It’s been awhile since people living with depression have had the option of a drug therapy that’s truly unique. Spravato, intranasal esketamine for treatment-resistant major depressive disorder, was approved by the United States Food and Drug Administration (US FDA) on March 5, 2019, less than 15 months after this phase II clinical study was published online.
Spravato is the first antidepressant to show a decrease in depressive symptoms after just 7 days. It is the first N-methyl-D-aspartate (NMDA) antagonist approved for depression. And, it is the first antidepressant with a novel mechanism of action since Prozac was approved in 1986.
Should the UK follow suit? Maybe, in good time. Esketamine is exciting in its mechanism of action. It deserves the respect due a street drug that has put in the work to change its image. But it also deserves a healthy dose of caution.
Esketamine is half of the ketamine molecule, the S enantiomer. In the UK, ketamine is a popular party drug and public health officials are worried that its use may be on the rise. It’s important to keep in mind that we want to help people who are living with treatment-resident major depressive disorder, and we want to do everything we can to prevent suicide. But we don’t want to trade the chronic health problems that come with depression for the chronic health problems that come with addiction. So far, no published study has addressed esketamine’s potential risk for addiction.
This study gives us hope that a fast-acting antidepressant is on the horizon. One week after adding intranasal esketamine to their current antidepressant, participants saw a statistically significant decrease in depressive symptoms. Dissociative symptoms and cardiovascular symptoms were the most serious side effects, and they resolved within 2 hours after receiving the dose.
From January 28, 2014 to September 25, 2015, investigators screened 126 medically stable adults (20-65 years old) and enrolled 67 participants in the United States and Belgium. All participants had treatment-resistant depression, defined as treatment failure with at least 2 antidepressants. They began the study with a score of 34 or more on the clinician-rated Inventory of Depressive Symptomatology. And, they all continued their current antidepressant throughout the trial.
Exclusion criteria included suicidal and homicidal ideation, bipolar disorders, psychotic disorders, posttraumatic stress disorder, and substance abuse disorders.
Symptoms were assessed using the Montgomery-åsberg Depression Rating Scale (MADRS) and interview guide. Participants were assessed on days 1 (pre-dose and 2 hours post-dose), 2, 8 (pre-dose), 9 and 15.
The trial was a phase II, double-blind, placebo-controlled trial, and it used intent-to-treat analysis.
In Period 1 (days 1 to 8), 67 participants were randomised 3:1:1:1 to placebo, esketamine 28mg, esketamine 56mg, or esketamine 84mg twice weekly.
At the end of Period 1, participants taking active drug continued to take the same dose twice weekly for 7 more days. Participants taking placebo were assessed by the Quick Inventory of Depressive Symptomology Self-Report. If they had mild symptoms, they continued on placebo. If they had moderate to severe symptoms, they were re-randomised and assessed as part of Period 2.
In Period 2 (days 8 to 15), participants that took placebo during Period 1 and had moderate to severe symptoms at the end of Period 1 were re-randomised 1:1:1:1 to placebo, esketamine 28mg, esketamine 56mg, or esketamine 84mg twice weekly.
In the open-label treatment period (days 15 to 74), the 57 participants that opted-in received esketamine 56mg on day 15. After day 15, the clinical investigator adjusted the dose based on the needs of the participant, and the dosing interval was gradually increased. The first 2 weeks, the esketamine dose was administered twice a week. The next 3 weeks, it was administered weekly. And after that, it was administered every other week.
In the 8-week follow up period, no study drug was given. Forty-one participants (80%) remained in the study and completed a follow-up assessment after the 8-week follow up period.
Results and Conclusions
The primary endpoint was a decrease in depressive symptoms after 7 days. When the data from periods 1 and 2 were combined, all three esketamine groups showed statistically significant improvement compared to placebo after 7 days.
Least squares mean difference from placebo (SE) in MADRS score after 7 days:
- Esketamine 28mg −4.2 (2.09) p=0.02
- Esketamine 56mg −6.3 (2.07) p=0.001
- Esketamine 84mg −9.0 (2.13) p=<.001
The study also looked at sustained antidepressant effect. After the 8-week open label period, 65% of participants showed at least a 50% improvement in MADRS score and 32% showed remission (MADRS score ≤ 10).
Adverse events leading to study discontinuation
1 event each of:
- Dissociative syndrome
- Ectopic pregnancy
Other adverse events
During the double-blind phase, 20 participants of 56 (36%) experienced dizziness, 12 (21%) headache, and 11 (20%) dissociative symptoms.
Adverse events were similar in the open-label phase, with 22 of 57 (39%) experiencing dizziness, 8 (14%) headache, and 14 (25%) dissociative symptoms. Open-label participants also experienced nausea (16%) and changes in their sense of taste (23%).
Dissociative symptoms were measured using the Clinician-Administered Dissociative States Scale (CADSS). All dissociative symptoms had resolved 2 hours after the dose.
Blood pressure and heart rate
For most participants, blood pressure and heart rate increased shortly after the esketamine dose was given and resolved within 2 hours.
- Systolic: 199 mm Hg
- Diastolic: 115 mm Hg
Maximum mean change:
- Systolic: 19.0 mm Hg
- Diastolic: 10.3 mm Hg
- Heart rate: 9.4 bpm
Strengths and limitations
While this was a small, phase II trial, it gives us hope for a fast-acting antidepressant. Depression scores showed statistically significant improvement after just 7 days. That’s a huge improvement over SSRIs, which can take 4 to 8 weeks to show significant improvement in mood.
This study also suggested that for some people the improvement in mood could last for 8 weeks or more.
The greatest limitation of the study was that it wasn’t long enough to study long-term effects. It would be helpful to know if some of the long-term problems with ketamine (urinary symptoms, withdrawal symptoms, potential for addiction) are also problems with intranasal esketamine.
The authors mentioned that 26 (39%) of participants were taking atypical antipsychotics. It might be interesting to see if that had any effect on the results, especially since Symbyax, (the only other drug indicated for treatment-resistant major depressive disorder) contains an atypical antipsychotic (olanzapine) and an antidepressant (fluoxetine).
The authors also may have a vested interest in Spravato’s commercial success. Renaissance Pharmaceuticals, LLC is manufacturing Spravato for Janssen Pharmaceuticals, Inc. Eight of the authors, including the lead author, work for Janssen Research & Development and hold stock in the company. As the U. S. Food and Drug Administration continues to provide less money for drug development, drug companies are picking up the slack. The impact of this funding trend on our patients is not yet known.
Implications for practice
Since esketamine hasn’t been approved yet for use in the UK, practitioners have time to weigh the pros and cons. Watch what’s happening in the United States with the explosion of ketamine clinics and how US practitioners end up using Spravato. Keep an eye on the ketamine drug scene in the UK. Watch for the results of phase III esketamine trials and ask for more. Maybe, a survey that assesses withdrawal and dependence after treatment has stopped?
It might be interesting to look at participants that do experience dissociative symptoms. My only experience with ketamine was during a brief internship in a paediatric ICU where ketamine was used because it caused amnesia. Ketamine made surgery less traumatic for kids. Are dissociative symptoms really an adverse effect, or is there a correlation between dissociative symptoms and the antidepressant effect of esketamine?
It might also be nice to follow the advice of Canuso et al, 2018. Their study showed that intranasal esketamine might decrease suicidal ideation, but they also acknowledged the abuse potential in esketamine and called for an ongoing human abuse liability study.
It’s important to note that while no deaths were reported in this trial, in the trials reported to the FDA for consideration, there were six deaths in the treatment arms. While none of the deaths were proven to be drug-related, three people died from suicide, one from a motorcycle accident, one had a heart attack, and the sixth person likely died as a result of complications from hypertension and obesity.
Until we have more data related to the safety of esketamine, we might want to listen to the American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments. On March 1, 2017, they published A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. Some of their suggestions included toxicology screening at follow-up appointments and asking patients if they obtained ketamine at other clinics. They also suggested that ketamine be used as a short-term solution and called for weaning patients off of it until we know more about the long-term effects.
If you are treating a patient that you feel would benefit from esketamine treatment, you can help them enroll in a clinical trial. Or you can refer them to the Ketamine Clinic at Warneford Hospital in Oxford.
Daly E, Singh J, Fedgchin M. et al (2018) Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018;75(2):139-148. doi:10.1001/jamapsychiatry.2017.3739
Abdallah CG, Adams TG, Kelmendi B. et al (2016) Ketamine’s Mechanism of Action: A Path to Rapid-Acting Antidepressants. Depress Anxiety. 2016 33(8) 689–697.
Canuso C, Singh J, Fedgchin M. et al (2018) Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study (PDF). Am J Psychiatry 2018 175 620-630.
Grunebaum M, Galfalvy H, Choo T, et al (2018) Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial. Am J Psychiatry 2018 175(4) 327-335.
Morgan C, Curran H. (2012) Independent Scientific Committee on Drugs: Ketamine use: a review. Addiction 2012 107 27-38. [PubMed abstract]
Sanacora G, Frye M, McDonald W, et al (2017) A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders (PDF). JAMA Psychiatry 2017 74(4) 399-405.
Singh, J, Fedgchin M, Daly E. et al (2016) Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study. Biol Psychiatry 2016 80(6) 424-431.
U.S. Food and Drug Administration (March 6, 2019) FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic [Press Release]