What is an evidence-based treatment protocol for major depressive disorder (MDD) that includes Spravato (esketamine)?

Evidence-Based Treatment Protocol for Major Depressive Disorder Including Spravato (Esketamine)

Initial Assessment and First-Line Treatment

Start with either an SSRI (sertraline 50 mg daily or escitalopram 10 mg daily) or cognitive behavioral therapy (CBT) as first-line treatment for MDD, as both demonstrate equivalent efficacy with moderate-quality evidence. 1, 2

SSRI Selection Criteria

• Sertraline or escitalopram are preferred first-line agents due to well-established efficacy and favorable tolerability profiles 2
• Choose bupropion instead if the patient has concerns about sexual dysfunction, as it has significantly lower rates of sexual adverse events compared to SSRIs 2
• Avoid paroxetine due to higher rates of sexual dysfunction compared to other SSRIs 1

Adequate Trial Definition

• Continue SSRI at therapeutic dose for 6-12 weeks before declaring treatment failure 2
• Monitor using PHQ-9 or Hamilton Depression Rating Scale (HAM-D) at each visit 2
• Treatment response is defined as ≥50% reduction in depression severity scores 1

Second-Line Treatment: Treatment-Resistant Depression (TRD)

If inadequate response after first SSRI trial (<50% symptom reduction), either switch to a different second-generation antidepressant OR augment with bupropion. 2

Switching Strategy

• Switch to bupropion, sertraline (if not already tried), or venlafaxine - moderate-quality evidence shows no significant difference between these switching options 1, 2
• Allow 6-12 weeks at therapeutic dose for the new agent 2

Augmentation Strategy

• Augment current SSRI with bupropion, which decreases depression severity more than buspirone augmentation 2
• Continue both medications for adequate trial period

Third-Line Treatment: Spravato (Esketamine) for Treatment-Resistant Depression

If patient fails two adequate trials of oral antidepressants (meeting TRD criteria), initiate Spravato (esketamine nasal spray) in conjunction with an oral antidepressant. 3

Eligibility Criteria for Spravato

• Documented failure of at least 2 adequate trials of oral antidepressants during current depressive episode 3, 4
• Exclude patients with psychotic depression, active suicidal ideation requiring immediate intervention, or history of substance abuse (due to abuse potential) 3, 5
• Baseline blood pressure must be acceptable (systolic <140 mmHg, diastolic <90 mmHg) 3

Spravato Dosing Protocol

Induction Phase (Weeks 1-4):

• Administer 56 mg or 84 mg intranasally twice weekly 3
• The 84 mg dose demonstrates superior efficacy with effect size of 0.63 compared to 0.48 for 56 mg 4
• Each dose must be administered under direct healthcare provider supervision 3

Maintenance Phase (Weeks 5-8):

• Administer 56 mg or 84 mg once weekly 3

Extended Maintenance (Week 9 onwards):

• Administer 56 mg or 84 mg every 2 weeks or weekly based on response 3

Critical Administration Requirements

• Patient must be monitored for at least 2 hours post-dose for sedation, dissociation, and respiratory depression 3
• Check blood pressure before dosing and at 40 minutes post-dose (corresponding to peak concentration) 3
• Patient cannot leave until clinically stable - blood pressure decreasing and patient appears stable 3
• Patient must avoid food for 2 hours before and liquids for 30 minutes before administration to reduce nausea/vomiting risk 3
• Continue concurrent oral antidepressant throughout esketamine treatment 3

Response Assessment Timeline

• Evaluate therapeutic benefit at end of 4-week induction phase to determine need for continued treatment 3
• Rapid response may occur as early as 4-24 hours after first dose, with mean improvement of -3.8 points on MADRS at 24 hours 6, 4
• Even patients without early response (at 24 hours or week 1) can still achieve response/remission by week 4 - 63.9% of 24-hour nonresponders achieved response at day 25 with esketamine versus 48.0% with placebo 7

Expected Adverse Events

• Most common adverse events (≥20%): dizziness, dissociation, nausea, somnolence, and headache 6
• These are typically transient and resolve within the 2-hour monitoring period 3
• Serious adverse events include sedation, dissociation, and respiratory depression requiring the 2-hour supervised monitoring 3

Alternative Third-Line Option: Spravato for Acute Suicidal Ideation

For patients with MDD and acute suicidal ideation or behavior, Spravato can be initiated earlier (not requiring 2 failed antidepressant trials) in conjunction with comprehensive standard of care including hospitalization. 3, 6

Acute Suicidality Protocol

• Administer esketamine 84 mg twice weekly for 4 weeks plus newly initiated or optimized oral antidepressant 6
• Demonstrates significantly greater improvement in depressive symptoms at 24 hours (least square mean difference -3.8 points) compared to placebo plus standard of care 6
• Particularly effective in patients with history of suicide attempt (Clinical Global Impression-Severity of Suicidality difference -0.31) 6
• Important limitation: effectiveness in preventing suicide or reducing suicidal behavior has NOT been demonstrated 3
• Hospitalization remains necessary even if patient improves after initial dose 3

Esketamine Monotherapy Option

Recent evidence supports esketamine monotherapy (without concurrent oral antidepressant) for TRD patients who cannot tolerate oral antidepressants. 4

• Both 56 mg and 84 mg doses as monotherapy demonstrate significant efficacy versus placebo at day 28 (LS mean difference -5.1 and -6.8 respectively, both P<.001) 4
• This addresses unmet need for patients with treatment-limiting tolerability concerns with oral antidepressants 4
• Use same dosing schedule as combination therapy (twice weekly for 4 weeks induction) 4

Common Pitfalls to Avoid

• Do not underdose or undertrial first-line SSRIs - ensure full 6-12 weeks at therapeutic dose before switching 2
• Do not skip the 2-hour post-dose monitoring period with esketamine - this is mandatory due to sedation, dissociation, and respiratory depression risks 3
• Do not use esketamine as first- or second-line treatment - it is indicated only after failure of at least 2 adequate antidepressant trials (except in acute suicidality context) 3, 5
• Do not abruptly discontinue SSRIs - taper to prevent discontinuation syndrome 2
• Do not administer esketamine if baseline blood pressure is elevated or if increase in blood pressure poses serious risk 3
• Do not assume early non-response to esketamine means treatment failure - continue full 4-week course as 63.9% of 24-hour nonresponders still achieved response by day 25 7

Continuation and Maintenance Treatment

After achieving response or remission, continue treatment for 4-9 months (continuation phase) and ≥1 year for maintenance in patients with multiple episodes. 2

• For esketamine responders, transition to maintenance dosing schedule (every 2 weeks or weekly) after week 8 3
• Continue concurrent oral antidepressant throughout esketamine maintenance 3
• CBT has lower relapse rates than antidepressants alone in long-term follow-up, suggesting combination with psychotherapy for sustained recovery 2