What is the best antidepressant to combine with Escitalopram (Lexapro)?

From the Guidelines

When considering an antidepressant to combine with Lexapro (escitalopram), bupropion is often the best choice. This recommendation is based on the most recent and highest quality evidence available, which suggests that augmenting escitalopram treatment with bupropion decreases depression severity more than augmentation with buspirone 1. The combination of escitalopram and bupropion may provide complementary effects, as they work on different neurotransmitters, with escitalopram targeting serotonin and bupropion targeting dopamine and norepinephrine.

Key Considerations

• The evidence from the American College of Physicians guideline suggests that low-quality evidence showed no difference in response or remission for augmentation of citalopram treatment with bupropion compared with augmentation with buspirone, but bupropion decreased depression severity more than buspirone 1.
• Moderate-quality evidence showed that discontinuation due to adverse events was lower with bupropion than with buspirone 1.
• Other possible combinations, such as adding mirtazapine or low-dose aripiprazole, may be considered as an augmentation strategy, but the evidence for these combinations is not as strong as for bupropion.

Dosage and Administration

• Typically, bupropion is added at 150 mg daily for one week, then increased to 300 mg daily if needed and tolerated.
• It is essential to initiate any medication combination under close medical supervision, considering individual factors such as medical history, current symptoms, and potential drug interactions.

Safety Considerations

• Combining two serotonergic antidepressants (like adding another SSRI or SNRI to Lexapro) should generally be avoided due to the risk of serotonin syndrome.
• The combination of escitalopram and bupropion should be monitored closely for potential adverse events, although the evidence suggests that discontinuation due to adverse events is lower with bupropion than with buspirone 1.

From the FDA Drug Label

1. 19 Drugs Metabolized by Cytochrome P4502D6 In vitro studies did not reveal an inhibitory effect of escitalopram on CYP2D6 In addition, steady state levels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with escitalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on escitalopram metabolism However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram, i.e., coadministration of escitalopram (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cmax and a 100% increase in AUC of desipramine.

The best antidepressant to combine with Escitalopram is not explicitly stated in the label. However, based on the information provided, desipramine is mentioned as an example of a tricyclic antidepressant that can be coadministered with escitalopram, but with caution due to a potential increase in desipramine plasma levels 2.

• Key points:
  • Coadministration of escitalopram and desipramine may increase desipramine plasma levels.
  • Caution is indicated when coadministering escitalopram with drugs metabolized by CYP2D6.

From the Research

Combination Therapies for Depression

When considering the best antidepressant to combine with Escitalopram (Lexapro), several options have been studied:

• Bupropion: Research suggests that bupropion can be an effective augmentation strategy for patients with partial response to selective serotonin reuptake inhibitors (SSRIs) like escitalopram 3, 4.
• Venlafaxine: There is evidence that combining venlafaxine with SSRIs can be beneficial for patients who have shown only a partial response to venlafaxine alone 5.
• Aripiprazole: Aripiprazole has been shown to be an effective augmentation strategy for improving therapeutic response in patients with treatment-resistant major depressive disorder when administered in combination with standard antidepressant therapy, including SSRIs like escitalopram 6.

Dosing Considerations

When combining antidepressants, dosing considerations are crucial:

• SSRIs: The dose-efficacy curve for SSRIs shows a gradual increase up to doses between 20 mg and 40 mg fluoxetine equivalents, with optimal acceptability in the lower licensed range between 20 mg and 40 mg fluoxetine equivalents 7.
• Venlafaxine: The dose-efficacy relationship for venlafaxine increases up to around 75-150 mg, with optimal acceptability in the lower range of its licensed dose 7.
• Bupropion: Bupropion is available in various formulations, including immediate release, sustained release, and extended release, with all three formulations being bioequivalent in terms of systemic exposure to bupropion 4.

Key Findings

Key findings from the studies include:

• Bupropion can be an effective and well-tolerated option for augmenting SSRIs like escitalopram 3, 4.
• Venlafaxine can be combined with SSRIs for patients with partial response to venlafaxine alone 5.
• Aripiprazole can be an effective augmentation strategy for improving therapeutic response in patients with treatment-resistant major depressive disorder 6.
• Optimal dosing for SSRIs, venlafaxine, and mirtazapine is crucial for achieving the best balance between efficacy, tolerability, and acceptability 7.