- Email: [email protected]
P.2.c.037 The serotonin transporter (SERT) occupancy in median raphe nucleus quantified with PET predicts treatment response to SSRIs in major depressive disorder
P.2.c. Affective disorders and antidepressants − Antidepressants (clinical) (P < 0.05), proportion of CAGGA haplotype that RSK(2/ 3/ 4) RSKL(1/ 2) gene loci SNPs constructed in remitter group was also close to significant higher that in non-remitter group (P = 0.0533, OR:1.705 95% CI: 0.990–2.935); But proportion of AAAGGG haplotype that RSK(2/ 3/ 4) -RSKL(1/ 2) gene loci SNPs constructed in male patients was significantly greater than that in nonremitter group (P < 0.05), proportion of CAAGGG Haplotype that RSK(2/ 3/ 4) -RSKL(1/ 2) gene loci SNPs constructed in remitter group was close to lower than that in non-remitter group (P = 0.079). 3. MEK1 (rs28730804) and RSK3 (rs2229712) in the Ras-Raf-MAPK signal pathway were of gene-gene interaction, and affected antidepressant drugs response in female depressed patients (P = 0.041), but it was not found in male patients. Conclusions: 1. Some SNPs in the Ras-Raf-MAPK signal pathway maybe was associated with antidepressant drugs response, especially A/G heterozygote of kinases encoding gene perhaps promote antidepressant drugs response. 2. Lower perception of CCAGA haplotype in female depressed patients may positively influence antidepressant drugs response, while higher perceptions of AAAGGG haplotype in male patients may positively influence antidepressant drugs response. 3. MEK1 (rs28730804) and RSK3 (rs2229712) in the Ras-Raf-MAPK signal pathway were of genegene interaction in female depressed patients, and remarkably affected antidepressant drugs response. Disclosure statement: This paper is financially supported by the grants from National Basic Research Program of China (973 Program, No. 2007CB512308) and National Hi-Tech Research and Development Program of China (863 Program, No. 2007AA0200Z435). P.2.c.037 The serotonin transporter (SERT) occupancy in median raphe nucleus quantified with PET predicts treatment response to SSRIs in major depressive disorder E. Akimova1 ° , R. Lanzenberger1 , M. Savli1 , D. H¨ausler2 , W. Wadsak2 , C. Spindelegger1 , U. Moser1 , M. Fink1 , K. Kletter2 , S. Kasper1 . 1 Medical University of Vienna, Dept. of Psychiatry and Psychotherapy, Vienna, Austria; 2 Medical University of Vienna, Dept. of Nuclear Medicine, Vienna, Austria Background: Psychiatrists today still lack sufficient tools to predict the clinical response to antidepressants (1). Impaired serotonin neurotransmission has been implicated in the pathophysiology of affective disorders based on the results of numerous preclinical and clinical investigations. The serotonin transporter (SERT) is being targeted in current research on the neurobiological correlates of Major Depressive Disorder (MDD) as Serotonin Reuptake Inhibitors (SSRIs) bind to SERT, thereby blocking serotonin reuptake from the synaptic cleft and increasing extracellular serotonin levels (2). This effect of SSRIs is known to be associated with treatment response. In order to investigate this mechanism, we test the hypothesis that serotonin transporter availability and occupancy in patients with MDD may be biological indicators capable of predicting treatment outcome. Methods: In a double-blind, randomized, longitudinal PET study using [11 C]DASB, 18 patients were treated with 10 mg/d escitalopram or 20 mg/d citalopram, i.e. equal doses of the enantiomer S-Citalopram. [11 C]DASB) is a new, highly selective PET radiotracer that shows a high affinity for SERT. Superior to other PET radioligands for SERT, [11 C]DASB permits reliable quantification of subcortical and cortical SERT binding Each patient was
S389
measured 3 times to assess SERT availability in the unmedicated state and SERT occupancy after a single-dose and later after the first 3 weeks of treatment with SSRIs. The Hamilton Depression Rating scale (HAM-D, 17 items) was assessed at the screening visit and before each PET scan. SERT availability at baseline and SSRI treatment-induced occupancies of SERT were quantified in ten brain regions (nucleus caudatus, putamen, midbrain, thalamus, dorsal raphe nucleus, median raphe nucleus, nucleus accumbens, amygdala, anterior cingulate cortex insula) and correlated with treatment response assessed by the HAM-D. Results: A single dose of SSRIs led to a considerable transporter blockage resulting in relatively high brain occupancies of 74.8%±6.8. Continuous SSRI treatment over 3 weeks showed occupancies of 84.0%±7.0. There was a significant correlation between SERT occupancy and treatment response regarding topology for MRN (rho=-0.470, p = 0.049) after 3 weeks of treatment. Significant correlations (Spearman) between the decrease in HAM-D scores and SERT availability were found in the midbrain (rho=-0.643, p = 0.004), median raphe nucleus (rho=-0.672, p = 0.002), and dorsal raphe nucleus (rho=-0.583, p = 0.011), i.e. lower pretreatment SERT availability in these regions indicated improved treatment response 3 weeks later. Conclusion: To our knowledge this is the first PET study with [11 C]DASB demonstrating a significant relationship between treatment response and SERT availability and occupancy. Some investigators suggest that availability and occupancy of SERT may be a key component in the response to SSRIs (3). In our sample we were able to show this for the raphe and midbrain regions. With our study we aim to provide a further contribution to the controversial research topic of biological markers and their significance as predictive instruments. Disclosure statement: S. Kasper has received grants/research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, Servier, Sepracor, GlaxoSmithKline, Organon has served as a consultant or on advisory boards for AstraZeneca, Austrian Science Fund, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Organon, Sepracor, Janssen, and Novartis and has served on speakers’ bureaus for AstraZeneca, Eli Lily, Lundbeck, Servier, Sepracor and Janssen. R. Lanzenberger has received a travel grant and research support from Lundbeck A/S, furthermore conference speaker honoraria from Lundbeck and AstraZeneca. C. Spindelegger has received a travel grant from Lundbeck U. Moser has received travel grants from Bristol-Myers Squibb and Astra Zeneca. References [1] Bauer M, Bschor T, Pfennig A, Whybrow PC, Angst J, Versiani M, M¨oller HJ on behalf of the WFSBP Task Force on Treatment Guidelines for Unipolar Depressive Disorders (2007) World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders in Primary Care. World Journal of Biological Psychiatry 8: 67–104. [2] Meyer JH. Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci 2007; 32(2): 86–102. [3] Kugaya A, Sanacora G, Staley JK, Malison RT, Bozkurt A, Khan S et al. Brain serotonin transporter availability predicts treatment response to selective serotonin reuptake inhibitors. Biol Psychiatry 2004; 56(7): 497–502.
S389
measured 3 times to assess SERT availability in the unmedicated state and SERT occupancy after a single-dose and later after the first 3 weeks of treatment with SSRIs. The Hamilton Depression Rating scale (HAM-D, 17 items) was assessed at the screening visit and before each PET scan. SERT availability at baseline and SSRI treatment-induced occupancies of SERT were quantified in ten brain regions (nucleus caudatus, putamen, midbrain, thalamus, dorsal raphe nucleus, median raphe nucleus, nucleus accumbens, amygdala, anterior cingulate cortex insula) and correlated with treatment response assessed by the HAM-D. Results: A single dose of SSRIs led to a considerable transporter blockage resulting in relatively high brain occupancies of 74.8%±6.8. Continuous SSRI treatment over 3 weeks showed occupancies of 84.0%±7.0. There was a significant correlation between SERT occupancy and treatment response regarding topology for MRN (rho=-0.470, p = 0.049) after 3 weeks of treatment. Significant correlations (Spearman) between the decrease in HAM-D scores and SERT availability were found in the midbrain (rho=-0.643, p = 0.004), median raphe nucleus (rho=-0.672, p = 0.002), and dorsal raphe nucleus (rho=-0.583, p = 0.011), i.e. lower pretreatment SERT availability in these regions indicated improved treatment response 3 weeks later. Conclusion: To our knowledge this is the first PET study with [11 C]DASB demonstrating a significant relationship between treatment response and SERT availability and occupancy. Some investigators suggest that availability and occupancy of SERT may be a key component in the response to SSRIs (3). In our sample we were able to show this for the raphe and midbrain regions. With our study we aim to provide a further contribution to the controversial research topic of biological markers and their significance as predictive instruments. Disclosure statement: S. Kasper has received grants/research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, Servier, Sepracor, GlaxoSmithKline, Organon has served as a consultant or on advisory boards for AstraZeneca, Austrian Science Fund, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Organon, Sepracor, Janssen, and Novartis and has served on speakers’ bureaus for AstraZeneca, Eli Lily, Lundbeck, Servier, Sepracor and Janssen. R. Lanzenberger has received a travel grant and research support from Lundbeck A/S, furthermore conference speaker honoraria from Lundbeck and AstraZeneca. C. Spindelegger has received a travel grant from Lundbeck U. Moser has received travel grants from Bristol-Myers Squibb and Astra Zeneca. References [1] Bauer M, Bschor T, Pfennig A, Whybrow PC, Angst J, Versiani M, M¨oller HJ on behalf of the WFSBP Task Force on Treatment Guidelines for Unipolar Depressive Disorders (2007) World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders in Primary Care. World Journal of Biological Psychiatry 8: 67–104. [2] Meyer JH. Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci 2007; 32(2): 86–102. [3] Kugaya A, Sanacora G, Staley JK, Malison RT, Bozkurt A, Khan S et al. Brain serotonin transporter availability predicts treatment response to selective serotonin reuptake inhibitors. Biol Psychiatry 2004; 56(7): 497–502.