Treatment-Resistant Depression

Definition and Diagnosis

• Treatment-resistant depression is defined as failure to respond to at least two adequate antidepressant trials from different classes, with adequate trials requiring minimum effective dosage for at least 4 weeks with verified compliance, and failure to achieve at least 25% improvement in depressive symptoms, as specified by the VA/DoD Clinical Practice Guidelines and the Delphi consensus guidelines 1, 2, 3
• TRD is associated with higher rates of comorbidity, double the rates of hospitalizations, seven times higher suicidal incidents compared to treatment-responsive depression, and 29-35% higher all-cause mortality 3

Treatment Options

• Electroconvulsive therapy (ECT) is strongly recommended as the next treatment option for patients with treatment-resistant depression who have failed multiple medication trials and have persistent functional impairment, according to the American Psychiatric Association 4
• ECT is highly effective for severe treatment-resistant depression, especially after multiple medication failures, with a significant reduction in suicide risk by 50% in the first year after treatment in patients with major depression 4
• Aripiprazole, brexpiprazole, cariprazine, quetiapine XR, and olanzapine-fluoxetine combination have FDA approval for TRD, showing strong evidence for efficacy in TRD 3
• Esketamine provides rapid antidepressant effects within 24 hours with benefits persisting for up to 28 days, requiring monitoring for 2 hours post-administration due to potential dissociation, blood pressure increases, and dizziness 1, 3
• Lithium augmentation is effective, especially for patients with suicidal ideation, while lamotrigine augmentation shows efficacy with fewer metabolic side effects 3
• Liothyronine (T3) augmentation is effective and well-tolerated, with insufficient evidence for levothyroxine (T4) 3
• Mirtazapine is an atypical antidepressant with alpha-2 antagonist properties, less likely to cause fatigue compared to SNRIs, and has appetite-stimulating properties, improves sleep quality, and demonstrated cardiovascular safety, making it a suitable alternative for patients with cardiac issues 5, 6
• Bupropion augmentation is more effective than buspirone for decreasing depression severity, and can be considered as an alternative augmentation strategy for patients with treatment-resistant depression 7

Non-Pharmacological Interventions

• Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive option with minimal adverse events, typically requiring multiple sessions over several weeks 1, 2, 3
• Transcranial Direct Current Stimulation (tDCS) is an emerging option with fewer side effects than ECT 3
• Cognitive Behavioral Therapy (CBT) is strongly recommended by the American College of Physicians, showing lower relapse rates compared to medication alone, and is as effective as second-generation antidepressants with fewer adverse effects 1, 7, 3

Assessment and Monitoring

• A pre-ECT assessment should include medical clearance with a focus on cardiovascular status, baseline cognitive assessment, and discussion of expected benefits, side effects, and consent process 4
• Standardized measurement of symptom severity before and after treatment trials is necessary, using validated rating scales, as recommended by the American Psychiatric Association 8
• Proper documentation of previous treatment trials, including specific medications, dosages, durations, and response, is essential for establishing drug resistance, according to the American Academy of Neurology 2
• Evaluate initial response within 1-2 weeks of starting treatment, using standardized measurement tools (PHQ-9, HAMD, MADRS10, QIDS-SR) to track symptoms 1, 2, 9, 3

Treatment Duration and Follow-up

• Treatment duration includes an acute phase of 6-8 weeks, a continuation phase of 4-9 months, and a maintenance phase of longer duration for patients with 2+ previous episodes, as recommended by the American Psychiatric Association 9, 3
• Regular follow-up is essential to assess both improvement and potential side effects, and to adjust treatment plans as needed, with assessment of adherence through clinical documentation and patient reporting, and addressing any medical or psychiatric comorbidities that may contribute to treatment resistance 2, 9, 3

Safety and Side Effects

• Common side effects of esketamine include dissociation (occurs in 61-75% of patients), nausea, dizziness, vertigo, and dysgeusia, generally appearing shortly after dosing and resolving within 1.5 hours 1
• Blood pressure increases are typically 7-10 mmHg systolic, 4-6 mmHg diastolic, and these effects are usually transient, occurring on the day of dosing and resolving within 1.5 hours 1
• Monitoring should include blood pressure before and after administration, and observation for 2 hours post-dose, as recommended by treatment guidelines 1
• Esketamine has a risk evaluation and mitigation strategy, requiring pharmacy and healthcare setting certification, and mandatory monitoring for 2 hours after treatment 1