What are the next steps for a patient who has failed to respond to a selective serotonin reuptake inhibitor (SSRI)?

From the Guidelines

For patients who have failed to respond to an SSRI, switching to a different antidepressant class like SNRIs (venlafaxine 75-225 mg daily or duloxetine 30-120 mg daily) or bupropion (150-450 mg daily) is a recommended next step. This approach is supported by the American College of Physicians, which suggests that clinicians modify treatment if the patient does not have an adequate response to pharmacotherapy with an SSRI 1. When choosing a new antidepressant, it is essential to consider the patient's symptom profile, side effect concerns, medical comorbidities, and patient preferences.

Some key points to consider when switching antidepressants include:

• Ensuring the initial SSRI was given at an adequate dose for sufficient duration (typically 4-6 weeks at therapeutic dose) before considering it a failure
• Individual responses to different antidepressants can vary, so switching to another SSRI or a different class of antidepressants may be beneficial
• Augmentation strategies, such as adding an atypical antipsychotic, lithium, or thyroid hormone, can also be effective
• Non-pharmacological approaches like cognitive behavioral therapy should be considered throughout treatment

According to a more recent study from 2016, there is no significant difference in response or remission when switching from one SGA to another, or when switching to cognitive therapy 1. However, augmenting with bupropion may decrease depression severity more than augmentation with buspirone.

In terms of specific treatment options, switching to venlafaxine or duloxetine may be a good alternative for patients who have failed to respond to an SSRI, as these medications have been shown to be effective in treating major depressive disorder. Additionally, bupropion may be a good option for patients who are concerned about sexual side effects, as it has been associated with a lower rate of sexual adverse events compared to some other antidepressants 1.

From the FDA Drug Label

In one study, in which patients responding during 8 weeks of acute treatment with venlafaxine HCI extended-release capsules were assigned randomly to placebo or to the same dose of venlafaxine HCI extended-release capsules (75,150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated A second longer-term study has demonstrated the efficacy of venlafaxine tablets, USP immediate-release in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or venlafaxine tablets,USP immediate-release for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i. d. schedule)

The next steps for a patient who has failed to respond to a selective serotonin reuptake inhibitor (SSRI) may include switching to a different antidepressant, such as venlafaxine.

• Dose: The dose of venlafaxine needed for maintenance treatment is not known to be identical to the dose needed to achieve an initial response.
• Key considerations: Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. 2

From the Research

Next Steps for SSRI Failure

When a patient fails to respond to a selective serotonin reuptake inhibitor (SSRI), several next steps can be considered:

• Switching to another SSRI or a different antidepressant, such as venlafaxine 3, 4
• Augmenting the current SSRI with another medication, such as benzodiazepines, buspirone, beta blockers, tricyclic antidepressants, or valproate sodium 5, 6
• Adding cognitive behavioral therapy (CBT) to the treatment plan, which has been shown to improve response rates in adolescents with SSRI-resistant depression 4
• Optimizing SSRI dosing, including starting at a low dose and slowly increasing to the target dose, and ensuring an adequate trial before switching to a different drug 6

Considerations for Switching or Augmenting

When deciding whether to switch or augment, several factors should be considered:

• The patient's initial response to the SSRI, including the presence of any partial response or residual symptoms 5
• The duration of the initial treatment trial, with longer trials potentially increasing the likelihood of response 3, 5
• The patient's tolerance of the initial treatment, with those tolerating 12 or more weeks of treatment potentially benefiting more from augmentation 5
• The presence of any comorbid conditions or symptoms, such as anxiety or suicidal ideation, which may influence the choice of next steps 4

Outcomes and Response Rates

The outcomes and response rates for patients who fail to respond to an initial SSRI can vary depending on the next steps taken:

• Approximately 20% of patients may remit with a second-step switch to another monoaminergic antidepressant 3
• Around 50% of responses and two-thirds of remissions may occur after 6 weeks of treatment with a new medication 3
• The combination of CBT and a switch to another antidepressant may result in a higher rate of clinical response than a medication switch alone, particularly in adolescents 4