What is the next appropriate medication for a 44‑year‑old man with recurrent major depressive disorder who has failed prior antidepressants and now has worsening suicidal ideation?

Medical Advisory BoardAll articles are reviewed for accuracy by our Medical Advisory Board
Educational purpose only • Exercise caution as content is pending human review
Article Review Status
Submitted
Under Review
Approved

Last updated: February 26, 2026 • View editorial policy

Personalize

Help us tailor your experience

Which best describes you? Your choice helps us use language that's most understandable for you.

Ketamine or Esketamine for Treatment-Resistant Depression with Suicidal Ideation

For a 44-year-old man with recurrent major depressive disorder who developed suicidal ideation and "strange thoughts" on prior antidepressants, intravenous ketamine or intranasal esketamine should be initiated immediately as the next treatment, given the acute suicidal risk and evidence of treatment resistance. 1

Rationale for Ketamine/Esketamine as First-Line in This Context

  • Ketamine produces rapid reduction in suicidal ideation within 24 hours, with 55% of patients reporting no suicidal ideation after 24 hours and 60% remaining free of suicidal thoughts at 7 days, making it uniquely suited for patients with active suicidal ideation. 1

  • The patient's history of "strange thoughts" (likely psychotic features or severe cognitive distortions) combined with suicidal ideation during antidepressant trials suggests treatment-emergent worsening, which occurs in approximately 4-7% of patients during SSRI/SNRI treatment and represents a medical emergency requiring a fundamentally different approach. 2, 3

  • Esketamine holds FDA approval specifically for "depressive symptoms in adults with major depressive disorder and acute suicidal ideation," making it the only medication with regulatory endorsement for this exact clinical scenario. 1

Implementation Protocol

Ketamine Administration Options

  • Intravenous ketamine: Single dose of 0.5 mg/kg infused over 40 minutes, with benefits beginning within 24 hours and continuing for at least 1 week (up to 6 weeks in some cases). 1

  • Intranasal esketamine: Requires REMS-certified pharmacy and treatment setting, with mandatory 2-hour post-dose observation period; administered twice weekly initially. 1

Mandatory Safety Monitoring

  • Blood pressure must be measured before, during, and after each ketamine/esketamine session due to transient hypertensive effects. 1

  • Assess for dissociative symptoms and sedation throughout administration, as these are expected acute effects that require clinical observation. 1

  • Continue close monitoring for suicidal ideation even after ketamine treatment, as the effect on preventing completed suicide (versus ideation reduction) has not been established. 1

Concurrent Cognitive-Behavioral Therapy

  • CBT should be initiated simultaneously with ketamine/esketamine, as adding psychotherapy to pharmacotherapy in treatment-resistant depression produces superior outcomes compared to medication alone. 1, 4

  • CBT reduces suicidal ideation and behavior by more than 50% in patients with recent suicide attempts, providing complementary benefit to rapid-acting pharmacotherapy. 1

Alternative Pharmacologic Strategy: Lithium

  • If ketamine/esketamine is unavailable or declined, lithium augmentation is the next evidence-based option for reducing suicidal behavior in unipolar depression, with several cohort studies and systematic reviews demonstrating fewer suicidal behaviors and deaths during lithium maintenance therapy. 1, 5

  • Lithium requires baseline and ongoing monitoring of thyroid function, renal function, and serum lithium levels (target 0.6-1.0 mEq/L for maintenance). 1

  • Lithium's antisuicidal effect may take weeks to manifest, making it less suitable than ketamine for acute suicidal ideation but appropriate for long-term suicide prevention. 5

What NOT to Do

  • Do not retry another SSRI or SNRI monotherapy, as the patient's history of treatment-emergent suicidal ideation and "strange thoughts" suggests these medications may worsen rather than improve outcomes in this individual. 2, 3

  • Avoid benzodiazepines as primary treatment, as sedative anxiolytics are virtually unstudied regarding suicidal risks and do not address the underlying depressive pathology. 5

  • Do not delay treatment with standard antidepressant switching strategies (which take 6-8 weeks to assess response) when acute suicidal ideation is present; this patient requires rapid-acting intervention. 1

Clinical Pitfalls to Avoid

  • Treatment-emergent suicidal ideation during prior antidepressant trials is a critical red flag that distinguishes this patient from typical treatment-resistant depression; approximately 7% of patients without baseline suicidal ideation develop it during SSRI treatment, with risk factors including severe depression and drug abuse history. 3

  • The "strange thoughts" reported by the patient may represent treatment-emergent psychotic features, agitation, or akathisia, all of which increase suicide risk and contraindicate simple antidepressant switching. 1, 2

  • Vigilance for suicide risk must continue through the entire 12-week acute treatment period, as approximately 1 in 5 patients experience emergent or worsening suicidal ideation during next-step medication treatments. 2

Long-Term Maintenance After Acute Stabilization

  • Once suicidal ideation resolves with ketamine/esketamine, transition to maintenance therapy with lithium or continue esketamine (which has evidence for sustained benefit up to 28 days with twice-weekly dosing). 1, 5

  • Maintain treatment for at least 1 year or longer given the patient's recurrent depression, as prolonged maintenance improves outcomes in recurrent episodes. 1

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

4
Guideline

Diagnostic Criteria and Treatment Options for Major Depressive Disorder

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

Related Questions

What is the next best treatment option for a patient with a history of depression or anxiety who experienced suicidal ideation (SI) while taking Lexapro (escitalopram)?
What are the next best steps for managing treatment-resistant depression with persistent suicidal ideation in a patient with a history of partial response to escitalopram and increased suicidal ideation with bupropion dose increase?
What is the next step in managing a 39‑year‑old female with treatment‑resistant major depressive disorder, anxiety, and passive suicidal ideation (no plan or intent) who is currently on venlafaxine 225 mg daily (maximally tolerated), mixed amphetamine salts 20 mg daily for ADHD, clonidine 0.3 mg daily, and has previously failed bupropion 300 mg, escitalopram 20 mg, aripiprazole 2.5 mg, and sertraline 50 mg, and is receiving weekly cognitive‑behavioral therapy?
Can I increase Abilify (aripiprazole) to 15 mg in a patient with persistent depressive symptoms and suicidal ideation after a recent dose increase from 5 mg to 10 mg?
What are the recommendations for a patient taking citalopram (Celexa) with a family history of suicidal ideation who has been prescribed generic Contrave (naltrexone-bupropion)?
What is the appropriate initial dose, titration, and monitoring plan for prescribing furosemide to an adult patient with symptomatic volume overload?
What is pleocytosis and what does a neutrophil‑predominant cerebrospinal fluid pleocytosis indicate in a patient with a KPC‑producing Klebsiella pneumoniae brain abscess?
How should I manage a 3‑week‑old infant with four days of nasal congestion, a mild cough that worsens when supine, frequent post‑prandial vomiting (6‑7 feeds of 50‑100 ml every 3 hours versus usual 5‑6 feeds of 100 ml), reduced urine output (no wet diaper last night and only a partially wet diaper this morning), no fever, normal temperature (36.6 °C) and respiratory rate (38 breaths per minute), and a tongue‑tie that is not currently affecting feeding?
What is the likelihood that a throat culture will be positive in an otherwise healthy adult with suspected streptococcal pharyngitis after a negative rapid antigen detection test?
In a patient with a KPC‑producing Klebsiella pneumoniae brain abscess, is peripheral blood neutrophilia equivalent to a neutrophil‑predominant cerebrospinal fluid pleocytosis?
In an adult with an adrenocorticotropic hormone (ACTH) level of 5 pg/mL, what does this low result indicate and how should it be evaluated and managed?

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

Have a follow-up question?

Our Medical A.I. is used by practicing medical doctors at top research institutions around the world. Ask any follow up question and get world-class guideline-backed answers instantly.

Ask Question