The Science Behind Spravato Treatment: How Esketamine Targets Treatment-Resistant Depression

At The Pearl Institute, we understand how frustrating and exhausting it can feel when traditional antidepressants don’t bring relief. For many individuals living with treatment-resistant depression (TRD), cycles of trial and error with standard medications can create a sense of hopelessness. That’s why we’re committed to offering evidence-based innovations like Spravato treatment, a breakthrough option that targets depression through a completely different mechanism. Understanding the science behind it empowers patients to choose the right path forward.

What Is Spravato?

Spravato is an FDA-approved nasal spray containing esketamine, a chemical cousin of ketamine that has been engineered specifically for clinical use. Spravato is designed to be taken in conjunction with an oral antidepressant or by itself and should be administered only in a certified healthcare setting. At The Pearl Institute, we offer esketamine treatments in a comfortable, monitored environment to ensure safe, therapeutic outcomes for our patients.

What Makes Esketamine Different From Traditional Antidepressants?

Most common antidepressants—including SSRIs and SNRIs—work by increasing levels of serotonin or norepinephrine in the brain. While effective for many, these medications don’t work for everyone. Esketamine Spravato for treatment-resistant depression stands apart because it works on a completely different neurotransmitter: glutamate.

Glutamate is the brain’s most abundant excitatory chemical messenger, and it plays a key role in learning, memory, mood regulation, and neural communication. Targeting this pathway allows esketamine to address depression from a new angle—especially valuable for individuals who haven’t responded to serotonin-based treatments.

The Brain Chemistry: How Spravato Acts on the Glutamate System

Spravato works by blocking NMDA receptors in the brain. This temporary interruption leads to a surge in glutamate transmission, which then activates AMPA receptors. This chain reaction increases synaptic activity and enhances communication between neurons.

This rapid neurological change often translates into faster relief. Whereas traditional antidepressants may take 6–8 weeks to show results, many patients experience meaningful improvement within hours or days of their first Spravato treatment.

Restoring Synaptic Connections: The “Rewiring” Effect

Long-term depression can reduce synaptic density—essentially weakening the brain’s internal communication network. Esketamine helps reverse this process by encouraging the growth of new synaptic connections. This is often referred to as “rewiring,” and it’s one of the reasons esketamine may support not just immediate relief but also longer-lasting improvement.

Patients at The Pearl Institute frequently describe feeling a renewed sense of energy, clarity, or emotional connection as these neurological changes begin taking effect.

Why Esketamine Works for Treatment-Resistant Depression

For individuals with TRD, traditional antidepressants may not work because the root cause of their symptoms isn’t centered on serotonin imbalance. By modulating glutamate, esketamine offers an alternative pathway for healing. Clinical studies consistently show that patients using esketamine treatments in combination with an oral antidepressant experience significant improvements in mood, functionality, and overall well-being, especially in combination with lifestyle changes.

What Patients Can Expect During Treatment

At The Pearl Institute, each Spravato session takes place in a private, calming room. Patients self-administer the nasal spray under clinical supervision, then relax while being monitored for approximately two hours. During this time, our team ensures comfort and safety as the medication takes effect.

Some patients experience mild, temporary sensations such as dissociation, dizziness, or fatigue. Because of these effects, driving is not allowed until the next day and a support person is required for transportation.

Safety, Side Effects, and Considerations

Our clinical team will always prioritize your safety and comfort, thoroughly reviewing your medical history to ensure Spravato is an appropriate and supportive treatment option for you. Side effects are generally mild and short-lived, often resolving on their own within a few hours. Because the medicine only remains in your system briefly—unlike traditional antidepressants that stay in the body long-term—most patients find the experience manageable.

Common side effects may include nausea, dissociation, increased blood pressure, or lightheadedness. Spravato may not be recommended for individuals with certain medical conditions, such as uncontrolled hypertension or specific cardiovascular concerns. Your clinician will guide you through all safety considerations during your consultation.

The Pearl Institute: Your Partner in Long-Term Healing

At The Pearl Institute, we believe in combining cutting-edge science with compassionate, whole-person care. Our esketamine program is designed to provide both immediate support and long-term stability for individuals facing treatment-resistant depression. If you’re ready to explore whether esketamine could be your next step toward healing, our Waynesville team is here to guide you with expertise, empathy, and unwavering support. Contact us today.