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

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

Initial Treatment Phase (Weeks 1-8)

For adults with newly diagnosed MDD, initiate treatment with either cognitive behavioral therapy (CBT) or a second-generation antidepressant (SGA), as both demonstrate equivalent efficacy with CBT having fewer adverse effects. 1

First-Line Treatment Options:

• Start with CBT monotherapy or an SGA after discussing treatment effects, adverse event profiles, cost, accessibility, and patient preferences 1
• CBT shows similar effectiveness to SGAs with lower discontinuation rates due to adverse events and reduced relapse rates 1
• If selecting pharmacotherapy, choose from SSRIs (escitalopram, sertraline, fluoxetine), SNRIs (duloxetine, venlafaxine), or other SGAs (bupropion, mirtazapine) 1
• Bupropion is preferred when sexual dysfunction is a concern, as it demonstrates lower rates of sexual adverse events compared to fluoxetine and sertraline 1
• Monitor response using PHQ-9 or HAM-D scales, with response defined as ≥50% reduction in severity 1

Treatment Phases:

• Acute phase: 6-12 weeks to achieve initial response 1
• Continuation phase: 4-9 months to prevent relapse 1
• Maintenance phase: ≥1 year to prevent recurrence 1

Second-Line Treatment for Non-Responders (After 6-12 Weeks)

For patients who fail to achieve remission after an adequate trial of one SGA, augment with bupropion as the preferred strategy, which demonstrates superior efficacy in decreasing depression severity compared to buspirone. 2

Augmentation Protocol:

• Bupropion augmentation: Start 37.5 mg every morning, increase by 37.5 mg every 3 days, up to maximum 150 mg twice daily 2
• Contraindications for bupropion: Avoid in patients with seizure disorders, brain metastases, or elevated seizure risk 2
• Alternative augmentation with buspirone: Safe for patients with comorbid anxiety and depression, though less effective than bupropion for depression severity 2
• Mirtazapine augmentation: 7.5 mg at bedtime up to 30 mg, particularly useful for agitated depression, insomnia, or poor appetite 2
• Monitor for serotonin syndrome when combining serotonergic medications, especially in first 24-48 hours after initiation 2

Treatment-Resistant Depression Protocol: Spravato Integration

For adults with treatment-resistant depression (defined as failure to respond to at least two adequate trials of antidepressants), initiate intranasal esketamine (Spravato) in conjunction with an oral antidepressant under direct healthcare provider supervision. 3

Eligibility Criteria:

• Adults ≥18 years with TRD who failed ≥2 adequate antidepressant trials 3
• Can be used as monotherapy or in conjunction with an oral antidepressant 3
• Exclude patients with: psychotic depression, active suicidal ideation requiring immediate intervention, uncontrolled hypertension (>140/90 mmHg), conditions where increased blood pressure or intracranial pressure poses serious risk 3

Spravato Dosing Protocol for TRD:

Induction Phase (Weeks 1-4):

• Administer 56 mg or 84 mg intranasally twice weekly 3
• Assess therapeutic benefit at end of week 4 to determine need for continued treatment 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 once weekly based on individual response 3

Administration Requirements:

• Pre-treatment assessment: Check blood pressure; if >140/90 mmHg, carefully weigh risks versus benefits 3
• Patient preparation: No food for 2 hours before administration, no liquids for 30 minutes prior 3
• Nasal medications: Administer corticosteroids or decongestants at least 1 hour before Spravato 3
• Post-administration monitoring: Observe patient for minimum 2 hours, including pulse oximetry for respiratory status 3
• Blood pressure monitoring: Reassess at 40 minutes post-dose (corresponding to Cmax) and as clinically warranted 3
• Discharge criteria: Patient must be clinically stable with decreasing blood pressure for at least 2 hours 3

Expected Response Timeline:

• Rapid onset: Antidepressant effects observed as early as 2-4 hours after first administration, maintained through 28 days 4
• Week 1 non-responders: Patients without response at week 1 still have 48.4% chance of response by day 25, justifying continuation of full 4-week course 5
• Meta-analysis shows modest but significant effect size of 0.15-0.23 at weeks 2-4 6

Safety Monitoring:

• Common adverse events: Dissociation, blood pressure elevation, nausea, vertigo, dysgeusia, dizziness, somnolence occur more frequently than placebo 4
• Serious risks: Sedation, dissociation, respiratory depression (observed in post-marketing), abuse potential 3
• REMS program: Spravato only available through restricted Risk Evaluation and Mitigation Strategy program 3
• Monitor for suicidal thoughts: Antidepressants increase risk in young adults; close monitoring required despite esketamine use 3

MDD with Acute Suicidal Ideation or Behavior

For adults with MDD and acute suicidal ideation or behavior, administer esketamine in conjunction with an oral antidepressant, though effectiveness in preventing suicide has not been demonstrated. 3

Dosing for Acute Suicidality:

• Same dosing schedule as TRD protocol 3
• Assess therapeutic benefit after 4 weeks; treatment beyond 4 weeks has not been systematically evaluated 3
• Hospitalization: Use of Spravato does not preclude need for hospitalization if clinically warranted 3
• Limitation: Effectiveness in preventing suicide or reducing suicidal ideation/behavior not established 3
• Resolution of suicidality greater at 2-4 hours but not statistically different at 24 hours or day 28 4

Clinical Pitfalls and Caveats:

• Esketamine efficacy is modest: Effect size similar to augmentation with atypical antipsychotics for TRD 6
• Not first-line: Reserve esketamine for true treatment-resistant cases after failure of at least two adequate antidepressant trials 7
• Abuse potential: Monitor for signs of misuse given ketamine's abuse liability 3
• Long-term effects unknown: Limited data beyond initial treatment phases 6
• Predictors of response: Positive family history of alcohol use disorder and childhood trauma may predict better ketamine response 8
• Dissociation severity: Does not correlate with treatment response 8