Dual Diagnosis vs Co-Occurring Disorders: Understanding the Differences

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)

Severe depression can feel like emotional numbness, crushing exhaustion, and hopelessness - and it can look like withdrawal, flat affect, and a person slowly losing the ability to function the way they used to.

For many people, the hardest part is the confusion. You may still show up, reply to messages, or get through the day on autopilot, while inside everything feels heavy, empty, or unreal. Others might only notice that you seem “off,” quieter, more irritable, or less present - even if you’re trying your best to hide it. In this article, we’ll break down what severe depression feels like and look like - including the emotional and physical feelings it creates and what evidence-based treatment options can actually help.

What is Severe Depression

Severe depression, clinically known as major depressive disorder (MDD), is a serious medical and emotional condition that goes far beyond feeling sad or having a bad day. It changes how a person thinks, feels, and functions in everyday life - often affecting sleep, appetite, energy, motivation, and relationships.

According to the National Institute of Mental Health, major depressive disorder is defined by a persistently depressed mood or loss of interest, combined with other symptoms that last most of the day, nearly every day, for at least two weeks and cause significant impairment in daily functioning.

What Does Severe Depression Look Like

Changes in Behavior

People with severe depression often start pulling away from normal life. Activities that once felt simple, like texting a friend, showering, and leaving the house, can begin to feel exhausting or pointless. This is not avoidance; it is the nervous system under strain.

Social withdrawal can deepen depression, which is why understanding the negative effects of social isolation matters.

Changes in Mood and Personality

Depression does not only affect how someone feels - it changes how they relate to themselves and others. Loved ones often say the person feels emotionally distant, flat, or “not like themselves anymore.”

Common emotional changes include:

• Persistent hopelessness or pessimism
• Emotional numbness or emptiness
• Increased irritability or anger
• Loss of emotional warmth or connection

Someone with severe depression may still laugh or smile occasionally, but underneath, their emotional world feels muted, heavy, or hollow. 

Changes in Daily Functioning

Severe depression doesn’t just affect mood - it begins to interfere with basic daily tasks and responsibilities. Even when someone wants to function normally, severe depression can disrupt the brain systems responsible for motivation, focus, and decision-making. As a result, basic tasks stop feeling automatic and begin to require intense mental and physical effort.

Common changes include:

• Inability to initiate tasks, even when they matter
• Extreme mental effort to complete simple actions
• Difficulty concentrating or making decisions
• Feeling “frozen” when trying to start or finish something

What Does Severe Depression Feel Like Physically

Fatigue and Low Energy

Individuals with severe depression often feel exhausted even after sleeping for many hours. The body feels heavy, slow, and drained, as if it is running on empty. Simple actions like standing up, showering, or walking outside can feel physically demanding.

This happens because depression disrupts the brain systems that regulate energy, motivation, and stress. As a result, the nervous system stays in a depleted state, making rest feel unrefreshing and movement feel difficult.

Sleep and Appetite Changes

Severe depression often throws off the body’s natural rhythms. Some people struggle with insomnia and lie awake feeling restless or wired, while others sleep excessively but still wake up exhausted. Appetite may also change - food can lose its appeal, or eating may become a way to cope with emotional emptiness.

These shifts create a cycle:

• Poor sleep increases fatigue
• Fatigue reduces motivation
• Low motivation worsens mood
• Worsening mood further disrupts sleep and eating

Pain, Aches, and Brain Fog

Many people with severe depression experience real physical discomfort. Headaches, muscle tension, back pain, and unexplained aches are common. At the same time, thinking can feel slow and foggy - like trying to focus through a thick mental haze.

This happens because depression affects how the brain processes pain, attention, and memory. The result is not just emotional suffering, but a full-body experience that makes even thinking clearly feel difficult.

When Severe Depression Becomes a Clinical Condition

Severe depression becomes a clinical condition when it is persistent, intense, and begins to interfere with daily life. Instead of coming and going with circumstances, the low mood, numbness, or hopelessness stay present for weeks or months. People may find it hard to work, connect with others, or take care of themselves, even when they want to.

At this point, depression is no longer just a reaction to stress or loss - it is a disorder of the brain and nervous system. That is what clinicians call major depressive disorder, and it requires professional treatment, not willpower.

Treatment Options for Severe Depression

Therapy and Psychological Support

Therapy helps people with severe depression understand what is happening in their mind and learn how to change the patterns that keep them stuck. Evidence-based approaches like cognitive behavioral therapy (CBT) and trauma-informed therapy focus on how thoughts, emotions, and behaviors interact.

In therapy, people learn how to:

• Recognize distorted or self-critical thinking
• Regulate overwhelming emotions
• Rebuild motivation and connection
• Develop healthier coping strategies

Medication for Severe Depression

When depression is severe, medication can play a critical role in stabilizing mood and restoring basic functioning. Antidepressants work by helping balance the brain chemicals involved in mood, sleep, and energy. When those systems are disrupted, people may feel constantly drained, emotionally numb, or overwhelmed.

Medication does not change who someone is - it helps reduce the intensity of symptoms so the person can think more clearly, engage in therapy, and begin rebuilding daily life. For many people with severe depression, medication creates the foundation that makes other forms of treatment possible. If you want a clearer explanation of how these meds work in the brain, see our article: How do mood stabilizers work?

Structured and Intensive Care

Some people need more support than weekly therapy can provide. Structured care offers a higher level of monitoring, treatment, and stability.

This stepped approach allows treatment to match the intensity of the illness.

How Amae Health Helps People With Severe Depression

Amae Health is a specialized mental health clinic designed for people struggling with serious and persistent mental health conditions, including severe depression. Our treatment offerings go beyond surface-level symptom management - we focus on understanding the whole person and building a treatment plan that fits their unique needs.

We provide psychiatric evaluation, therapy, medication management, and structured services for people who need more than occasional support. Whether someone is newly experiencing severe symptoms or has been struggling for a long time, our team works to create stability, safety, and a path forward.

You can reach Amae Health directly or refer a loved one by contacting our clinic to begin a confidential assessment and explore the right level of care.

Psychotic conditions, such as schizophrenia and bipolar disorder, can be difficult to manage without proper treatment and support. Unfortunately, these conditions can often appear during adolescence and can be misunderstood and stigmatized, making it challenging for adolescents to seek help. If you or someone you know is struggling with their mental health, it’s important to understand the symptoms of psychosis and the treatment options that are available to you.

In this blog, we will explore common misconceptions surrounding psychotic disorders, symptoms of these conditions, coping strategies, the importance of medication and therapy, and how to find an adolescent mental health clinic near you.

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Understanding the Symptoms of Psychotic Disorders

Psychotic conditions in adolescents can manifest in a variety of ways. Symptoms may include hallucinations, delusions, disorganized speech or behavior, and difficulty with thinking or concentration. Some adolescents with psychotic disorders may also experience mood disturbances, such as depression or mania. These symptoms can be very distressing and can interfere with daily life and the ability to care for oneself. This highlights the importance of accessing care for psychosis as early as possible.

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Coping Strategies for Living with Psychotic Disorders

Living with psychosis can be challenging, but there are many coping strategies that can help. One of the most important things is to maintain a routine and a sense of structure in one’s daily life. This can include things like setting a regular sleep schedule, eating nutritious meals, and engaging in meaningful activities. It’s also important to have a support network of family, friends, or healthcare professionals who can offer emotional support and practical assistance, when needed.

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The Importance of Medication and Therapy in Managing Psychotic Disorders

Medication and therapy are essential components of managing adolescent psychotic disorders. Medications can help alleviate symptoms and improve overall quality of life, but finding the right medication and dosage can take time and adjustments may be required before landing on the right medication regimen. Therapy, such as cognitive behavioral therapy or psychoeducation, can help adolescents learn coping strategies, improve social skills, and manage symptoms. This highlights the importance of finding a mental health clinic that provides specialized treatment for adolescent mental health.

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Misconceptions and Stigmas Surrounding Psychotic Disorders

Adolescents with psychotic disorders often face discrimination, fear, and prejudice due to common misconceptions surrounding these conditions. One of the most prevalent stigmas is the belief that people with psychotic conditions are violent or dangerous. In fact, research has shown that when treated, adolescents with psychotic disorders are more likely to be victims of violence than perpetrators. Other misconceptions include the idea that adolescents with these conditions are lazy or lack motivation, or that they are unable to function in society. These misunderstandings are untrue and many people with psychosis recover and go on to live rich and fulfilling lives.

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Finding an Adolescent Mental Health Clinic Near You

Finding an adolescent mental health clinic near you is crucial for adolescents living with psychotic conditions. A clinic like Amae Health that specializes in psychosis, schizophrenia and bipolar disorder can provide tailored treatment and support to help manage symptoms of these conditions and improve overall quality of life. It’s important to connect with others who understand what you’re going through and can offer empathy, advice, and encouragement.

In summary, if you or someone you know is in need of care, it’s important to take action. At Amae Health, we’re ready to help and can help you get back on track with life. We can be reached by email at hello@amaehealth.com. By understanding the symptoms and finding an adolescent mental health clinic that provides specialized treatment, individuals with psychotic conditions can lead fulfilling and meaningful lives.

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