Do patients with the SS genotype respond poorly to Selective Serotonin Reuptake Inhibitors (SSRIs)?

SS Genotype and SSRI Response: Evidence-Based Clarification

You are correct that the SS genotype of the serotonin transporter promoter polymorphism (5-HTTLPR) is associated with reduced SSRI response, but current evidence does not support withholding SSRIs or routine genetic testing to guide initial treatment selection. 1

Understanding the SS Genotype Effect

The SS genotype is indeed associated with slower symptom improvement and potentially reduced response to SSRIs compared to patients carrying the L allele. 1 However, the clinical significance of this finding must be understood in context:

• The American College of Medical Genetics acknowledges the association but does not recommend routine genetic testing to guide initial SSRI selection for anxiety or depression treatment. 1
• The EGAPP Working Group found insufficient evidence to recommend routine serotonin transporter genetic testing for patients starting SSRI treatment, rating most supporting studies as quality level 3-4 out of 5. 1

Research Evidence Supporting Reduced Response

Multiple studies demonstrate the SS genotype's impact on SSRI efficacy:

• Patients with the L allele show significantly greater symptom reduction compared to SS genotype carriers across multiple SSRIs. 2
• SS genotype patients had significantly poorer response to escitalopram (P > 0.0001) in open-label studies. 3
• The L/L genotype was associated with significantly better response to fluoxetine for impulsive-aggressive behavior (P<0.05 total score, P<0.01 aggression subscale) compared to S allele carriers. 4
• Paroxetine was significantly more effective than fluvoxamine in SS carriers after 4 weeks (P=0.012 for total score reduction), but not in L/S carriers. 2

Paradoxical Plasma Concentration Findings

An important nuance exists regarding dosing in SS patients:

• In SS genotype patients, lower paroxetine plasma concentrations were significantly negatively correlated with better MADRS improvement at week 6, suggesting lower doses may be more effective in this subgroup. 5
• In SL/LL genotype patients, higher plasma concentrations showed positive correlation with improvement, though this did not reach significance in multivariate analysis. 5

Practical Clinical Management

Standard first-line SSRIs (sertraline, escitalopram, fluoxetine) remain appropriate initial choices regardless of genotype. 1 The evidence does not support withholding SSRIs or selecting alternative medication classes in SS patients. 1

For Patients with Known SS Genotype:

• Implement closer early monitoring, assessing response at 2-3 weeks rather than the standard 4-6 weeks, as SS patients may require longer to show improvement. 1
• Consider fluoxetine as a preferred SSRI choice, as it has less CYP2C19-dependent metabolism compared to citalopram or escitalopram. 1
• For paroxetine specifically, consider lower doses in SS patients who fail to respond at standard doses, given the inverse plasma concentration-response relationship. 5

When Genetic Information Becomes Clinically Relevant:

The SS genotype information is most useful after initial treatment failure or intolerable side effects with one or more SSRIs, rather than for initial drug selection. 1

CYP2C19 Considerations

A separate but related issue involves CYP2C19 metabolizer status:

• CYP2C19 poor metabolizers on escitalopram were more likely to switch antidepressants, have side effects, and discontinue treatment earlier compared to normal metabolizers. 6
• CYP2C19 poor and intermediate metabolizers on citalopram exhibited increased odds of discontinuation and shorter treatment durations. 6
• The Dutch Pharmacogenetics Working Group classifies CYP2C19 genotyping as "potentially beneficial" rather than mandatory before starting escitalopram, citalopram, and sertraline. 7

Bottom Line

While the SS genotype is associated with reduced SSRI response, this should not prevent initiating SSRI treatment, as SSRIs remain first-line therapy with proven efficacy across genotypes. 8, 1 The genetic information is most valuable for guiding subsequent treatment decisions after initial failure, implementing closer monitoring schedules, and potentially selecting specific SSRIs (favoring fluoxetine) or adjusting doses (considering lower paroxetine doses in SS patients). 1, 5, 4