Letter to the Editor

Molecular Psychiatry (2012) 17, 236–237; doi:10.1038/mp.2011.132; published online 25 October 2011

Therapygenetics: the 5HTTLPR and response to psychological therapy

T C Eley1, J L Hudson2, C Creswell3, M Tropeano1, K J Lester1, P Cooper3, A Farmer1, C M Lewis1, H J Lyneham2, R M Rapee2, R Uher1, H M S Zavos1 and D A Collier1

  1. 1King's College London, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London, UK
  2. 2Centre for Emotional Health, Department of Psychology, Macquarie University, Sydney, NSW, Australia
  3. 3Winnicott Research Unit, School of Psychology and Clinical Language Sciences, University of Reading, Reading, UK

Correspondence: TC Eley, E-mail: thalia.eley@kcl.ac.uk

Although pharmacogenetic research thrives,1 genetic determinants of response to purely psychotherapeutic treatments remain unexplored. In a sample of children undergoing cognitive behaviour therapy (CBT) for an anxiety disorder, we tested whether treatment response is associated with the serotonin transporter gene promoter region (5HTTLPR), previously shown to moderate environmental influences on depression. Children with short-short genotype were significantly more likely to respond to CBT than those carrying a long allele.

There is considerable evidence of association between anxiety/depression and the 5HTTLPR, particularly in response to stress.2 Moreover, the low-expression S allele, typically associated with poorer outcomes following stress, is also associated with better outcomes under low stress and may reflect sensitivity to the environment.3 We hypothesised that this allele would be associated with enhanced response to psychological therapies.4

We collected DNA from 584 anxiety-disordered children aged 6–13 years, undergoing manual-based CBT5 at research clinics in Sydney, Australia and Reading, UK. We focus on 359 children with four white European grandparents (entire sample findings similar; see Supplementary Information). Families provided data pre-treatment, post-treatment and at follow-up (usually 6 months, for detailed Methods see Supplementary Information).

Parental DNA was obtained for 389 children (267 white), and parents self-rated depression, anxiety and stress.6 Parents provided informed consent, children assent. Genomic DNA was extracted from buccal and blood samples using established procedures. The 5HTTLPR genotypes were in Hardy–Weinberg equilibrium. There was no significant difference in genotypic frequencies between cases and 459 white European psychiatrically well controls7 (χ22=0.40, P=0.82).

Treatment response was considered as the absence of the primary (primary anxiety response), or any (all anxiety response) anxiety disorder. As all analyses test the same core hypothesis, we did not correct for multiple testing. The 5HTTLPR was significantly associated with both ‘primary’ and ‘all’ anxiety response at follow-up (Figure 1a); a recessive model was indicated. Positive ‘primary’ (all) anxiety response at follow-up was seen in 20.0% (18.8%) more children with the SS than the SL/LL genotypes; 78.4 vs 58.4%, P<0.01 (60.8 vs 42.0%, P<0.02). The influence of 5HTTLPR remained significant even after controlling for significant clinical predictors of treatment response (mood disorders, pre-treatment symptom severity and maternal psychopathology), and time (to follow-up), age, gender and treatment site. The odds ratios for 5HTTLPR-SS were 0.39, P=0.02 (0.44, P=0.03) for ‘primary’ (all) anxiety response. Furthermore, the 5HTTLPR also significantly predicted change in symptom severity from pre-treatment to follow-up (Figure 1b), even after controlling for significant clinical covariates (β=−0.17, P<0.01). For full Results see Supplementary Information.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Response to CBT in child anxiety by 5HTTLPR. Panel a shows the proportion of children free of their primary anxiety disorder and free of all anxiety disorders (left and right-hand sets of bars respectively) at follow-up by 5HTTLPR genotype. Panel b shows reductions in symptom severity of the primary anxiety disorder from pre-treatment to post-treatment and follow-up by 5HTTLPR genotype. Note: (a) There were significant associations at follow-up between both ‘primary anxiety response’ and ‘all anxiety response’ respectively, using either a genotypic (χ22=8.61, P=0.01; χ22=6.60, P=0.04) or recessive (χ21=7.03, P=<0.008; χ21=5.88, P=0.02) model. (b) Children with the SS genotype showed significantly greater reduction in symptom severity from pre-treatment to follow-up (β=−0.15, P<0.01). At post-treatment the difference was not significant (β=−0.03, P=0.55).

Full figure and legend (56K)Download PowerPoint slide (585 KB)

This is the first study to explore the association between a genetic marker and response to a purely psychological treatment. One previous pilot study (N=69) found an association between COMTval158met and CBT response in adult panic disorder, but many subjects were also medicated.8 A naturalistic study (N=111) of adult bulimia found that those with the 5HTTLPR S allele were less likely to respond to treatment, be it CBT, medication or both.9 We found that in anxiety-disordered children, those with the 5HTTLPR SS genotype were 20% more likely to be disorder-free by follow-up than those with SL/LL genotypes. Although these findings hold true in the white subset and the entire data set, the sample is relatively small and there is no independent replication, hence, they must be considered preliminary. Furthermore, the association with 5HTTLPR was only seen at follow-up. The period between post-treatment and follow-up is typically characterised by continued improvement as the child applies the skills learnt;10 thus, it is possible that the genotype influences capacity for continued benefit from the intervention.

These findings are important both clinically and conceptually. First, our data suggest that ‘therapygenetics’, similar to pharmacogenetics,1 may have the potential to inform treatment choices. Second, the possibility that the 5HTTLPR influences responsivity to psychological treatment,4 is in keeping with the hypothesis that this marker reflects environmental sensitivity.3 In conclusion, if replicated, these results may provide a tool that could help decide whether an individual is likely to benefit from standard CBT alone or whether enhanced treatment is required.


Conflict of interest

The authors declare no conflict of interest.



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Supplementary Information accompanies the paper on the Molecular Psychiatry website