What are the next treatment options for a patient with anxiety and depression who has failed multiple SSRIs?

Treatment Options for Anxiety and Depression After Failed SSRI Trials

For patients who have failed multiple SSRI trials (Zoloft, Lexapro, Prozac) for anxiety and depression, switching to a non-SSRI antidepressant such as venlafaxine (an SNRI) or bupropion is strongly recommended as the next step in treatment.

Next Treatment Options After Failed SSRIs

Switch to a Different Class of Antidepressant

• SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)

  • Venlafaxine (Effexor) is recommended as an effective option for patients who have failed multiple SSRI trials 1
  • Venlafaxine has shown efficacy for both depression and anxiety symptoms 2
  • One fair-quality trial showed statistically significantly better response and remission rates for venlafaxine compared to fluoxetine in patients with anxiety symptoms 3

• Bupropion (Wellbutrin)

  • Considered an effective alternative when switching from SSRIs 4
  • Particularly useful if the patient experienced sexual side effects or weight gain with SSRIs 1
  • The STAR*D trial showed that bupropion was equally effective as other switch options after SSRI failure 3

• Mirtazapine (Remeron)

  • Has a faster onset of action compared to SSRIs 3
  • May be particularly helpful for patients with insomnia and poor appetite 3
  • Can be effective for both depression and anxiety symptoms 2

Treatment Algorithm

1. First step: Switch to a non-SSRI antidepressant

   • Venlafaxine (SNRI) - starting at low dose (37.5mg) and titrating up as tolerated 5
   • Bupropion SR - if anxiety is less prominent than depression 1
   • Mirtazapine - if sleep disturbance is a prominent symptom 3

2. If first switch fails: Consider combination or augmentation strategies

   • Antidepressant + second-generation antipsychotic (e.g., aripiprazole, quetiapine) 6
   • Antidepressant + mood stabilizer (e.g., lamotrigine, lithium) 6
   • Combination of antidepressants (e.g., SNRI + mirtazapine) 6

Important Clinical Considerations

• Duration of trial: Allow adequate time (at least 8-12 weeks) on the maximum tolerated dose of the new medication before determining efficacy 4

  • In the STAR*D trial, two-thirds of remissions occurred after 6 weeks of treatment with the switch medication 4
  • 33% of responses occurred after ≥9 weeks of treatment 4

• Dosing considerations:

  • For SNRIs like venlafaxine, higher doses may be needed to engage both serotonergic and noradrenergic mechanisms 5
  • Gradual titration is recommended to minimize side effects 5

• Monitoring response:

  • Patients with at least 20% reduction in depressive symptoms around week 2 are six times more likely to ultimately respond or remit 4
  • However, no reliable early triage point exists, so adequate trial duration is essential 4

Potential Pitfalls and Caveats

• Discontinuation symptoms: When switching from an SSRI, be aware of potential discontinuation symptoms, particularly with paroxetine and shorter-acting SSRIs 3

  • Consider cross-tapering rather than abrupt discontinuation 5

• Expectations management: Only about 25% of patients achieve remission with a second-step switch to another antidepressant after SSRI failure 4

  • More than half of patients may not achieve meaningful benefit with a second-step switch 4

• Drug interactions: Be cautious about potential drug interactions when switching between antidepressant classes

  • Allow sufficient washout periods, especially when switching to or from MAOIs 5
  • Venlafaxine requires at least 7 days after stopping before starting an MAOI 5

• Side effect profiles: Consider the different side effect profiles when selecting the next agent

  • SNRIs may cause more noradrenergic side effects (increased blood pressure, sweating) 2
  • Bupropion has lower risk of sexual dysfunction but may increase anxiety in some patients 1
  • Mirtazapine commonly causes sedation and weight gain 3

Remember that treatment resistance in depression and anxiety often requires multiple approaches, and expectations should be managed accordingly. The goal is to find the most effective medication with the most tolerable side effect profile for each individual patient.