From the Guidelines
Esketamine is a recommended treatment option for patients with treatment-resistant depression (TRD) who have failed at least two previous adequate trials of antidepressant medications. According to the 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guideline 1, esketamine has been shown to improve depressive symptoms in patients with MDD. The guideline suggests that esketamine can be used as an augmentation therapy to ongoing oral antidepressant use, with twice-weekly dosing improving depressive symptoms and remission rates in patients with TRD at up to 28 days of follow-up.
Key points to consider when prescribing esketamine include:
- Administration as a nasal spray in conjunction with an oral antidepressant
- Typical regimen involves twice-weekly treatments for the first month, followed by once-weekly treatments for the second month, and then once-weekly or once every two weeks for maintenance
- Each dose ranges from 56-84mg, with patients starting at 56mg and potentially increasing to 84mg based on response
- Esketamine must be administered in a certified healthcare setting under medical supervision due to potential side effects such as dissociation, sedation, and blood pressure changes
The mechanism of action of esketamine, which targets the glutamate system through NMDA receptor modulation, provides rapid relief of depressive symptoms, sometimes within hours or days rather than weeks 1. This makes it particularly valuable for patients who haven't responded to at least two different antidepressant medications. While side effects typically resolve within a few hours after administration, patients should be monitored closely and remain at the facility for at least two hours after administration. Overall, esketamine shows promising sustained effects when used as directed in the appropriate clinical context, making it a valuable treatment option for patients with TRD.
From the FDA Drug Label
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice Treatment-Resistant Depression In Conjunction with an Oral Antidepressant SPRAVATO was evaluated for safety in 1709 adults diagnosed with treatment-resistant depression (TRD) [see Clinical Studies (14. 1)] from five Phase 3 studies (3 short-term and 2 long-term studies) and one Phase 2 dose-ranging study.
Esketamine for Depression: Esketamine (SPRAVATO) is used in conjunction with an oral antidepressant for the treatment of treatment-resistant depression (TRD) in adults. The most commonly observed adverse reactions in patients treated with SPRAVATO plus oral AD include:
- Dissociation
- Dizziness
- Nausea
- Sedation
- Vertigo
- Hypoesthesia
- Anxiety
- Lethargy
- Blood pressure increased
- Vomiting
- Feeling drunk 2
From the Research
Esketamine for Depression
- Esketamine has been approved by the US Food and Drug Administration for treating treatment-resistant depression (TRD) in adults, in conjunction with an oral antidepressant 3.
- Studies have shown that intranasal esketamine can significantly reduce depression symptoms in TRD, with two short-term trials (TRANSFORM-1 and -2) finding a statistically significant reduction in the Montgomery-Asberg Depression Rating Scale score at day 28 3.
- Oral esketamine has also been found to be effective in improving depressive symptom severity in highly treatment-resistant depressive patients, with a study showing a significant reduction in the Hamilton Depression Rating Scale (HDRS17) score from 21.2 to 15.8 (p < 0.001) 4.
- A systematic review and meta-analysis found that esketamine's efficacy as an add-on to antidepressants is modest in treatment-resistant depression, similar to augmentation strategies with atypical antipsychotics, but its effect on suicidality is not significant 5.
- Esketamine has been found to have a rapid onset of action, with significant and rapid improvement in depression compared to placebo, making it a valuable treatment option for patients with TRD 6.
- A case report found that a patient with TRD and multiple comorbidities had two-years stability with intranasal esketamine, suggesting that patients with complex representations may benefit from ketamine treatment at different times of life development 7.
Adverse Effects
- Common adverse effects of esketamine include dizziness, dysgeusia, somnolence, dissociation, suicidal thoughts and behaviors, and increased heart rate and blood pressure 3.
- Oral esketamine has been found to be well-tolerated, with side effects reported frequently but overall well-managed 4.
- A systematic review and meta-analysis found that esketamine's abuse potential and long-term effects are still not fully known, and some alarming signs concerning deaths and emerging suicidality during the testing phase have been reported 5.
Treatment Considerations
- Esketamine's role in treatment will likely be limited by cost, administration, and diversion concerns 3.
- The use of esketamine as an adjunctive therapy for TRD requires careful consideration of its potential benefits and risks, as well as its place in therapy compared to other treatment options 3, 5.
- Further research is needed to fully understand the efficacy and safety of esketamine for TRD, particularly in the long term 5, 6.