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Predicting Onset of Improvement under Antidepressants and Antipsychotics

Individual-Case Approach

Using the "individual-case" approach, we have investigated the time course of improvement under antidepressants in a sample of 2’788 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.

Biological Predisposition

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, resilience-related 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.

Molecular-Genetic Discrimination Between Early-, Late-, and Non-Improvers

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 resilience-related 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

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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 2008 (submitted for publication)
discrimination
Fig. 8a: Genetic vector space spanned by 23 polymorphisms within candidate genes revealed clear differences on the genotype level between response groups under psychotropic drugs: circles designate non-improvers (n = 53), triangles early improvers (n = 123), and squares late improvers (n = 81). The 257 patients were projected onto the hyperplane through the eigenvectors associated with the 2 largest eigenvalues.
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