Breathomics (Breath gas markers) for clinical states and NMDAR functioning in depression”

Brain disorders cost Europe almost €800 billion (US$1 trillion) a year - more than cancer, cardiovascular disease and diabetes put together. One of the most common psychiatric disorder is major depressive disorder (MDD) that can effectively be treated with psychotherapy and/or antidepressants acting at serotonergic, noradrenergic and nowerdays glutamatergic neurotransmission. However, still one third of patients do not respond to at least two different serotonergic/noradrenergic antidepressant trials and might need as early as possible different treatment options.

There is compelling evidence that environmental stress, in particular through the action of glucocorticoids, induces enhancement of excitatory (glutatmatergic) neurostransmission leading to dendritic remodeling in a number of brain regions associated with behavioural changes(1). This hypothesis is known as glutamate hypothesis of depression. Glutamate acts on postsynaptic glutamate receptors to regulate several neuronal functions, such as neuronal migration, excitability, plasticity, long-term potentiation (LTP) and long-term depression (LTD). Glutamate receptors are transmembrane proteins and are numerous with the N-Methyl-D-Apartate receptor (NMDAR) involved in depression pathology. NMDAR hyperfunction is proposed to lead to excitotoxic atrophy which could contribute to depressive traits(2). In line with this finding, substances that inhibit NMDA receptors like ketamine have recently been found to be a novel possibility to improve depressive symptomatology rapidly(3)and thus are highly warranted novel therapy options.

The glutamate system is the major neurotransmitter system in the brain and is influenced by many other molecular pathways known to be affected in MDD. Brain’s glutamate cannot easily be measured, but indirectly it might be possible to obtain signatures associated with the glutamatergic system. Within the current study we propose to identify non-invasive and easy to use signatures by use of breath gas mass spectrometry and to investigate their association with established glutamatergic markers derived from electrophysiology and 7 T MR Spectroscopy.

Because the lungs act as a gas exchanger between the internal and external environment, the impact of disorders like MDD may be easily assessed through the analysis of exhaled breath. Breath gas analysis was recently successfully applied by our cooperation partner Prof. Hoeschen at the department for medical techniques of our university in humans and animal experimental research.
This technique was recently successfully applied in a human study with patients with diabetes (personal communication and(4)), thus demonstrating clinical applicability.
Goal of the study is to investigate
(1) whether expiratory breath gas includes VOCs that can distinguish patients with clinical diagnosed MDD from age and gender matched healthy controls and whether these signatures are associated with severity of depression and anxiety.

(2) if there is an association between cortisol awakening response, an often used biological test in MDD, and breath gas awakening response in MDD.

(3) which signatures from breath gas are associated with glutamatergic neurotransmission as derived by MR-spectroscopy and EEG/EP measures (in a subsample of 20 patients with MDD).

(4) which signatures from breath gas are associated with current and past stress experiences.