What is the recommended next-step management for an adult with major depressive disorder and passive suicidal ideation, currently on desvenlafaxine (Pristiq) 50 mg ineffective, normal renal function (creatinine 0.8 mg/dL) and mildly elevated liver enzymes (ALT 73 U/L, AST 45 U/L), who has failed trials of fluoxetine, sertraline, escitalopram, citalopram, venlafaxine, duloxetine, mirtazapine, quetiapine, risperidone, aripiprazole, and valproate?

Treatment-Resistant Depression with Passive Suicidal Ideation: Next-Step Management

For this patient with treatment-resistant depression (TRD) who has failed multiple antidepressant trials including desvenlafaxine 50 mg, the most appropriate next step is to add intranasal esketamine or IV ketamine infusion to ongoing antidepressant therapy, given the presence of passive suicidal ideation and failure of at least two adequate antidepressant trials. 1

Defining Treatment Resistance in This Case

• This patient meets criteria for TRD, defined as failure to respond to two or more adequate antidepressant trials within the current episode 2
• Before proceeding, confirm that the current Pristiq (desvenlafaxine) trial has been adequate: minimum 4 weeks at the maximum FDA-approved dose of 50 mg with documented adherence 2
• The extensive medication list (fluoxetine, sertraline, escitalopram, citalopram, venlafaxine, duloxetine, mirtazapine) represents multiple failed SSRI/SNRI trials, plus failed augmentation attempts with atypical antipsychotics (quetiapine, risperidone, aripiprazole) and mood stabilizer (valproate) 1

Critical Safety Assessment

• Passive suicidal ideation requires immediate attention—ketamine/esketamine has demonstrated short-term reduction in suicidal ideation in patients with MDD, though effectiveness in preventing suicide has not been established 1
• The mildly elevated liver enzymes (ALT 73, AST 45) are not contraindications to ketamine/esketamine but require monitoring 1
• Normal renal function (creatinine 0.8) permits standard dosing of most interventions 3, 4

Primary Recommendation: Ketamine or Esketamine

Esketamine (intranasal) or ketamine (IV infusion) should be initiated as augmentation to ongoing antidepressant therapy for this patient who has failed multiple adequate trials and presents with passive suicidal ideation. 1

Evidence Supporting Ketamine/Esketamine

• Meta-analysis of 20 RCTs demonstrated that ketamine used as monotherapy or in conjunction with an antidepressant in patients with TRD resulted in significant improvement in depressive symptoms after 24 hours, with improvements persisting at 3- and 4-day follow-up 1
• When ketamine was added to ongoing antidepressant treatment, significant improvements compared with controls were observed for up to 7 days in the TRD group 1
• Meta-analysis of 5 RCTs examining esketamine as augmentation therapy found that twice-weekly dosing improved depressive symptoms and remission rates in patients with TRD at up to 28 days of follow-up 1
• Esketamine is FDA-approved for treatment-resistant depression and for depressive symptoms in adults with MDD and acute suicidal ideation 1

Practical Implementation

• Esketamine requires Risk Evaluation and Mitigation Strategy (REMS) certification: pharmacy and health care setting must be certified, with mandatory 2-hour post-treatment monitoring 1
• Ketamine infusions lack long-term efficacy and safety trials but have consistent evidence for short-term (7-day) efficacy in patients who have not responded to adequate antidepressant trials 1
• These agents are not recommended as initial treatment but are reserved for patients for whom previous therapies have failed 1

Alternative Evidence-Based Strategies

If Ketamine/Esketamine Is Not Accessible or Declined

Add cognitive-behavioral therapy (CBT) to ongoing pharmacotherapy, as combination therapy produces statistically superior outcomes compared to antidepressant monotherapy in treatment-resistant depression 2

• The American College of Physicians strongly recommends adding CBT for treatment-resistant depression, with remission rates nearly doubling (57.5% vs 31.0%, P < 0.001) compared to medication alone 2
• CBT can be initiated immediately while pursuing other interventions 2

Pharmacological Augmentation Options

Given the extensive list of failed medications, lithium augmentation remains an evidence-based option for TRD 5:

• Lithium augmentation has demonstrated efficacy in multiple trials for patients who have not responded to antidepressants 5
• Requires baseline and ongoing monitoring of thyroid function, renal function, and lithium levels
• The mildly elevated liver enzymes do not contraindicate lithium use

Lamotrigine augmentation is another option supported by evidence 5:

• Effective augmentation strategy for TRD 5
• Requires slow titration to minimize risk of Stevens-Johnson syndrome
• Generally well-tolerated with favorable side effect profile

What NOT to Do

• Do not try another SSRI or SNRI monotherapy—this patient has failed multiple agents from both classes, and no evidence supports superior efficacy of one SSRI/SNRI over another 1
• Do not increase desvenlafaxine above 50 mg—the FDA-approved maximum dose is 50 mg daily for depression, and higher doses (100-400 mg) showed no additional therapeutic benefit in clinical trials 3, 4, 6
• Do not retry previously failed atypical antipsychotics (quetiapine, risperidone, aripiprazole) as augmentation—these have already been attempted without success 5

Monitoring Requirements

• Assess suicidal ideation at every encounter, particularly during the first 1-2 months after any treatment change, as suicide risk peaks during this period 2
• Monitor liver enzymes given baseline elevation—while mild elevations (ALT 73, AST 45) are not contraindications, desvenlafaxine has been associated with liver enzyme elevations 3
• If ketamine/esketamine is initiated, monitor blood pressure during and after each treatment session, as both agents can cause transient hypertension 1
• Assess for dissociative symptoms and sedation during ketamine/esketamine administration 1

Treatment Duration After Response

• Once satisfactory response is achieved, continue treatment for at least 4-9 months for a first episode 2
• Given the severity and treatment resistance in this case, consider maintenance therapy for ≥1 year or longer 2
• Long-term maintenance use of esketamine has been studied primarily in patients who have not responded to trials of antidepressants, with evidence supporting longer-term use 1

Common Pitfalls to Avoid

• Inadequate documentation of prior trials—confirm that each "failed" medication was given at adequate dose and duration (minimum 4 weeks at therapeutic dose) before declaring treatment resistance 2
• Overlooking adherence issues—up to 50% of patients with MDD demonstrate non-adherence, which can masquerade as treatment resistance; consider checking plasma levels if adherence is uncertain 2
• Premature switching—allowing inadequate trial duration before changing medications leads to missed opportunities for response 2
• Ignoring psychotherapy—combination therapy with CBT demonstrates superior outcomes to medication alone in severe and treatment-resistant depression 2