5-HTTLPR and efficacy of antidepressants

I have heard many patients tell me: “My psychiatrist told me that the genetic testing result showed that I won’t respond to SSRI antidepressants.”

Below are segments from genetic testing reports from two different companies referring to this issue. Is it true that 5-HTTLPR polymorphisms can predict who will or will not respond to an SSRI?

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The most recent meta-analysis on this topic as of May 2017 (Porcelli et al., 2010) found an association, in Caucasians with major depressive disorder, between having the L allele and:

— responding to an SSRI for major depression (odds ratio 1.6), and

— having remission with an SSRI (odds ratio 1.5).

So, the odds of response with the L allele are only a little bit better than those without an L allele.

In Caucasian patients with major depressive disorder taking an SSRI the remission rates were as follows:

L/L or L/S genotype: 52.8% (996/1885 patients)

S/S genotype: 45.6% (197/432 patients)

In Caucasian patients with major depressive disorder taking an SSRI the response rates were as follows:

L/L genotype: 61.6% (250/406 patients)

L/L or L/S genotype: 60.5% (579/957 patients)

S/S genotype: 48.8% (102/209 patients)

We should be clear that the S/S polymorphism only predicts a slightly lower probability of response to an SSRI. It does not mean, as the genetic testing report shown above seems to claim, that there is a “high risk of non-response,” or that an SSRI should not be used. Let’s help our patients to understand this as well.

But there are five factors that moderate this effect and in a subgroup of patients, the difference in response rates between the S/S and L/L genotypes becomes greater.

1. SSRIs

The association between 5-HTTLPR and response to antidepressants applies only to SSRIs.

2. Caucasians

The association between 5-HTTLPR polymorphisms and response to SSRIs applies only to Caucasians. In Asians, no significant association was found between 5-HTTLPR polymorphisms and response to SSRIs (Porcelli et al., 2010)

3. Females

Similarly, it has been suggested in a small study that the S/S genotype of 5-HTTLPR predicts a poorer response to treatment with serotonergic antidepressants in females (odds ratio 3.5) but not in males (Smits et al., 2008)

4. Age at onset of illness

The difference between the response rates with the L/L  genotype compared to S carriers was greater with increasing age at onset of illness (Porcelli et al., 2010).

5. Current age

The difference between the response rates with the L/L  genotype compared to S carriers was greater with increasing age at the time of the study (Porcelli et al., 2010).

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