Human genome-guided identification of memory-modulating drugs
2013, Papassotiropoulos, Andreas, Gerhards, Christiane, Heck, Angela, Ackermann, Sandra, Aerni, Amanda, Schicktanz, Nathalie, Auschra, Bianca, Demougin, Philippe, Mumme, Eva, Elbert, Thomas, Ertl, Verena, Gschwind, Leo, Hanser, Edveena, Huynh, Kim-Dung, Jessen, Frank, Kolassa, Iris-Tatjana, Milnik, Annette, Paganetti, Paolo, Spalek, Klara, Vogler, Christian, Muhs, Andreas, Pfeifer, Andrea, de Quervain, Dominique J.-F.
In the last decade there has been an exponential increase in knowledge about the genetic basis of complex human traits, including neuropsychiatric disorders. It is not clear, however, to what extent this knowledge can be used as a starting point for drug identification, one of the central hopes of the human genome project. The aim of the present study was to identify memory-modulating compounds through the use of human genetic information. We performed a multinational collaborative study, which included assessment of aversive memory—a trait central to posttraumatic stress disorder—and a gene-set analysis in healthy individuals. We identified 20 potential drug target genes in two genomewide-corrected gene sets: the neuroactive ligand–receptor interaction and the long-term depression gene set. In a subsequent double-blind, placebo-controlled study in healthy volunteers, we aimed at providing a proof of concept for the genome-guided identification of memory modulating compounds. Pharmacological intervention at the neuroactive ligand–receptor interaction gene set led to significant reduction of aversive memory. The findings demonstrate that genome information, along with appropriate data mining methodology, can be used as a starting point for the identification of memory-modulating compounds.
Spontaneous Remission From PTSD Depends on the Number of Traumatic Event Types Experienced
2010, Kolassa, Iris-Tatjana, Ertl, Verena, Eckart, Cindy, Kolassa, Stephan, Onyut, Lamaro Patience, Elbert, Thomas
As exposure to different types of traumatic stressors increases, the prevalence of PTSD increases. However, little is known about the effects of cumulative exposure to traumatic stress on the maintenance and remission from PTSD. In 2006/2007, we investigated 444 refugees from the 1994 Rwandan genocide, assessing exposure to traumatic events, current and lifetime PTSD, and PTSD symptom severity. Higher trauma exposure was associated with higher prevalence of current and lifetime PTSD, with lower probability of spontaneous remission from PTSD, and with higher current and lifetime PTSD symptom severity in clear dose-response effects. The results suggest traumatic load as a root cause of both PTSD chronicity and symptom severity and support the hypothesis of a neural fear network in the etiology of PTSD.
No PTSD-related differences in diurnal cortisol profiles of genocide survivors
2009, Eckart, Cindy, Engler, Harald, Riether, Carsten, Kolassa, Stephan, Elbert, Thomas, Kolassa, Iris-Tatjana
Posttraumatic stress disorder (PTSD) has been associated with reduced cortisol levels. Opposing results have been interpreted as resulting from methodological differences between studies.We investigated the diurnal profile of salivary cortisol in a population of highly traumatized adult males from Rwanda with and without PTSD, who spent the whole day of examination together under amaximally standardized schedule. Besides the detection of PTSDrelated alterations in cortisol release we aimed at determining physiologically relevant effects of cumulative trauma exposure on HPA functioning in interaction with or independent of diagnosis. There were no differences in the diurnal pattern of cortisol release between subjects with and without PTSD. We observed an increasing prevalence of PTSD with increasing number of different traumatic event types experienced, replicating earlier results on a building-block effect of multiple traumatization. However, size of cumulative exposure was not related to any of the cortisol measures. The results suggest that besides methodological constraints also confounding factors not previously controlled for, e.g., sex differences or current life stress, might contribute to the diverging results of lowered, unchanged or enhanced cortisol secretion in PTSD. Future research should therefore closely monitor these possible confounds to optimize models for cortisol in research on stress-dependent illnesses.