Treatment of Depression after SSRI Failure

Introduction to Alternative Treatments

For patients who have not responded to SSRIs, switching to a serotonin-norepinephrine reuptake inhibitor (SNRI) such as venlafaxine is recommended as the most effective next step, according to the American College of Cardiology 1

Duloxetine can be started at 30 mg daily for 1 week, then increased to 60 mg daily, and is effective for both depression and neuropathic pain, as recommended by the Mayo Clinic 2
Duloxetine is simpler in dosing than venlafaxine, with 60 mg once daily appearing as effective as 60 mg twice daily, according to the Mayo Clinic 2
Venlafaxine is preferred for patients with depression and anxiety or OCD, at a dose of 75-225 mg daily, as recommended by the American College of Cardiology 1
Duloxetine is preferred for patients with depression and neuropathic pain, at a dose of 60 mg daily, as recommended by the American College of Cardiology and the Journal of the American College of Cardiology 2, 3

Nortriptyline or desipramine (secondary-amine TCAs) can be considered, starting at 10-25 mg at bedtime and gradually increasing to 75-100 mg daily, with caution required for ECG monitoring in patients over 40 years or with cardiac history, as recommended by the Mayo Clinic 2, 3

Gabapentin can be considered for neuropathic pain, starting at 300 mg at bedtime and increasing to 1800-3600 mg/day, as recommended by the Journal of the American College of Cardiology and Clinical Infectious Diseases 3, 4
Venlafaxine or gabapentin can be considered for menopausal symptoms if SSRIs have failed, as recommended by Annals of Oncology 5
Venlafaxine has shown a 76% response rate in SSRI-resistant OCD, according to the American College of Cardiology 1

Blood pressure and heart rate should be monitored, especially with venlafaxine, due to the risk of increased blood pressure and heart rate 1
Suicidal ideation, particularly in the first weeks of treatment, should be monitored, as recommended by the Journal of the American Academy of Child and Adolescent Psychiatry 6
Serotonin syndrome symptoms, such as confusion, agitation, tremors, and hyperthermia, should be monitored, especially when combining multiple serotonergic medications, as recommended by the Journal of the American Academy of Child and Adolescent Psychiatry 6

Allow 4-6 weeks at therapeutic doses to evaluate efficacy, and consider augmentation strategies if partial response after 8 weeks, as recommended by the Mayo Clinic 2
If no response after 8 weeks on adequate dose, switch to another class of medication, and consider referral to psychiatry if two medication trials have failed, as recommended by the American College of Cardiology 1