The Serotonin Transporter Promoter Polymorphism (5-HTTLPR) Affects the Relation between Antidepressant Serum Concentrations and Effectiveness in Major Depression

Abstract

Introduction:

Both the serotonin transporter promotor polymorphism (5-HTTLPR) and serum concentrations of SSRIs have been shown to affect response to SSRIs. Results, however, are inconsistent. The aim of this study was to investigate whether remission or response to SSRIs is influenced by an interaction of 5-HTTLPR and SSRI serum concentrations.

Methods:

49 patients with major depression and SSRI treatment were genotyped for the 5-HTTLPR locus including the rs25531. Drug serum concentrations and depression severity were measured weekly.

Results:

Logistic regression analysis revealed a significant association between 5-HTTLPR, SSRI serum concentrations and response to treatment. A favourable treatment outcome correlated with SSRI serum concentration in 5-HTTLPR-L_A allele carriers (r²=34.3%; p=0.001), but not in S/L_G-allele carriers (p=0.31)

Discussion:

In the group of L_A allele carriers, those MDD patients with a high antidepressant serum concentrations responded better to treatment than patients with a low serum concentration. We conclude that the 5-HTTLPR might affect reponse to SRRI subject to serum concentrations. If replicated this might be a starting point for prospective clinical trials.

Key words

5-HTTLPR - SSRI - TDM - depression

• References

• 1 Trivedi MH, Rush AJ, Wisniewski SR et al., STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163: 28-40
• 2 Rush AJ, Trivedi MH, Wisniewski SR et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163: 1905-1917
• 3 Bauer M, Whybrow PC, Angst J et al., World Federation of Societies of Biological Psychiatry (WFSBP). Guidelines for biological treatment of unipolar depressive disorders, part 1: acute and continuation treatment of major depressive disorder. World J Biol Psychiatry 2002; 3: 5-43
• 4 Adli M, Baethge C, Heinz A et al. Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed? A systematic review. Eur Arch Psychiatry Clin Neurosci 2005; 255: 387-400
• 5 Corruble E, Guelfi JD. Does increasing dose improve efficacy in patients with poor antidepressant response: a review. Acta Psychiatr Scand 2000; 101: 343-348
• 6 Benkert O, Szegedi A, Wetzel H et al. Dose escalation vs. continued doses of paroxetine and maprotiline: a prospective study in depressed out-patients with inadequate treatment response. Acta Psychiatr Scand 1997; 95: 288-296
• 7 Dornseif BE, Dunlop SR, Potvin JH et al. Effect of dose escalation after low-dose fluoxetine therapy. Psychopharmacol Bull 1989; 25: 71-79
• 8 Schweizer E, Rynn M, Mandos LA et al. The antidepressant effect of sertraline is not enhanced by dose titration: results from an outpatient clinical trial. Int J Clin Psychopharmacol 2001; 16: 137-143
• 9 Licht RW, Qvitzau S. Treatment strategies in patients with major depression not responding to first-line sertraline treatment: a randomised study of extended duration of treatment, dose increase or mianserin augmentation. Psychopharmacology 2002; 161: 143-151
• 10 Ostad Haji E, Tadić A, Wagner S et al. Association between citalopram serum levels and clinical improvement of patients with major depression. J Clin Psychopharmacol 2011; 3: 281-286
• 11 Meyer JH, Wilson AA, Sagrati S et al. Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [¹¹C]DASB positron emission tomography study. Am J Psychiatry 2004; 161: 826-835
• 12 Kelly MW, Perry PJ, Holstad SG et al. Serum fluoxetine and norfluoxetine concentrations and antidepressant response. Ther Drug Monit 1989; 11: 165-170
• 13 Preskorn SH. Clinical pharmacology of selective serotonin reuptake inhibitors. Clin Pharmacokinetics 1997; 32 (Suppl. 01) 1-21
• 14 Tasker TC, Kaye CM, Zussman BD et al. Paroxetine plasma levels: lack of correlation with efficacy or adverse events. Act Psychiatr Scand 1989; 350 (Suppl) 152-155
• 15 Heils A, Teufel A, Petri S et al. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996. 66 2621–2624
• 16 Lesch KP, Bengel D, Heils A et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 29: 1527-1531
• 17 Eichhammer P, Langguth B, Wiegand R et al. Allelic variation in the serotonin transporter promoter affects neuromodulatory effects of a selective serotonin transporter reuptake inhibitor (SSRI). Psychopharmacology (Berl) 2006; 66: 294-297
• 18 Pollock BG, Ferrell RE, Mulsant BH et al. Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 2000; 23: 587-590
• 19 Smeraldi E, Zanardi R, Benedetti F et al. Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 1998; 3: 508-511
• 20 Zanardi R, Benedetti F, Di Bella D et al. Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacol 2000; 20: 105-107
• 21 Zanardi R, Serretti A, Rossini D et al. Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol Psychiatry 2001; 50: 323-330
• 22 Kraft JB, Peters EJ, Slager SL et al. Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample. Biol Psychiatry 2007; 61: 734-742
• 23 Durham LK, Webb SM, Milos PM et al. The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder. Psychopharmacology (Berl) 2004; 174: 525-529
• 24 Serretti A, Kato M, De Ronchi D et al. Metaanalysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry 2007; 12: 247-257
• 25 Grasmäder K, Lohmann PL, Kuss HJ et al. Therapeutisches Drug-Monitoring von Antidepressiva- therapeutischer und gesundheitökonomischer Nutzen. Med Med Monatsschr Pharm 2003; 26: 162-164
• 26 Hamilton M. A rating scale for depression. JNNP 1960; 23: 56-61
• 27 Hu X, Oroszi G, Chun J et al. An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 2005; 29: 8-16
• 28 Frahnert C, Rao ML, Grasmäder K. Analysis of eighteen antidepressants, four atypical antipsychotics and active metabolites in serum by liquid chromatography: a simple tool for therapeutic drug monitoring. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 794: 35-47
• 29 Greiner C, Hiemke C, Bader W et al. Determination of citalopram and escitalopram together with their active main metabolites desmethyl (es-)citalopram in human serum by column-switching high performance liquid chromatography (HPLC) and spectrophotometric detection. J Chromatogr B 2007; 848: 391-394
• 30 Baumann P, Hiemke C, Ulrich S et al. The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry 2004; 37: 243-265
• 31 Lundmark J, Reis M, Bengtsson F. Therapeutic drug monitoring of sertraline: variability factors as displayed in a clinical setting. Ther Drug Monit 2000; 22: 446-454
• 32 Härtter S, Wetzel H, Hammes E et al. Serum concentrations of fluvoxamine and clinical effects. Pharmacopsychiatry 1998; 31: 199-200
• 33 Lundmark J, Reis M, Bengtsson F. Serum concentrations of fluoxetine in the clinical treatment setting. Ther Drug Monit 2001; 23: 139-147
• 34 Lundmark J, Bengtsson F, Nordin C et al. Therapeutic drug monitoring of selective serotonin reuptake inhibitors influences clinical dosing strategies and reduces drug costs in depressed elderly patients. Acta Psychiatr Scand 2000; 101: 354-359
• 35 Ruhé HG, Booij J, Weert HC et al. Evidence why paroxetine dose escalation is not effective in major depressive disorder: a randomized controlled trial with assessment of serotonin transporter occupancy. Neuropsychopharmacology 2009; 34: 999-1010
• 36 Müller MJ, Dragicevic A. Standardized rater training for the Hamilton Depression Rating Scale (HAMD-17) in psychiatric novices. J Affect Disord 2003; 77: 65-69
• 37 Voineskos AN, Wilson AA, Boovariwala A et al. Serotonin transporter occupancy of highdose selective serotonin reuptake inhibitors during major depressive disorder measured with [¹¹C]DASB positron emission tomography. Psychopharmacology (Berl) 2007; 193: 539-545
• 38 Ruhé HG, Ooteman W, Booij J et al. Serotonin transporter gene promoter polymorphisms modify the association between paroxetine serotonin transporter occupancy and clinical response in major depressive disorder. Pharmacogenet Genomics 2009; 1: 67-76
• 39 Murthy NV, Selvaraj S, Cowen PJ et al. Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [¹¹C]-DASB binding in the living human brain. Neuroimage 2010; 52: 50-54
• 40 Tanum L, Strand LP, Refsum H. Serum concentrations of citalopram  −  dose-dependent variation in R- and S-entantiomer ratios. Pharmacopsychiatry 2010; 43: 190-193