Coming Soon: Newer Generation Antidepressant From Max Planck

Recently, scientists from the Max Planck Institute for Psychiatry (Munich) have carried out studies on the genomes of 4,088 patients and 11,001 healthy control subjects from all over the world. They have identified a new risk gene variant for depression. They were able to show genetic correlation with depression. They demonstrated physiologically measurable changes in the brains of healthy carriers of this risk allele which affected a transporter protein involved in the production of an important neuronal transmitter. Since, traditional drugs interact with similar transporter molecules; the researchers believe this factor as the target structure of future antidepressant medication.

Over the past several years, studies have been carried out to identify the genetic causes of depression. Such a study is also carried out by Martin Kohli, Susanne Lucae, Bertram Müller-Myhsok and Elisabeth Binder. While comparing the genetic material of depressive patients with that of healthy control subjects,the researchers discovered that the individual base exchanges, so-called single-nucleotide polymorphisms (SNP), clearly arose in the context of major depression. The researchers were very disappointed, however, when they had to establish that this section on the chromosome does not contain any genes. "Instead of getting our hands on a 'depression gene', we found ourselves back in a 'genetic desert' so to speak," Florian Holsboer, Director of the Max Planck Institute for Psychiatry in Munich, explains.

Hence, the scientists wondered whether a gene located further away could possibly be influenced by the genetic variation and whether susceptibility for depression could arise that way. In this case, the SLC6A15 gene was identified as a promising candidate. SLC6A15 is involved in the transportation of amino acids like proline and leucine to the contact sites of neurons in the brain, known as synapses. It may therefore be also involved in the regulation of glutamate which is an important excitatory neurotransmitter found in neurons. Leucine is a structural precursor of glutamate. "Because it is assumed that the communication between the neuron clusters is disturbed in depression, we considered whether the gene we had identified could possibly influence this process through glutamate," explains Elisabeth Binder, research group leader at the MPI.

Subsequently, the Max Planck scientists have succeeded in showing that the changes in the DNA sequence located a total of 287,000 bases away from the gene influenced its activity. Therefore, cells of the risk genotype displayed a lower level of gene activity than cells carrying the protective genotype. Moreover, tests carried out using the magnetic resonance imaging scanner confirmed that even healthy subjects who are carriers of the risk allele have smaller amounts of the brain metabolic substances N-acetylaspartate (NAA) and glutamate (Glx) compared to healthy subjects without genetic susceptibility.

Morphological changes such as shrinking of certain brain regions may also arise in the course of major depression. This can eventually be observed in depressive patients. Therefore, in addition to genetic susceptibility, other factors must affect the organism to trigger the development of major depression. Stress is considered as an important environmental factor in the depression and research on this aspect has been carried out for many years at the Max Planck Institute for Psychiatry. It has been found, for example, that the likelihood of developing the disease is raised by a factor of two to three if a person is exposed to chronic social stress.