What's Being Reported
A new clinical review published in Psychiatric Times examines how clinicians are approaching treatment-resistant depression (TRD) in 2026, with particular focus on esketamine (Spravato) as a rapid-acting option for patients who have not responded to conventional antidepressants. The piece outlines the factors clinicians weigh when selecting TRD interventions, including patient preferences, logistical access barriers, and the emerging role of glutamatergic agents in cases involving acute suicidal ideation.
Treatment-resistant depression is generally defined as a failure to achieve adequate relief after two or more antidepressant trials at therapeutic doses. It affects an estimated 30% of people with major depressive disorder — a population that carries disproportionately high rates of hospitalization, disability, and suicide risk. The review reflects a broader shift in psychiatric practice toward faster-acting, mechanism-diverse treatments for this group.
The Evidence Behind Esketamine
Esketamine, the S-enantiomer of ketamine, is administered as a nasal spray under the brand name Spravato. It received FDA approval in 2019 for TRD and in 2020 for major depressive disorder with acute suicidal ideation or behavior — making it one of the very few treatments with a regulatory indication specifically tied to suicide risk reduction.
Its mechanism differs fundamentally from traditional antidepressants. Rather than modulating serotonin or norepinephrine over weeks, esketamine acts on NMDA glutamate receptors and can produce measurable symptom relief within hours to days. This speed is clinically significant for patients in acute crisis, where the typical 4-to-6-week lag of SSRIs is simply not acceptable.
The clinical trial data supporting esketamine is real but not without nuance. The pivotal TRANSFORM trials demonstrated statistically significant improvements in depression scores compared to placebo, and the ASPIRE trials showed meaningful reductions in suicidal ideation. However, critics have noted that effect sizes in some trials were modest, placebo response rates were substantial, and long-term durability data remains limited. The Psychiatric Times review appropriately situates esketamine as one tool among several — not a universal solution.
It is also worth distinguishing esketamine from the compounded racemic ketamine infusions offered at many independent clinics. Esketamine (Spravato) is FDA-approved, administered in certified healthcare settings with mandatory two-hour post-dose monitoring, and covered by many insurance plans for qualifying diagnoses. IV ketamine infusions remain off-label for depression and are typically paid out-of-pocket. Both share a similar underlying mechanism, but their regulatory status, administration context, and insurance coverage differ substantially.
Access Barriers Remain a Real-World Problem
One of the more practically important themes in the Psychiatric Times piece is its acknowledgment of access barriers — an issue that affects both esketamine and ketamine therapy broadly. Even when esketamine is covered by insurance, patients frequently encounter prior authorization requirements, limited certified treatment centers in their geography, and scheduling constraints that create delays inconsistent with the drug's rapid-acting promise.
For patients exploring IV ketamine at independent clinics, access barriers take a different form: cost. A typical course of six ketamine infusions can run $2,000–$4,500 out-of-pocket, with maintenance infusions adding ongoing expense. The review's attention to patient preferences underscores something the field has been slow to act on — that even an effective treatment fails if patients cannot realistically obtain it or sustain it.
Clinicians, the review suggests, are increasingly factoring these practical realities into treatment planning. A theoretically superior option that a patient cannot access, afford, or tolerate is not a superior option in practice.
Key Takeaway for Patients and Families
If you or someone you care for has not responded to multiple antidepressants, esketamine (Spravato) is an FDA-approved option worth discussing with a psychiatrist — particularly in cases involving suicidal thinking. However, approval and access are not the same thing. Be prepared to navigate insurance prior authorization, verify that a certified REMS-compliant treatment center is available near you, and ask your provider about both esketamine and IV ketamine options so you can weigh the evidence, logistics, and costs together. Neither treatment is a guarantee, and both work best as part of a broader care plan that includes ongoing psychiatric support.
What This Means If You're Evaluating Ketamine Therapy
For patients and families currently researching ketamine or esketamine, this clinical review reinforces several things worth keeping in mind. First, the conversation around rapid-acting glutamatergic treatments has matured — these are no longer experimental fringe options but are being actively discussed in mainstream psychiatric literature as legitimate choices for a specific, well-defined patient population.
Second, the distinction between TRD and general depression matters when evaluating your options. Esketamine's strongest evidence base, and its FDA indication, is specifically for patients who have failed prior antidepressant treatments. If you haven't yet tried multiple antidepressants under the guidance of a psychiatrist, that history is both clinically relevant and likely required before insurance will authorize esketamine.
Third, when selecting a provider — whether for Spravato or IV ketamine — the quality of the surrounding clinical infrastructure matters as much as the treatment itself. Look for providers who conduct thorough intake evaluations, coordinate with your existing mental health team, and offer a clear plan for what happens after the initial treatment course. The Psychiatric Times review's emphasis on patient preferences and individualized care planning is a useful reminder that the best treatment decisions are collaborative ones.
Source: Psychiatric Times — Esketamine for Treatment-Resistant Depression
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