What is the best treatment approach for an adult patient with treatment-resistant depression (TRD) and chronic suicidal ideation (SI), possibly with a history of severe depression, previous psychiatric hospitalizations, substance abuse, or other comorbid psychiatric conditions?

Treatment-Resistant Depression with Chronic Suicidal Ideation

For adults with treatment-resistant depression (TRD) and chronic suicidal ideation, electroconvulsive therapy (ECT) should be prioritized as the primary intervention, as it reduces suicide risk by 50% in the first year post-treatment and provides the most robust mortality benefit in this high-risk population. 1

Immediate Risk Stratification and Safety

• Hospitalization is indicated for patients with severe suicidal ideation with specific plans or intent, as approximately 90% of suicide deaths occur in patients with treatable psychiatric disorders, most commonly mood disorders 1
• Chronic suicidal ideation in TRD patients carries a completed suicide incidence of 0.47 per 100 patient-years and attempted suicide incidence of 4.66 per 100 patient-years, representing extremely high risk 2
• TRD patients have 1.21-1.24 years shorter life expectancy compared to non-TRD depressed patients, with suicide accounting for the majority of excess life years lost 1

Primary Treatment: Electroconvulsive Therapy

ECT should be the first-line intervention for TRD with chronic suicidal ideation because it provides both rapid antidepressant effects and direct suicide risk reduction. 1

• ECT reduces suicide risk by 50% in the first year after discharge in hospitalized patients with severe depression 1
• ECT is particularly beneficial for patients aged 45 years or older and those with psychotic features 1
• Unlike other treatments, ECT addresses both treatment resistance and suicidality simultaneously, though symptom improvement may still require 1-2 weeks 1

Secondary Treatment: Ketamine/Esketamine for Acute Suicidal Ideation

If ECT is not immediately available or declined, ketamine infusion or intranasal esketamine should be used as adjunctive treatment specifically for acute suicidal ideation reduction. 1, 3

• Ketamine reduces suicidal ideation with hazard ratios of 0.65 at 1-7 days, 0.78 at 1-30 days, and 0.83 at 1-270 days compared to standard antidepressants 3
• The VA/DoD guidelines support ketamine infusions as adjunctive treatment for short-term reduction in suicidal ideation in patients with MDD and suicidal ideation 1
• Esketamine (intranasal) is FDA-approved for depressive symptoms in adults with MDD and acute suicidal ideation, though effectiveness in preventing suicide has not been established 1
• Critical limitation: Ketamine/esketamine are reserved for patients who have failed at least 2 adequate antidepressant trials and should not be used as initial treatment 1
• Esketamine requires REMS certification with mandatory 2-hour post-treatment monitoring 1

Pharmacological Augmentation Strategy

After stabilizing acute suicidal risk, implement evidence-based augmentation with lithium as the preferred agent due to its unique anti-suicide properties independent of mood stabilization. 1

• Lithium is effective in lowering suicide risk in mood disorders independent of its mood-stabilizing effect 1
• Lithium decreases aggression, impulsivity, and regulates stress response, all relevant to suicide prevention 1
• Monitor therapeutic blood levels for lithium augmentation 4
• Alternative FDA-approved augmentation options include aripiprazole, quetiapine, or olanzapine-fluoxetine combination 5, 6
• Olanzapine-fluoxetine combination: Start 5mg olanzapine + 20mg fluoxetine once daily in evening, range 5-20mg olanzapine + 20-50mg fluoxetine 5, 6

Critical Assessment Before Treatment Escalation

Before initiating any augmentation strategy, systematically evaluate six essential confounders that predict treatment failure: 4

1. Substance use disorders: Strongly associated with suicide, particularly alcohol and sedatives, which disinhibit suicidal behaviors by increasing impulsivity 1, 7
2. Psychiatric comorbidities: Anxiety disorders and personality disorders significantly increase suicide attempt risk (OR 3.788) 7
3. Depression severity at baseline: Higher HAM-D scores predict suicide attempts (OR 1.057 per point) 7
4. Duration of current episode: Longer episodes increase suicide risk 4
5. Prior treatment intolerance: Affects available treatment options 4
6. Prior augmentation attempts: Informs next-step selection 4

Treatment Duration and Monitoring

Maintain augmentation therapy for minimum 2 months to allow adequate dose titration and response assessment. 4

• For severely resistant patients, longer trials are needed given increased relapse risk 4
• Track depressive symptoms using HAM-D or MADRS at every visit 5
• Monitor suicidality explicitly as a primary outcome measure, not just depression severity 2
• Assess anxiety symptoms at week 2, as poorer early anxiety improvement predicts non-remission 8
• The goal is complete remission, not just response (≥50% symptom reduction) 5

Common Pitfalls to Avoid

• Do not start a third antidepressant trial without augmentation or switching to ECT/ketamine, as starting another antidepressant trial worsens mortality risk and increases suicide deaths 1
• Do not use gabapentin for TRD, as it is not recommended by guidelines 4, 5
• Do not rely on hospitalization alone to prevent suicide, as inpatient suicide remains a commonly reported sentinel event 1
• Do not wait for standard antidepressants to work in acute suicidal crisis, as they may take 1-2 weeks or longer to affect suicidal ideation 1
• Do not overlook bipolar depression, which requires mood stabilizers as foundation, not antidepressants alone 5
• Do not exclude patients from treatment trials based solely on number of prior failures if they meet TRD criteria 4, 5

Integrated Psychotherapy

Cognitive behavioral therapy should be used in conjunction with pharmacotherapy, not as monotherapy in confirmed TRD. 5

• CBT combined with medication addresses both biological and psychological suicide risk factors 1
• Psychotherapy helps target anxiety and suicidal ideation specifically, which mediate the relationship between depression severity and remission 8

Algorithm Summary

1. Immediate: Assess for hospitalization need based on suicide plan specificity and intent 1, 9
2. First-line: Initiate ECT for combined TRD and suicide risk reduction 1
3. If ECT unavailable/declined: Add ketamine/esketamine for acute suicidal ideation while continuing antidepressant 1, 3
4. Concurrent: Evaluate and treat substance use disorders and psychiatric comorbidities 7
5. Maintenance: Add lithium augmentation for long-term suicide prevention 1
6. Alternative augmentation: Aripiprazole, quetiapine, or olanzapine-fluoxetine if lithium contraindicated 5, 6
7. Throughout: Monitor suicidality explicitly at every visit, with particular attention to anxiety improvement at week 2 2, 8