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From the outside, you look fine. You show up, you apologize first, you keep your voice level. Inside, a small comment from a friend can set off hours of shame, a spiral of "they're going to leave," and a quiet decision to pull away before anyone can hurt you. That pattern has a name people search for: quiet BPD. It describes borderline personality disorder (BPD) turned inward, where the intense emotions are real but almost nobody sees them.

Quiet BPD isn't a separate diagnosis. It's a way of describing how BPD can look when anger, fear, and despair are directed at yourself instead of at other people. And because it's so easy to miss, people often live with it for years before anyone names it.

Is quiet BPD a real diagnosis?

Not formally. The DSM-5 describes one borderline personality disorder, with no official subtypes. "Quiet BPD," "silent BPD," "internalized BPD," and "hidden BPD" are informal terms that patients and clinicians use for the same inward-facing pattern.

The idea has roots in research, though. Psychologist Theodore Millon described four subtypes of BPD, including a "discouraged" type and a "petulant" type. The discouraged type, marked by avoidant and dependent traits, unexpressed anger, guilt, and shame, is the closest match to what people now call quiet BPD. (We've written separately about the outward-facing petulant type of BPD.)

Newer data points the same way. A 2023 study of 109 patients with BPD in a psychiatric day clinic, published in Personality Disorders: Theory, Research, and Treatment, sorted patients into three groups by symptom pattern. Thirty-five fit an "internalizing" profile, and that group had more co-occurring mood disorders than the others.

So the label is informal. The pattern is not.

Quiet BPD symptoms and signs

The core symptoms of quiet BPD are the same ones the NIMH lists for borderline personality disorder. What changes is the direction they travel.

• Fear of abandonment shows up as hypervigilance and pre-emptive withdrawal. You don't beg someone to stay. You leave first, or go silent, so the rejection can't land.
• Intense, shifting moods happen behind a calm face. An episode can last a few hours to a few days, and the people around you may never know it happened.
• Anger gets swallowed and turned into self-criticism. Instead of an outburst, there's a long internal prosecution of everything you did wrong.
• An unstable sense of self feels like not knowing who you are without someone else's approval, and shape-shifting to fit whoever you're with.
• Chronic emptiness can look like flatness or "I'm just tired" to everyone else.
• Dissociation, feeling cut off from yourself or your surroundings, often under stress.
• Rejection sensitivity: replaying a conversation for days, reading a short text as proof someone is done with you.
• Self-harm or suicidal thoughts, kept hidden.

People with this presentation are often described as perfectionists, people-pleasers, or "the easy one" in the family. That's part of why the condition goes unrecognized.

Quiet BPD vs. "classic" BPD

The difference isn't severity. It's visibility.

In the presentation most people picture, distress spills outward: arguments, accusations, impulsive spending or drinking, visible crises in relationships. In quiet BPD, the same emotional storm happens internally. The person who might shout "you never cared about me" instead thinks "of course they don't care, I'm too much," and quietly stops replying to messages.

Both reflect the same underlying difficulty regulating emotions. Both cause real suffering. One is just far easier to overlook.

Why quiet BPD gets missed

Quiet BPD often arrives in a clinic labeled as something else, usually depression or anxiety. The internal pattern of shame, emptiness, and withdrawal overlaps heavily with both, and BPD frequently co-occurs with them: the NIMH notes that people with BPD may also experience depression, anxiety disorders, PTSD, eating disorders, and substance use disorders. If you're treated for depression alone and keep cycling back, the underlying pattern may not have been named. (For more on that overlap, see how anxiety and depression overlap.)

There's a second reason. People with quiet BPD are skilled at appearing okay, including in a therapist's office. They minimize. They worry about being a burden. A clinician who only sees the composed surface can miss what's underneath.

What causes quiet BPD?

No single cause explains BPD, quiet or otherwise. Genes and environment both contribute.

On the genetic side, a 2021 study of more than 1.8 million people in Swedish national registries estimated the heritability of diagnosed BPD at 46%. Risk was highest among identical twins and fell as relatives became more distant. The remaining variance came from environmental factors unique to each person.

On the environmental side, clinicians often hear about childhoods where feelings were dismissed, punished, or simply never acknowledged. Some people learned early that expressing anger or need made things worse, so they stopped. That's one plausible route from a sensitive temperament to an inward-facing pattern, though research hasn't yet separated what makes one person's BPD quiet and another's outward.

Self-harm and safety

Quiet doesn't mean low-risk. The NIMH notes that people with BPD are more likely to engage in self-harm, and the inward-facing pattern makes it easier to hide. Families sometimes learn about self-harm or suicidal thoughts only after a crisis.

If you or someone you love is having thoughts of suicide, call or text the 988 Suicide & Crisis Lifeline at 988. In an emergency, call 911.

Treatment for quiet BPD

BPD is treatable, and the evidence is strongest for specialized psychotherapy. A 2020 Cochrane review pooled 75 randomized trials with 4,507 participants. Across 22 trials comparing psychotherapy with usual care, therapy reduced BPD symptom severity. The two most-studied approaches were:

• Dialectical behavior therapy (DBT), which was developed specifically for BPD and teaches skills for intense emotions, distress tolerance, and relationships.
• Mentalization-based treatment (MBT), which builds the ability to understand your own and other people's mental states, especially under stress.

For quiet BPD, part of the work is simply making the inner experience visible: learning to notice and name anger, shame, and fear before they turn into silent withdrawal.

Medication plays a supporting role. According to the NIMH, the benefits of medication for BPD are unclear and it isn't a first-line treatment. Clinicians may use it alongside therapy for specific symptoms or co-occurring conditions such as depression.

Can quiet BPD get better?

Yes. There's no long-term research on quiet BPD specifically, but the data on BPD overall is more hopeful than most people expect. In a 10-year study of 290 adults with BPD first assessed during a psychiatric hospital stay, published in the American Journal of Psychiatry in 2010, 93% reached a symptom remission lasting at least two years. Full recovery, meaning remission plus good work and social functioning, was harder: about half got there. That gap is the case for treatment that goes beyond symptoms to rebuild relationships, work, and daily life.

How we treat BPD at Amae Health

Borderline Personality Disorder is one of the conditions our clinics specialize in. Our care teams bring psychiatrists, therapists, primary care physicians, peer mentors, and care coordinators under one roof, working from one treatment plan. For someone with quiet BPD, that matters: the more people who know your history, the harder it is for a composed surface to hide what's going on. Read more about how we approach care.

Frequently asked questions

Is quiet BPD real?

Yes, as a pattern. "Quiet BPD" isn't an official DSM-5 diagnosis, but it describes a recognized way borderline personality disorder can present, close to the "discouraged" subtype Theodore Millon described and the "internalizing" group seen in newer research.

Is there a test for quiet BPD?

There's no validated test for quiet BPD specifically. Online quizzes can prompt reflection, but a BPD diagnosis comes from a clinical evaluation by a mental health professional who looks at your history, patterns over time, and co-occurring conditions.

How is quiet BPD different from depression?

They overlap and often occur together. Depression centers on low mood and loss of interest. Quiet BPD adds intense fear of abandonment, an unstable sense of self, rapid shifts in mood, and relationship patterns driven by rejection sensitivity.

How can I help someone with quiet BPD?

Notice withdrawal instead of reading it as disinterest, and ask directly how they're doing. Avoid pressing for an explanation in the moment. Our guide on how to help someone with mental health issues covers more. If they mention self-harm or suicide, take it seriously and contact 988.

Key takeaways

• Quiet BPD is an informal name for borderline personality disorder expressed inward: hidden anger, shame, withdrawal, and self-blame.
• It's not a separate DSM-5 diagnosis, but research has identified a similar "internalizing" pattern.
• It's often mistaken for depression or anxiety, and self-harm can stay hidden.
• Specialized psychotherapy such as DBT and MBT has the strongest evidence, and long-term remission is common.

If you recognize yourself here, or you're worried about someone who seems fine but isn't, you can request an intake appointment. Our team will explain how an evaluation works and what to expect from your first visit.

Two people walk into the same psychiatrist's office with the same sentence: "I think I'm depressed." The first has been hit, in the last few weeks, by something that feels like a door closing. Sleep is wrong, food is wrong, work has become impossible, and the idea of the next year feels heavier than she can carry. The second has felt something different for as long as she can remember. Not a door closing, but a dim room she has always lived in. Lower energy, lower mood, lower hope, all at a level just functional enough that she learned to call it her personality. The difference between what each of them is experiencing is, in clinical terms, major depressive disorder vs persistent depressive disorder.

Both women are clinically depressed, but they may not be experiencing the same condition. MDD and PDD share symptoms but differ in severity, duration, and the treatment approach that actually works.

What Is Major Depressive Disorder (MDD)?

Major depressive disorder, often called clinical depression or a major depressive episode, is defined by an acute, intense period of depression lasting at least two weeks. Functioning is usually significantly impaired. Work, relationships, basic self-care, and the ability to find pleasure in anything can all grind to a halt.

A diagnosis of MDD requires five or more of the following symptoms during the same two-week period:

• Depressed mood most of the day, nearly every day
• Loss of interest or pleasure in nearly all activities
• Significant changes in sleep or appetite
• Fatigue or loss of energy
• Feelings of worthlessness or excessive guilt
• Difficulty concentrating or making decisions
• Thoughts of death or suicide

MDD is episodic. Episodes start, they end, and people generally return to a stable baseline between them. Roughly half of patients who experience one episode will experience another, and the risk increases sharply with each subsequent episode (Burcusa & Iacono, Clinical Psychology Review, 2007).

What Is Persistent Depressive Disorder (PDD)?

Persistent depressive disorder, also known as dysthymia, is the chronic form of depression. The diagnosis requires a depressed mood most of the day, more days than not, for at least two years in adults (one year in children and adolescents). The intensity is usually lower than a major depressive episode, but the duration is longer, and the functional cost adds up.

Common hallmark traits include:

• Long-term low mood that rarely lifts fully
• Persistent low energy
• Low self-esteem
• Reduced motivation
• Trouble concentrating or making decisions
• A sense of hopelessness that has become background

Many people with PDD describe their mood as "just how I am." That is part of what makes the condition easy to miss. A person who has felt this way since high school does not usually show up asking for treatment for depression. They shows up asking about sleep, or work, or a relationship that keeps falling apart.

Major Depressive Disorder vs Persistent Depressive Disorder: Key Differences

At a glance:

The two conditions are not mutually exclusive. A person with PDD can have a full major depressive episode on top of her chronic baseline. Clinicians sometimes call this double depression. On a day-to-day level, it looks like someone whose mood has been low for a decade suddenly experiences a period where getting out of bed is not just hard, but actually impossible.

Double depression tends to be more difficult to treat and has a higher risk of relapse than either MDD or PDD alone. Recognizing the chronic baseline underneath the acute episode is what changes the treatment plan.

Causes and Risk Factors of MDD and PDD

MDD and PDD share most of their underlying risk factors. Both are shaped by a mix of biological vulnerability, psychological patterns, and environmental stressors. No single cause explains either condition, and the interaction between genes and environment matters more than either alone.

Shared Risk Factors

Research consistently points to a handful of contributors:

• Family history of mood disorders, which raises risk for both conditions
• Trauma, especially in childhood, which is strongly linked to chronic depression in particular
• Chronic stress at work, in caregiving, or in financial or social conditions
• Substance use, which can precipitate, deepen, or mimic depression
• Medical conditions like hypothyroidism, chronic pain, and other systemic illnesses

How Are MDD and PDD Diagnosed?

There is no blood test for either condition. Diagnosis is clinical, made by a psychiatrist, psychologist, or trained primary care clinician based on a structured interview, symptom history, and functional assessment. Medical causes such as thyroid disease, anemia, or medication side effects are ruled out first because they can mimic depressive symptoms.

The evaluation looks at the pattern of symptoms over time, not only how a person feels today. A current snapshot cannot distinguish MDD from PDD. But a careful history can.

How the DSM-5 Classifies MDD and PDD

The DSM-5 uses three main dimensions to tell the conditions apart: symptom count, duration, and functional impairment.

MDD requires at least five of nine specific symptoms during a two-week period, with significant impairment. PDD requires fewer symptoms (at least two alongside depressed mood) but for a much longer time: at least two continuous years, with no more than two symptom-free months at a stretch. Accurate classification matters because the treatment path, expected duration of care, and relapse-prevention plan all look different.

Persistent Depressive Disorder vs Major Depressive Disorder Treatment Differences

Both MDD and PDD respond to the same general toolkit: psychotherapy, medication, and in some cases advanced interventions. The way that toolkit is applied differs.

For MDD, the goal is to resolve the episode and prevent the next one. Antidepressant medication (commonly SSRIs or SNRIs) is frequently started early in an episode. Evidence-based therapies like cognitive behavioral therapy (CBT) and interpersonal therapy are effective on their own and work better in combination with medication for moderate-to-severe presentations (Cuijpers et al., World Psychiatry, 2014). For patients who do not respond to two or more antidepressant trials, advanced options like TMS or Spravato (esketamine, FDA-approved for treatment-resistant depression in 2019) can help (FDA News Release, March 2019).

For PDD, treatment runs longer because the condition itself runs longer. Medication alone often falls short for chronic depression. A specialized psychotherapy called CBASP (Cognitive Behavioral Analysis System of Psychotherapy), developed specifically for chronic depression, is one of the few therapies explicitly targeted to PDD. A landmark trial found a combination of CBASP with an antidepressant produced an 85% response rate in patients who completed treatment (Keller et al., New England Journal of Medicine, 2000). Relapse prevention is a bigger part of the plan for PDD because the baseline is chronic.

When to Seek Professional Help

If you have had symptoms of depression for weeks that will not lift, if you have felt "low" for years and simply gotten used to it, or if your functioning at work, school, or in relationships has shifted in a way that worries you or the people close to you, it is time for a clinical evaluation. For immediate safety concerns, call 988 for the Suicide and Crisis Lifeline.

For deeper reading on the experience of MDD itself, see our guide to what severe depression feels like.

MDD and PDD Treatment at Amae Health

At Amae Health, accurate diagnosis is the first step. The treatment plan for MDD looks different from the plan for PDD, and the plan for double depression looks different from either. A comprehensive psychiatric evaluation at intake sorts out which picture fits, what the medical workup needs to rule out, and what the next 6 to 12 months should look like.

From there, our integrated care model coordinates therapy, medication management, primary care, and advanced options when appropriate. A typical path:

1. Schedule an assessment with our intake team
2. Receive a personalized care plan built around your specific diagnosis and goals
3. Begin structured, evidence-based treatment with a coordinated clinical team

If depression has been running your life for weeks or for years, you do not have to figure it out alone. Request an intake appointment to start.

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Citations

1. Burcusa & Iacono, "Risk for Recurrence in Depression," Clinical Psychology Review, 2007. Tier 1 (peer-reviewed).
2. Cuijpers et al., "Adding Psychotherapy to Antidepressant Medication in Depression and Anxiety Disorders: A Meta-Analysis," World Psychiatry, 2014. Tier 1 (peer-reviewed).
3. FDA News Release, "FDA Approves New Nasal Spray Medication for Treatment-Resistant Depression," March 2019. Tier 2 (government).‍
4. Keller et al., "A Comparison of Nefazodone, the Cognitive Behavioral-Analysis System of Psychotherapy, and Their Combination for the Treatment of Chronic Depression," New England Journal of Medicine, 2000. Tier 1 (peer-reviewed).

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Spravato success rate figures are easy to find and hard to compare. In the trial that supported its FDA approval, 69.3% of people who finished 4 weeks of Spravato with a new antidepressant had responded, and 52.5% were in remission. A study of routine care in Italy found 64.2% response and 40.6% remission at 3 months. The numbers answer slightly different questions, but they agree on the essentials: Spravato helps many people with treatment-resistant depression, response is more common than remission, and no single percentage tells the whole story.

Spravato also leaves a real share of people without enough relief.

Spravato is the brand name for esketamine, a nasal spray FDA-approved for treatment-resistant depression: depression that hasn't responded adequately to at least two antidepressants, each given at a proper dose for long enough.

What "Success" Means: Response vs. Remission

Nearly every Spravato statistic comes from one yardstick, the Montgomery-Åsberg Depression Rating Scale (MADRS). It's a 10-item interview a clinician scores from 0 to 60, where higher means more severe, and people entering Spravato's main approval trial averaged about 37. Two thresholds turn that score into a success rate:

• Response means the MADRS score has fallen by at least half from where it started.
• Remission means the score has dropped to 12 or lower, the cutoff the Spravato trials used.

The distance between the two is wide. Someone who starts at 38 and falls to 19 counts as a responder and may still have symptoms that get in the way of work, sleep, or relationships. Remission is the fuller recovery and the harder bar, so every remission figure below sits under its response figure.

Spravato's Success Rate in the Trial Behind Its Approval

The short-term trial that supported FDA approval was TRANSFORM-2, published in The American Journal of Psychiatry in 2019. Researchers at 39 outpatient centers enrolled adults with moderate to severe depression who hadn't responded to at least two antidepressants in their current episode. Everyone switched to a new oral antidepressant. One group also received Spravato, 56 or 84 mg twice a week, and the other a placebo spray. Of 227 people randomized, 197 finished the 4-week double-blind phase, and MADRS scores in the Spravato group fell 4 points more, on average.

The European Medicines Agency's review of the trial data translates that into response and remission:

Look first at the comparison group: more than half of the people who started a new antidepressant with a placebo spray also responded. The trial's finding is the gap. Among people who completed 4 weeks, adding Spravato meant about 17 more responders and 21 more remitters in every 100.

The counting method matters too, and it explains much of the inconsistency online. Figures near 69% count only people who finished. Figures near 63% for response, or 48% for remission, carry forward the last score of everyone who stopped early.

Real-World Success Rates

Trials select their patients carefully and follow them for weeks. Routine care is messier, which is what makes REAL-ESK useful. That 2022 study, published in the Journal of Affective Disorders, reviewed the medical records of 116 people with treatment-resistant depression treated with Spravato at several Italian mental health services, with assessments at 1 and 3 months.

By 3 months, 64.2% had responded and 40.6% were in remission, and both rates had climbed sharply between the first month and the third. The authors called that later response one of the study's novel findings. They also found no difference in effectiveness between people with other psychiatric conditions and people without them.

Lining those numbers up against TRANSFORM-2 doesn't work cleanly. REAL-ESK had no placebo or comparison group, everyone knew they were receiving Spravato, ratings weren't checked for consistency across centers, and 3 months is a different finish line from 4 weeks. It's encouraging evidence from everyday practice, not a controlled measure of effect.

Who Spravato Is Approved and Studied For

Spravato has two FDA-approved uses, built on separate trials, according to its prescribing information:

• Treatment-resistant depression in adults, on its own or with an oral antidepressant. The original 2019 approval required an oral antidepressant alongside it; standalone use was added in January 2025.
• Depression with acute suicidal thoughts or behavior, in adults with major depressive disorder, given alongside an oral antidepressant to treat the depressive symptoms.

The second use came from trials of a different group: adults with moderate to severe depression and active suicidal thoughts with intent, all of whom began with an inpatient psychiatric stay and standard care, and 63% of whom had attempted suicide before. Those results shouldn't be mixed with the treatment-resistant depression results.

The label is explicit about one boundary. Spravato hasn't been shown to prevent suicide or to reduce suicidal thoughts or behavior, and it doesn't replace hospitalization when that's needed, even if someone feels better after the first dose. It isn't approved for children. If suicidal thoughts are part of what you're living with right now, care for suicidal thoughts comes first, and 988 answers calls and texts at any hour.

How Fast Results Typically Appear

Spravato's reputation for speed comes from the first day. In TRANSFORM-2, most of the difference from placebo was already visible at 24 hours, the label reports; both groups kept improving through day 28, and the gap held steady rather than widening. The monotherapy trial behind the 2025 approval showed an effect at about 24 hours that lasted through day 28. In the suicidal-thoughts trials, the difference appeared as early as 4 hours.

Early movement isn't the same as response. In TRANSFORM-2, only 7.9% of people on Spravato had a response that began by day 2 and held through day 28, compared with 4.6% on placebo spray, a difference that wasn't statistically significant in the EMA review. The label calls for judging benefit at the end of the 4-week induction phase, after which sessions drop from twice a week to weekly.

And as REAL-ESK suggests, for some people even 4 weeks is early.

What Affects Individual Success

Research points to a handful of factors linked to outcomes, none of them a forecast for any one person:

• Time on treatment. Benefit is formally assessed after the 4-week induction phase, and in REAL-ESK, many responses and remissions arrived between the first and third month.
• Continuing after a good response. In a maintenance study described in the label, people in stable remission who kept taking Spravato went significantly longer before relapsing than people switched to a placebo spray, and the same held for people in stable response.
• Age. The evidence is weaker in older adults. In a separate short-term trial of adults 65 and older, response at day 28 was 27.0% with Spravato versus 13.3% with placebo spray, and the trial's main measure narrowly missed statistical significance, per the EMA review.
• Other psychiatric conditions. REAL-ESK found people with additional psychiatric diagnoses did as well as people without them.
• With or without an oral antidepressant. Spravato has shown benefit both ways, but no trial in the label compared the two head to head.

Limits and Risks

The same data show where Spravato falls short.

• Many people don't reach remission. Nearly half of the people who completed TRANSFORM-2 on Spravato weren't in remission at day 28, and in REAL-ESK, about six in 10 weren't in remission at 3 months.
• Not every trial was positive. Of the three short-term trials submitted for approval, only TRANSFORM-2 met its main goal. A fixed-dose trial in adults and the trial in older adults both fell short of statistical significance, according to the EMA review.
• It carries a boxed warning for sedation, dissociation, breathing problems (respiratory depression), and misuse or abuse, plus the risk of suicidal thoughts and behaviors that antidepressants carry for children and young adults. Sedation showed up in 48% to 61% of trial participants on Spravato, and dissociation, a sense of detachment that can warp time, space, or surroundings, in 61% to 84%.

Those risks shape how Spravato is given. It's only available through a restricted program called the Spravato REMS. You use the spray yourself under supervision in a certified healthcare setting, your blood pressure is checked before and after, and you're monitored for at least 2 hours before you're cleared to leave. Driving is off-limits until the next day, after a night of restful sleep. People with certain blood vessel problems, including an aneurysm, an abnormal connection between arteries and veins, or past bleeding in the brain, can't take it at all.

Talking to a Psychiatrist About Your Options

A Spravato success rate is a group statistic. It shows that Spravato helps a substantial share of people with treatment-resistant depression and that remission is harder to reach than response. It can't tell you what will happen for you. That depends on your diagnosis, what you've tried and for how long, your medical history, and the rest of your care.

We don't offer Spravato at Amae. Major depressive disorder is among the conditions our clinics specialize in, and when it hasn't eased with medication, our psychiatrists treat it within our integrated care model, which puts psychiatry, medication management, therapy, and primary care on one team. TMS therapy runs at three of our clinics: Los Angeles, Los Altos, and San Mateo. Our comparison of TMS, ketamine, and Spravato and our look at TMS success rates lay out how those options differ. To go over your history with someone who can see all of it, schedule an evaluation with an Amae psychiatrist. Anyone in immediate danger should call 911.

Frequently Asked Questions

What is Spravato's success rate in clinical trials?

In TRANSFORM-2, the short-term trial behind FDA approval, 69.3% of people who completed 4 weeks of Spravato plus a new antidepressant responded and 52.5% reached remission, versus 52.0% and 31.0% with a placebo spray plus a new antidepressant. Counting people who left early, remission was 48.2% versus 30.3%.

Does Spravato work better in real-world use than in trials?

The figures look similar, but they can't be compared directly. REAL-ESK, a study of 116 people treated in routine care in Italy, found 64.2% response and 40.6% remission at 3 months, with no placebo group and a longer follow-up than the 4-week trials.

How fast does Spravato start working?

Average scores often pull ahead of placebo within 24 hours, and in trials of people with suicidal thoughts, within 4 hours. A lasting response that early is uncommon, so benefit is judged after the 4-week induction phase, and some people improve later still.

Does Spravato work for everyone?

No. In TRANSFORM-2, nearly a third of people who completed treatment didn't respond, and nearly half didn't reach remission. Two other short-term trials, including one in adults 65 and older, didn't reach statistical significance on their main measure.

What happens if Spravato doesn't work for me?

A psychiatrist looks at the whole picture again: the diagnosis, whether treatment ran long enough, other medications, and other conditions. Next steps might include a different medication strategy, adding or changing therapy, or another treatment for treatment-resistant depression, such as TMS or ECT.

Is Spravato's success rate different for suicidal depression versus treatment-resistant depression?

Yes, and the two shouldn't be blended. The suicidal-thoughts trials measured average score changes 24 hours after the first dose in hospitalized adults receiving standard care. Spravato lowered depression scores more than placebo, but it didn't improve a rating of suicidality more than placebo, and it hasn't been shown to reduce suicidal thoughts.

Citations

1. Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. The American Journal of Psychiatry. 2019;176(6):428-438. https://pubmed.ncbi.nlm.nih.gov/31109201/ (Tier 1)
2. European Medicines Agency. Spravato: EPAR public assessment report (EMA/614876/2019). 2019. https://www.ema.europa.eu/en/documents/assessment-report/spravato-epar-public-assessment-report_en.pdf (Tier 2, regulatory review)
3. Martinotti G, Vita A, Fagiolini A, et al. Real-world experience of esketamine use to manage treatment-resistant depression: a multicentric study on safety and effectiveness (REAL-ESK study). Journal of Affective Disorders. 2022;319:646-654. https://pubmed.ncbi.nlm.nih.gov/36167246/ (Tier 1)
4. U.S. Food and Drug Administration. SPRAVATO (esketamine) nasal spray prescribing information, revised April 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211243s019lbl.pdf (Tier 2)
5. 988 Suicide and Crisis Lifeline. https://988lifeline.org (Tier 2)