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Molecular-Genetic Approaches to Modeling Onset of Improvement

Study of 2'848 MDD Patients

Using the "individual-case" approach, we have investigated the time course of improvement under antidepressants in a sample of 2’848 MDD patients treated with 7 different types of antidepressants or placebo to address the question of the extent to which the various active compounds possess a faster or slower onset of action, compared to placebo. Among patients who met the improvement/response criteria, the distribution of the individual onsets was approximately normal (slightly left-skewed), covering a wide range from early to late response with mean values around day 12-14 (improvement) and day 18-20 (response). Unexpectedly, there were almost no differences between treatment modalities in this respect, with differences between active compounds, or between active compounds and placebo, being reflected only by the total number of improvers and responders.

Differences Between Treatment Modalities

Our results suggested that patients are likely to possess a biological predisposition that controls the time characteristics of recovery but not the response to a particular treatment, as demonstrated in our study for 7 pharmacologically different antidepressants. Response to currently available psychotropic drug treatment appeared to be to a substantial part determined by a nonspecific "recovery-genetic" component, which is ethnicity-independent and also largely independent of diagnostic entities, since psychotropic drugs seem to be "polyvalent" in the sense that they induce a therapeutic response under various clinical indications. For example, antidepressants are also effective in anxiety disorders and neuroleptics are successfully used in the treatment of bipolar illness.

Configuration of Genes

In a molecular-genetic pilot study of 257 patients genotyped for 120 candidate genes, we searched for configurations of genes that modify the time characteristics of psychotropic drug response. Using the genotype patterns of 105 patients as learning samples, we found a 23-locus configuration significantly correlated with onset of improvement, thus enabling discrimination between "early", "late", and "non"-improvers at classification rates exceeding 75%. Applied to the independent replication sample of 152 patients, the same configuration of loci yielded 85.4% correctly classified "early" and 65.9% "late" improvers. In consequence, response to psychotropic drug treatment appears substantially determined by an unspecific "recovery-genetic" component, which is independent of treatment modality and can be triggered by various exogenous and endogenous factors. By contrast, a much smaller, ethnicity-specific "pharmaco-genetic" component apparently causes the inter-individual variation in dose, blood-level, weight gain, and other side effects.

References

Stassen HH, Angst J, Scharfetter C, Szegedi A: Therapie mit Antidepressiva: Erfolg von genetischen Faktoren abhängig? Leading Opinions, Neurologie & Psychiatrie 2005; 6: 25-27
Szegedi A, Rujescu D, Tadic A, Mueller MJ, Ralf Kohnen R, Stassen HH, Dahmen N: The catechol-O-methyltransferase Val108/158Met-polymorphism affects short-term treatment response to mirtazapine, but not to paroxetine in Major Depression. Pharmacogenomics 2005; 5(1): 49-53
Stassen HH, Szegedi A, Scharfetter C: Modeling Activation of Inflammatory Response System. A Molecular-Genetic Neural Network Analysis. BMC Proceedings 2007, 1 (Suppl 1): S61, 1-6
Stassen HH, Angst J, Hell D, Scharfetter C, Szegedi A: Is there a common resilience mechanism underlying antidepressant drug response? Evidence from 2'848 patients. J Clin Psychiatry 2007; 68(8): 1195-1205
Tadic A, Rujescu D, Muller MJ, Kohnen R, Stassen HH, Dahmen N, Szegedi A: A monoamine oxidase B gene variant and short-term antidepressant treatment response. Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31(7): 1370-1377
Tadic A, Muller MJ, Rujescu D, Kohnen R, Stassen HH, Dahmen N, Szegedi A: The MAOA T941G polymorphism and short-term treatment response to mirtazapine and paroxetine in major depression. Am J Med Genet B Neuropsychiatr Genet. 2007; 144(3): 325-331
Tadic A, Rujescu D, Dahmen N, Stassen HH, Muller MJ, Kohnen R, Szegedi A: Association Analysis between Variants of the Interleukin-1? and the Interleukin-1 Receptor Antagonist Gene and Antidepressant Treatment Response in Major Depression. Neuropsychiatr Dis Treat 2008; 4(1): 269-276
Stassen HH, Hoffmann K, Scharfetter C: The Difficulties of Reproducing Conventionally Derived Results through 500k-Chip Technology. BMC Genet Proc. 2009; 3 Suppl 7: S66
Hoffmann K, Planitz C, Rüschendorf F, Müller-Myhsok B, Stassen HH, Lucke B, Mattheisen M, Stumvoll M, Bochmann R, Zschornack G, Wienker TF, Nürnberg P, Reis A, Luft FC, Lindner TH: A novel locus for arterial hypertension on chromosome 1p36 maps to a metabolic syndrome trait cluster in the Sorbs, a Slavic population isolate in Germany. J Hypertens 2009; 27: 983-990
Gravemann S, Schnipper N, Meyer H, Vaya A, Nowaczyk MJM, Rajab A, Hofmann WK, Salewsky B, Tönnies H, Neitzel H, Stassen HH, Sperling K, Hoffmann K. Dosage effect of zero to three functional LBR-genes in vivo and in vitro. Nucleus 2010; 1(2): 1-12
Giegling I, Drago A, Schäfer M, Hartmann AM, Sander T, Toliat MR, Möller HJ, De Ronchi D, Stassen HH, Rujescu D, Serretti A: Lack of association between 71 variations located in candidate genes and response to acute haloperidol treatment. Psychopharmacology 2011; 214(3): 719-728
Giegling I, Drago A, Dolzan V, Plesnicar BK, Schäfer M, Hartmann AM, Sander T, Toliat MR, Möller HJ, Stassen HH, Rujescu D, Serretti A: Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol. Pharmacogenet Genomics. 2011; 21(4): 206-216
Drago A, Giegling I, Schäfer M, Hartmann AM, Friedl M, Konte B, Möller HJ, De Ronchi D, Stassen HH, Serretti A, Rujescu D: AKAP13, CACNA1, GRIK4 and GRIA1 genetic variations may be associated with haloperidol efficacy during acute treatment. Eur Neuropsychopharmacol. 2012 [Epub ahead of print]
Drago A, Giegling I, Schäfer M, Hartmann AM, Möller HJ, De Ronchi D, Stassen HH, Serretti A, Rujescu D: No association of a set of candidate genes on haloperidol side effects. PLoS One. 2012; 7(10): e44853
Giegling I, Balzarro B, Porcelli S, Schäfer M, Hartmann AM, Friedl M, Konte B, Krämer P, Möller HJ, De Ronchi D, Stassen HH, Serretti A, Rujescu D: Influence of ANKK1 and DRD2 polymorphisms in response to haloperidol. Eur Arch Psychiatry Clin Neurosci. 2013; 263(1): 65-74

 

Onset of improvement
Fig. 9: Time to sustained 20% baseline score reduction in patients who showed improvement under imipramine, amitriptyline, moclobemide, fluoxetine, paroxetine, mirtazapine, oxaprotiline and placebo (n=2'171; pooled analysis). The empirical data suggest an approximately normal, slightly left-skewed distribution with mean around day 13 (green: empirical percentages; red: theoretical distribution).
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