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What is Spravato (esketamine) for Treatment Resistant Major Depressive Disorder?

Updated: Nov 18, 2022

Feeling sad or down is a big problem with many challenges. These feelings of depression can affect how you handle life problems and how you are able to handle simple tasks such as the energy and motivation to eat, sleep, perform at school or work, and can affect your ability to make decisions and concentrate. Sometimes the depression does not improve with common treatments such as antidepressants, mood stabilizers, and therapy. Fortunately, there are now more options if you are facing treatment resistant depression. This article will explore a new FDA-approved treatment for medication-resistant depression called Spravato (esketamine).

What is Spravato (esketamine)?

Spravato (esketamine) can help lower the frequency of suicidal thoughts and lessen the symptoms of depression. While it is known that Spravato antagonizes N-methyl-D-apartate (NMDA) neural receptors, the exact mechanism of how Spravato works to lower depression symptoms is currently unknown. (1)

Spravato (esketatime) is an FDA-approved nasal spray that can improve symptoms of major depression in adults who have not improved on two or more traditional antidepressant medications or for adults who are having suicidal thoughts due to their major depression. Because it "may be subject to abuse and diversion", Spravato is an FDA-controlled substance and can only be used under a restricted program. (2) While you must continue on a traditional antidepressant while taking Spravato (esketamine), most of the treatment response you will be see occurs within 24 hours of starting Spravato. By 4 weeks, the response rate is 69% and the depression remission rate is 52.5%. (1) It is important to note that it is not to be used in place of hospitalization.

How is Spravato (esketamine) Different Than Ketamine?

Spravato (esketamine) is derived from ketamine, a drug that has been used for its anesthetic properties for more than 50 years. In the past ketamine has also been used off-label to treat chronic pain, post-traumatic stress disorder (PTSD), and depression. Spravato (esketamine) is an inhaled medication taken under medical supervision with FDA-approved indications for treatment resistant depression and suicidal thoughts. In contrast, ketamine is a compound that is most often given as an IV infusion but can be given intramuscularly (IM), subcutaneous (SC), oral, sublingual (SL), or compounded intranasal. Ketamine currently is not approved by any regulatory authority for the treatment of depression in any formulation. (2) This generally means that insurances will reimburse for Spravato, but insurances will not likely reimburse for ketamine treatments. It is important to note that Spravato is the S-enantiomer of racemic ketamine.(2) Although their antidepressant mechanisms of actions are thought to be similar, intranasal Spravato is not the same thing as compounded intranasal ketamine.

Unfortunately, as of July 2022, there are no prospective, randomized, head-to-head studies of ketamine and Spravato to evaluate their efficacy and safety in comparison to each other. Fortunately, there are three short-term studies and two long-term studies that support the efficacy and safety of Spravato (esketamine) for the treatement of treatment resistant depression and suicidal ideations. (2)

Benefits and Risks of Spravato (Esketamine)

Recently, the FDA has approved Spravato (esketamine), an inhaled medication for treatment resistant major depression and suicidal ideation. One of Spravato's many benefits is that its effects can be seen within 24 hours of starting the medication, whereas most pills can take from 2-4 weeks before effects are seen. Even with this wait time, many people do not see significant positive effects of traditional oral medications. Because Spravato targets glutamate directly, the effects are fast and notable. Most of the treatment response you will be see occurs within 24 hours of starting Spravato. By 4 weeks, the response rate is 69% and the depression remission rate is 52.5%. (1)

Although safe and effective, Spravato does have potential side effects and adverse reactions associated with it. One of the most common clinical side effects is sedation. Up to 61% of Spravato patients experienced some level of sedation with up to 0.4% of patients experiencing loss of consciousness.(1) It is because of this side effect and its potential complications that patients on Spravato must be monitored in a healthcare setting after administration and must have a driver after the treatment to return home. Another common side effect of Spravato treatment is changes in perception or dissociation. Also, because Spravato is a medication that can be misused, it is an FDA- controlled substance. It is for this reason that you cannot purchase and bring the medication to the office for administration. It can cause a temporary peak in blood pressure, so your blood pressure is monitored during treatment sessions. Spravato can cause short-term cognitive impairments that resolve by 2 hours post treatment. While there have been reports of long-term impairments with those who misuse or abuse ketamine, no long-term cognitive effects have been seen in studies with Spravato. Those who misuse/abuse ketamine have also reported cases of ulcerative and interstitial cystitis. While no Spravato patients have reported ulcerative or interstitial cystitis, there has been a higher rate of lower urinary tract symptoms than those not using Spravato in clinical studies.

Spravato is not indicated for treatment in those under the age of 18 or pregnant/lactating women.

What A Typical Spravato (esketamine) Treatment Looks Like

Because Spravato is an FDA-controlled substance, it must be administered in a monitored setting. A typical appointment starts with checking in at the front desk with whomever your intended driver is at the end of the treatment session. A healthcare provider will take you to have your initial vitals recorded and then you are brought to the treatment room. You will then be given your medication. You will recline the chair, self-administer one inhalation and 5 minutes later, self-administer the other inhalation. Your blood pressure will be recorded 40 minutes after the first inhalation and then at the end of treatment. A healthcare provider with then check and decide when you are ready to go home. Your driver will check out with you. It is recommended that you do not drive or operate machinery until the next day after treatment.

Other Treatment Resistant Approaches

The good news is that most people will respond positively with inhaled Spravato and can return to a better level of life-functioning. However, there are other approaches for treatment resistant depression as well. If you go through treatment with Spravato and decide its not right for you, your provider may suggest other treatments reserved for people who don’t respond to traditional approaches. These other treatments for depression in people that don’t respond to traditional approaches include the following:

  • Electroconvulsive therapy (ECT)

  • Trans magnetic brain stimulation (TMS)

  • Vagus Nerve Stimulation (VNS)

Integrated Treatment with Spravato (esketamine) and Transcranial Magnetic Stimulation (TMS)

Treatment of individuals with treatment resistant depression and suicidal thoughts can vary. There have been no studies on combined treatments of Spravato (esketamine) and transcranial magnetic stimulation (TMS) to date. Their has been one small retrospective study on combination TMS and IV-infused ketamine. The good news is that there was a significant decrease in depression symptoms maintained over two years, but more research is needed with randomized studies prior to recommendation of combined treatment with any of these modalities.(3)

Treatment For Long-Term Success

At Pine Ridge Mental Healthcare, we’ve found success using a variety of approaches to major depressive disorder. Discussing these approaches with a trusted provider is the first and most important step. Getting your depression under control is a key to improving how you feel.

Our mental health team works to reduce your reliance on medications by educating you about the different tools available and how life situations can affect your mood. In addition, we help keep you on track with regular check-ins to monitor how you are doing.

For more information about if you may have depression, take our simple online depression quiz, or for help managing your health, schedule an appointment online or over the phone at Pine Ridge Mental Healthcare in Owasso, Oklahoma. If you are interested in other services we provide, check out our services page.


  1. Best SRD, Pavel DG, Haustrup N. Combination therapy with transcranial magnetic stimulation and ketamine for treatment-resistant depression: A long-term retrospective review of clinical use. Heliyon. 2019 Aug 9;5(8):e02187. doi: 10.1016/j.heliyon.2019.e02187. PMID: 31440588; PMCID: PMC6700321.

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