, etc.) are acute but intense, requiring supervision on the dosing day (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). SSRIs carry a well-known black box warning for increased suicidal ideation in young adults (usually early in treatment), whereas esketamine’s black box warns of sedation/dissociation and also a possible temporary spike in suicidal thoughts right after use (FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic | FDA). Long-term, SSRIs can have withdrawal symptoms if abruptly stopped; esketamine doesn’t cause a classic withdrawal syndrome, but if a patient stops treatment, their depression might return (as with any antidepressant). One safety advantage of esketamine is that, in a controlled setting, immediate medical help is available if any reaction occurs, whereas someone taking an SSRI at home might not have that safety net (though serious acute reactions to SSRIs are rare).
• Other therapies: It’s also useful to compare Spravato to non-drug therapies for resistant depression. Electroconvulsive therapy (ECT) has the highest efficacy for treatment-resistant depression, often leading to remission in a significant number of patients, and it also works relatively quickly. However, ECT requires hospital visits, anesthesia, and can have cognitive side effects; some patients refuse ECT due to stigma or fear. Spravato offers an outpatient alternative that, while less effective than ECT on average, is easier to undergo for many and doesn’t have ECT’s memory side effect profile. Therapy (psychotherapy) is always a cornerstone, and esketamine is not a replacement for therapy. Ideally, patients receiving esketamine will also engage in therapy, as the reduction in symptoms can make it easier for them to participate in counseling and make life changes. Transcranial Magnetic Stimulation (TMS) is another treatment for depression that’s used after medication failures. TMS is an outpatient procedure (daily sessions for several weeks) that uses magnetic pulses to stimulate brain regions. It doesn’t require anesthesia and has minimal side effects (mostly scalp discomfort). TMS doesn’t work as quickly as esketamine (it usually takes a few weeks to show effect), but it doesn’t have systemic side effects. When comparing esketamine to TMS or ECT, one might say esketamine is less effective than ECT in TRD (based on remission rates), possibly similar in efficacy to TMS (no direct comparison yet), but esketamine works faster than both and has its unique pros/cons.
• Use in treatment algorithm: SSRIs/SNRIs are first-line treatments for most depression due to their efficacy and safety profile in the general population. Spravato, due to cost and risk, is reserved for later-line (after multiple failures). It’s an adjunct treatment – meaning it’s added on to whatever standard treatment the patient is already on (initially, it had to be combined with an oral antidepressant by regulation, and even as a monotherapy it’s often still used along with therapy or other supports). This is similar to how psychiatrists might add other agents (like lithium or atypical antipsychotics) for resistant cases. Ketamine infusion (off-label) had already been in use by some clinics for years for TRD, but Spravato’s approval standardized the dosing and made the treatment more accessible within mainstream medicine (Ketamine ‘saved my life’: Depressed, anxious Floridians turn to unregulated psychedelics) (Ketamine ‘saved my life’: Depressed, anxious Floridians turn to unregulated psychedelics). Now, instead of seeking an experimental IV ketamine clinic, patients can get a prescribed intranasal esketamine treatment from credentialed doctors in major medical centers.

In essence, Spravato doesn’t replace existing antidepressants but rather complements them. It fills a gap: providing a rapid and effective option for those who didn’t benefit from typical medications. Its introduction has actually been compared to the introduction of antibiotics before widespread – offering a lifeline where there was previously very little to offer. Psychiatrists now have the ability to mix and match treatments in a more versatile way: for example, keep a patient on an SSRI for maintenance of general mood and add esketamine intermittently for a boost, or use esketamine to bridge a suicidal patient until an SSRI and therapy can take hold. Having this new modality broadens the comparison from “which SSRI do we try next” to “should we try a different approach altogether.” And for the field, it has opened the door to developing more treatments outside the traditional neurotransmitter theories of depression (Advisory Panel Recommends FDA Approval of Esketamine, with New Mechanism to Treat Resistant Depression | Brain & Behavior Research Foundation).

One major consideration with Spravato (esketamine) is its cost and how accessible the treatment is to those who need it. Below is a breakdown of these practical aspects:

• Medication cost: Spravato is an expensive treatment. According to estimates around the time of launch, the cost for the first month of treatment ranges from $4,720 to $6,785 (Psychiatry.org – FDA Approves Novel Depression Treatment). This is because the first month (the induction phase) involves twice-weekly dosing (so about 8 sessions). After the first month, if the treatment is continued, the frequency typically reduces to once a week for a while and then perhaps once every two weeks. The monthly maintenance cost was expected to be roughly half the initial, on the order of $2,300–$3,500 per month (Psychiatry.org – FDA Approves Novel Depression Treatment) (depending on dosing frequency). To break it down per session, a single dose of Spravato (which might be 56 mg or 84 mg, depending on what the doctor prescribes) can cost somewhere around $600-$900 at list price. These numbers can vary based on contracts with insurers, healthcare provider charges, etc., but there’s no question it is a costly therapy – far more than a generic antidepressant pill.
• Insurance coverage: Given the high cost, insurance coverage is crucial for most patients. The good news is that many insurers do cover Spravato for treatment-resistant depression, recognizing it as a medical necessity in that context. For example, insurance companies have set criteria: usually the patient must have a diagnosis of major depressive disorder, severe, and documentation of at least two antidepressant trials that failed to help (often from two different classes, to ensure it wasn’t just one type that didn’t work) (Esketamine (Spravato) – Medical Clinical Policy Bulletins | Aetna). Insurers often also require that the treatment be prescribed by a psychiatrist and that it’s given in a certified facility (which is inherently required by the REMS anyway) (Esketamine (Spravato) – Medical Clinical Policy Bulletins | Aetna) (Esketamine (Spravato) – Medical Clinical Policy Bulletins | Aetna). Medicare covers Spravato as well under Part B (since it’s administered in a clinic, it’s considered a medical benefit, not a pharmacy benefit). Typically, when insurance covers it, the patient might be responsible for co-pays for specialist visits and a co-pay per treatment, depending on their plan. Johnson & Johnson, through Janssen, introduced a patient assistance program called “Spravato with Me” that could reduce co-pays to as low as $10 per treatment for eligible commercially insured patients ([PDF] Savings Program – SPRAVATO withMe) (Patient Support: SPRAVATO withMe), and there are programs to provide the drug at lower or no cost for uninsured or underinsured patients who qualify. Still, navigating insurance approval can be an involved process, often requiring prior authorization and paperwork from the prescribing doctor.
• Administration and facility fees: It’s important to note that the cost of the drug itself is only part of the equation. Each Spravato session takes place in a medical office with a healthcare provider’s time and resources. Clinics may charge a facility fee or observation fee for the two hours of monitoring. Those costs might be billed to insurance as well (often under a medical code for “observation” or “therapy session”). Insurance usually covers this as part of the treatment session, but patients might see separate charges for the administration on their bills. For someone without insurance, these facility fees out of pocket could be prohibitive.
• Accessibility of treatment centers: Because Spravato can only be given at certified locations, one potential barrier is geography. Not all clinics or hospitals are certified to offer esketamine. Initially, only select sites (often academic medical centers or large psychiatric clinics) provided the treatment. Over time, the network has expanded; many community hospitals and specialty clinics have sought certification as the demand grew. For example, Johns Hopkins Hospital announced in 2019 that it would begin offering FDA-approved esketamine treatment in a supervised clinic setting to serve patients with intractable depression (Esketamine: A New Approach for Patients with Treatment-Resistant Depression | Johns Hopkins Medicine). As of now, there are hundreds of certified sites across the U.S., and patients can find locations via the Spravato official website or referral networks. However, in rural areas or smaller towns, patients might still have to travel to reach a treatment center. This can mean driving a few hours to a city for each session, which is a significant commitment.
• Logistical considerations: A typical Spravato session requires the patient to plan around a half-day of time. They need to have someone who can drive them or otherwise ensure they don’t drive. Some clinics require the patient to have a companion present to take them home; others will discharge the patient on their own if they’ve arranged a ride (it varies by clinic policy). These factors make the therapy less accessible to people who don’t have a strong support system or flexible work schedule. Some patients have had to take a leave from work or adjust work hours to accommodate twice-weekly then weekly appointments. On the flip side, for those severely ill with depression, the structure and regular contact with healthcare providers can be seen as a benefit – they are closely monitored and supported through the early weeks of treatment.
• Global availability: Beyond the U.S., esketamine has been under consideration or approved in other countries as well. The European Union, for instance, approved esketamine (with similar restrictions) later in 2019. As of the last few years, Spravato (or its equivalent) has been approved in dozens of countries for treatment-resistant depression (The SPRAVATO® Story: A Paradigm Shift in Depression Treatment). This global reach is important because depression is everywhere, and many countries also have large populations of patients not helped by existing drugs. However, the cost and need for medical infrastructure pose challenges worldwide as well. Some national health systems have been slower to adopt esketamine widely due to cost-effectiveness questions.
• Comparative cost perspective: When comparing to other treatments for severe depression, Spravato’s cost is high, but not completely out of line. For example, a course of ECT treatments (including hospital fees, anesthesia, etc.) can cost several thousands of dollars as well. Newer therapies like TMS can cost $8,000-$12,000 for a full course (though again often covered by insurance after failures of medications). So Spravato’s cost is in the range of other specialized treatments. The difference is those others eventually end (e.g., ECT or TMS courses have a finite number of sessions), whereas a patient who does well on Spravato might continue maintenance treatments indefinitely (though at a reduced frequency). This raises the question of long-term cost: if someone stays on Spravato for a year, that could easily be tens of thousands of dollars. Health economists and insurers are actively watching the real-world outcomes to decide how to best allocate such treatments. If many patients achieve remission and can stop Spravato after a time, that’s ideal; if everyone needs it for life, the costs accumulate.
• Patient perspective on cost: From the patient’s point of view, the introduction of Spravato has been both a blessing and a frustration. A blessing because it’s a new option that can genuinely help; a frustration because accessing it can be cumbersome (insurance hoops, travel to clinics, taking time off, etc.). Some patients have reported that they had to advocate strongly to get referred for the treatment, as not all psychiatrists immediately adopted it in their practice. Over time, as knowledge spreads and more doctors become comfortable with esketamine, it’s likely to become a more routine offering in psychiatric care for those who meet criteria.

In summary, cost and accessibility remain significant considerations with esketamine therapy. Insurance coverage often makes it feasible, but the requirement of in-clinic administration and the high price of the drug mean that its reach is somewhat limited compared to a typical antidepressant prescription. Efforts by the manufacturer to provide financial support and the increasing number of treatment sites help mitigate these issues. For a patient who has been struggling with severe depression, the consensus is that if Spravato can work for them, the benefits (renewed life quality) can far outweigh these inconveniences and costs.

The advent of a ketamine-based antidepressant stirred a lot of discussion in the psychiatric community. Here we’ll cover what experts have said about Spravato, as well as some perspectives from patients who have experienced the treatment.

Expert opinions:
When Spravato was approved, many experts hailed it as a much-needed innovation. Dr. John Krystal of Yale, one of the pioneers in ketamine research, called esketamine “a game changer” in the treatment of depression (How Ketamine Drug Helps with Depression > News > Yale Medicine). He emphasized that it validates a new approach to treating mood disorders, one that actually reverses some of the brain changes associated with depression rather than just tweaking neurotransmitter levels slowly. The fact that patients who had not improved for years could get better within days clearly impressed clinicians. Researchers like Dr. Dennis Charney (of Mount Sinai) and Dr. Carlos Zarate (of NIH) – who had studied ketamine’s antidepressant effects since the early 2000s – noted that this approval was a culmination of years of work and offered proof of concept that targeting glutamate can help patients.

At the same time, caution and moderation were common themes in expert commentary. Psychiatrists know all too well that initial excitement for new drugs must be tempered with real-world experience. The American Psychiatric Association (APA) put out statements reminding practitioners that Spravato is not a first-line therapy and highlighting the safety requirements. An APA blog article summarized, “Esketamine (Spravato) has the potential to be extremely useful for people who have not responded to other treatments… However, it comes with specific restrictions on its distribution and usage, potentially serious side effects, a high cost, and cautions from experts including the potential for misuse or dependence.” (Psychiatry.org – FDA Approves Novel Depression Treatment). This encapsulates the mixed sentiment: excitement about a new tool, but careful attention to the downsides.

Some experts raised concerns about the limited data from trials – noting that only one short-term trial was clearly positive, and long-term safety data were sparse. There were also philosophical discussions: what does it mean to have to take a psychedelic-like experience to relieve depression? Could that experience itself be therapeutic, and how do we integrate that into treatment? These questions, while academic, hint that esketamine blurs the line between a purely biochemical treatment and something that affects patients’ subjective experience in-session (more akin to emerging psychedelic therapies).

Regulatory experts and the FDA’s own psychiatrists (like Dr. Tiffany Farchione, quoted earlier) underscored that the decision to approve was not taken lightly. They pointed to the seriousness of treatment-resistant depression as a justification for moving forward despite some uncertainties, essentially saying that the risk of not treating these patients was greater than the risk of the drug itself, given the controls in place.

Going forward, many psychiatrists have expressed optimism that with proper patient selection (i.e., those truly in need) and careful monitoring, Spravato can be a valuable part of their practice. They also stress that it’s not a standalone solution – it should be combined with ongoing therapy, lifestyle support, and often other medications to ensure a patient has the best chance at recovery.

Patient perspectives:
For patients who have received esketamine treatment, the experiences vary, but there are some common threads. First is hope – many patients who qualify for Spravato have been through years of various treatments with little success. The very fact of trying something new, especially one that’s been called groundbreaking, can boost one’s hope.

Anecdotally, there are numerous success stories circulating in articles and online forums. One patient described her experience after several weeks of Spravato treatment as transformative: “I couldn’t function. I wouldn’t leave my room… I completely lost who I was,” she said about her life before ketamine. After trying ketamine treatment, “He basically saved my life… It’s the best decision I could have ever made,” she remarked, referring to the person who recommended it (Ketamine ‘saved my life’: Depressed, anxious Floridians turn to unregulated psychedelics). This kind of testimony – “ketamine saved my life” – is something that comes up often and underscores how powerful the change can be for someone who felt helpless and hopeless from depression. Patients report things like improved mood, but also improvements in cognitive function and motivation – for example, having the energy to clean their home, go outside, reconnect with friends, or think about the future again.

Another notable patient perspective is on the experience of the treatment itself. Ketamine’s psychoactive effects can be strange or intense. Some patients feel anxious about that “trip-like” aspect going in, but many, with proper coaching and support, tolerate it well and even find it interesting or cathartic. A patient might say that during the session they felt as if they were observing their mind from a distance, which sometimes helped them see their problems more objectively or with less pain attached. Others simply endure the weird sensations knowing it will pass, focusing on the relief that comes afterwards. Clinics often create a soothing environment for the session – dim lighting, comfortable chair or couch, calming music – to help patients through the dissociative phase. There are reports of patients coming out of the session feeling emotionally raw or contemplative, sometimes shedding tears (not of distress, but as a release) as they process feelings that arose. This is where having a therapist or trained provider to talk with post-session can be helpful, to integrate the experience.

Not all patient experiences are positive; some people do not respond to esketamine. For them, it can be disappointing, especially after the buildup of trying a “novel” treatment. Others might find the logistics too burdensome – for instance, someone who starts it might stop after a few weeks because they can’t manage the time off work or the travel. Side effects like nausea or anxiety during the session can also turn people off. It’s important to note that Spravato is not a panacea; there are individuals for whom it doesn’t work, just as any treatment. For those patients, other approaches (like perhaps ECT or newer research trials) might be considered next.

On the whole, patient perspective highlights gratitude for a new option. The depression community (patients and families) often shares stories online, and when Spravato was approved, many expressed optimism: even if they themselves didn’t try it, it signaled progress in a field that had seen little innovation. For those who have undergone treatment and seen improvement, Spravato can feel like “waking up” after years in darkness. As one person put it, “It’s like my brain can experience joy and calm again, where before it was nothing but fog and pain.” Such accounts, while anecdotal, illustrate the human impact beyond the clinical numbers.

It’s also worth noting that patient advocacy groups have generally supported the approval of esketamine, while also calling for continued research. They emphasize that no one treatment works for everyone and having more choices means a better chance for each individual to find something that helps.

The approval of Johnson & Johnson’s ketamine nasal spray opens a new chapter in depression treatment, with several important future implications:

• New treatment paradigm: Spravato’s success is a proof of concept that targeting glutamate and promoting neuroplasticity can effectively treat mood disorders. This represents a paradigm shift in psychopharmacology. It validates decades of research into rapid-acting antidepressants and is likely to encourage pharmaceutical companies and researchers to invest more in this area. We may see further development of ketamine-like drugs – for example, compounds that have similar rapid effects but potentially fewer side effects. There is already interest in R-ketamine (the other enantiomer of ketamine) and other NMDA modulators to see if they might provide benefits with less dissociation or abuse potential. Additionally, the success here dovetails with the burgeoning field of psychedelic-assisted therapy (using substances like psilocybin or MDMA for depression and PTSD). While esketamine is not a classic psychedelic, its ability to alter perception and rapidly improve mood has drawn comparisons, and it has somewhat opened minds to the therapeutic potential of substances that were once considered fringe. In essence, the mental health field is expanding beyond the “serotonin-only” era and exploring a wider range of biological targets for treatment.
• Broader indications: The journey of esketamine is continuing. After the initial approval for treatment-resistant depression, researchers pursued and achieved additional indications. In August 2020, the FDA approved Spravato for use in adults with major depressive disorder with acute suicidal ideation or behavior (Janssen Announces U.S. FDA Approval of SPRAVATO® (esketamine) CIII Nasal Spray to Treat Depressive Symptoms in Adults with Major Depressive Disorder with Acute Suicidal Ideation or Behavior). This was a landmark because it specifically addressed patients in crisis. Normally, antidepressants are not approved for such an acute scenario, since they don’t work fast enough. Esketamine, however, demonstrated it could reduce depressive symptoms in as little as 4 hours in some patients with suicidal thoughts (Janssen Announces U.S. FDA Approval of SPRAVATO® (esketamine) CIII Nasal Spray to Treat Depressive Symptoms in Adults with Major Depressive Disorder with Acute Suicidal Ideation or Behavior). The 2020 approval means that in ERs or psychiatric urgent care settings, doctors have a new option to administer to actively suicidal patients to rapidly stabilize them (although it’s given with the understanding that it’s an emergency measure alongside standard care like safety planning or hospitalization; studies didn’t prove it reduces suicide per se, only symptoms (Janssen Announces U.S. FDA Approval of SPRAVATO® (esketamine) CIII Nasal Spray to Treat Depressive Symptoms in Adults with Major Depressive Disorder with Acute Suicidal Ideation or Behavior)). Looking ahead, there is interest in whether ketamine or esketamine could help other conditions. For example, could a version of this treatment help bipolar depression (current trials are exploring ketamine in bipolar disorder), or post-traumatic stress disorder, or depression in adolescents? Each of these would require separate research since the populations differ. There’s also ongoing research into using ketamine for chronic pain and other issues, which, while separate from depression, could benefit from what we learn in psychiatric use.
• Refinement of use: The medical community is still learning the best ways to use esketamine. Over time, doctors will refine who is the ideal candidate, what dosing schedule is optimal, and how long to continue treatment. Already, there’s discussion about whether some patients might do well tapering off esketamine after a certain period versus continuing indefinitely. In some cases, after achieving remission, doctors might try to space out the doses more and more and possibly stop, to see if the patient can maintain wellness with just their oral antidepressant or therapy. In other cases, maintenance for a longer term might be needed. There’s also interest in combining esketamine with psychotherapy in a more structured way – somewhat similar to how psychedelics are paired with therapy. Because patients are in a suggestible, open state during and after the ketamine experience, it could be a window for therapeutic interventions (some clinics report doing talk therapy or cognitive behavioral therapy shortly after a Spravato session, and patients being more receptive). These practices will likely increase as clinicians gain experience. On the regulatory front, in January 2025, the FDA approved Spravato as a standalone (monotherapy) treatment for adults with TRD (SPRAVATO® (esketamine) approved in the U.S. as the first and only monotherapy for adults with treatment-resistant depression). Initially, it had to be given with an oral antidepressant; this change recognizes that some patients might not need or tolerate an oral drug alongside esketamine. It provides more flexibility in treatment planning. This refinement came after evidence from a trial that esketamine alone was effective for TRD, leading to remission in a subset of patients (SPRAVATO® (esketamine) approved in the U.S. as the first and only monotherapy for adults with treatment-resistant depression).
• Integration into practice: A new treatment modality means guidelines and practice patterns will evolve. The American Psychiatric Association may incorporate esketamine into its depression treatment guidelines, advising when and how to consider it. It is likely to become part of standard algorithms for treatment-resistant cases: for example, after two failures, consider Spravato or TMS or ECT, etc. The existence of esketamine may also shift prescribing earlier in the course for some – e.g., if a patient has a history of non-response in a family or severe episodes, a doctor might move to esketamine sooner rather than trying a third or fourth traditional antidepressant in vain. There will also be more training for providers on managing the treatment. Right now, many Spravato treatments are overseen by psychiatrists, but in the future, it could be that nurse practitioners or other healthcare professionals in a clinic administer and monitor it, once protocols are well-established, expanding the capacity to treat more patients. In primary care, it’s unlikely doctors will directly use esketamine (since it’s specialized and controlled), but primary care providers might refer patients to psychiatric centers for this therapy more routinely, similar to referring for specialty care. We’re also seeing the proliferation of ketamine clinics (offering IV ketamine, often outside of insurance). The FDA approval might actually encourage some standardization of those services or bring some of that patient base back into academic or officially certified clinics for intranasal treatment that insurance can cover.
• Ketamine-based therapies & research: The story of ketamine in psychiatry isn’t ending with esketamine; it’s arguably just begun. Researchers are investigating how to extend the rapid benefits of ketamine. One idea is combining ketamine with other agents to prolong its antidepressant effect (so that maybe one wouldn’t have to dose as frequently). Another line of research is in finding biomarkers – clues that can predict who will respond to ketamine. For instance, some studies are looking at brain wave patterns or inflammatory markers in the blood to see if they correlate with ketamine response. This could help personalize treatment – identifying which patients are good candidates for esketamine vs. who might need a different approach. There’s also interest in developing oral medications that work on the same pathway. An oral NMDA modulator might not have the same punch as ketamine, but could be useful for maintenance. In fact, some compounds (like d-cycloserine or GLYX-13/rapastinel) were tested as glutamate modulators, though results have been mixed. The success of esketamine will likely keep companies interested in pursuing these. Beyond depression, ketamine’s rapid effects on reducing suicidal ideation have prompted discussions: could ketamine (or esketamine) be a regular tool in emergency rooms for people who come in with suicidal thoughts? Some ERs already use IV ketamine off-label in this way. With an approved intranasal form, protocols might be developed to administer it in crisis units more widely. This could change the standard of care for acute suicidality (currently often handled with hospitalization and waiting for oral meds to kick in).
• Patient community impact: From a future standpoint, having a high-profile new treatment like this can change how patients perceive their illness. It sends a message that “if you’re not getting better, we have something else we can try.” This alone can alleviate some despair. The hope is that with more options, fewer people will feel that their depression is untreatable. We might also see a reduction in some of the long-term disability associated with chronic, treatment-resistant depression if more patients achieve relief. Over years, that could mean more people able to work, engage with family, and reduce the overall societal burden of depression. It’s early, but these are the kinds of outcomes that advocates are looking toward.

In conclusion, the FDA approval of J&J’s ketamine nasal spray represents a major milestone in the fight against depression. It has brought an entirely new mechanism of action into mainstream use, offering hope for those with the most stubborn depressive illnesses. Experts are optimistic but measured – emphasizing that this is the beginning of a new era, not a magic bullet for all depression. The approval has spurred a wave of innovation and curiosity in psychiatric medicine, breaking a long period of stagnation in antidepressant development (Advisory Panel Recommends FDA Approval of Esketamine, with New Mechanism to Treat Resistant Depression | Brain & Behavior Research Foundation) (Advisory Panel Recommends FDA Approval of Esketamine, with New Mechanism to Treat Resistant Depression | Brain & Behavior Research Foundation). For patients, Spravato has already made a profound difference in many lives, and for future patients, it paves the way for more breakthroughs. As research continues and we refine the use of esketamine and related therapies, we move closer to a world where major depression is a more treatable and temporary condition, rather than a life sentence. The story of ketamine in psychiatry – from a anesthetic and club drug to a fast-acting antidepressant – underscores how science can find new hope in unexpected places. And with that hope, thousands of people are rediscovering light in the darkness of depression. (Advisory Panel Recommends FDA Approval of Esketamine, with New Mechanism to Treat Resistant Depression | Brain & Behavior Research Foundation) (How Ketamine Drug Helps with Depression > News > Yale Medicine)