Europe PMC Funders Group Author Manuscript World J Biol Psychiatry. Author manuscript; available in PMC 2017 April 01. Published in final edited form as: World J Biol Psychiatry. 2017 April ; 18(3): 162–214. doi:10.1080/15622975.2016.1190867. Europe PMC Funders Author Manuscripts Biological markers for anxiety disorders, OCD and PTSD: A consensus statement. Part II: Neurochemistry, neurophysiology and neurocognition Borwin Bandelowa, David Baldwinb, Marianna Abellic, Blanca Bolea-Alamanaci, Michel Bourine, Samuel R. Chamberlainf,g, Eduardo Cinosih, Simon Daviesd,i, Katharina Domschkej, Naomi Finebergf, Edna Grünblattj,k,l,m, Marek Jareman, Yong-Ku Kimo, Eduard Maronp,q,t, Vasileios Masdrakisr, Olya Mikovas, David Nuttt, Stefano Pallantiu, Stefano Pinic, Andreas Ströhlev, Florence Thibautw, Matilde M. Vaghixx, Eunsoo Wono, Dirk Wedekinda, Adam Wichniakn, Jade Woolleyb, Peter Zwanzgery,z, and Peter Riedererj aDepartment of Psychiatry and Psychotherapy, University of Göttingen, Germany bFaculty of Medicine, University of Southampton, Southampton, UK cDepartment of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Pisa, Italy dCentre for Addiction and Mental Health, Geriatric Psychiatry Division, University of Toronto, Toronto, Canada eNeurobiology of Anxiety and Mood Disorders, University of Nantes, Nantes, France fHertfordshire Partnership University NHS Foundation Trust and University of Hertfordshire, Parkway, UK gDepartment of Psychiatry, University of Cambridge, Cambridge, UK hDepartment of Neuroscience Imaging and Clinical Sciences, Gabriele D’Annunzio University, Chieti, Italy iSchool Europe PMC Funders Author Manuscripts of Social and Community Medicine, Academic Unit of Psychiatry, University of Bristol, Bristol, UK jDepartment of Psychiatry Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany kDepartment of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Zurich, Switzerland lNeuroscience Center Zurich, University of Zurich and the ETH Zurich, Zurich, Switzerland mZurich Center for Integrative CONTACT Prof. Dr. Borwin Bandelow [email protected] von-Siebold-Str. 5, Department of Psychiatry and Psychotherapy, University of Göttingen D-37075 Göttingen, Germany. All other authors reported no conflicts of interest to declare. ORCID Borwin Bandelow http://orcid.org/0000-0003-2511-3768 Marianna Abelli http://orcid.org/0000-0002-3877-7048 Michel Bourin http://orcid.org/0000-0002-7268-4590 Samuel R. Chamberlain http://orcid.org/0000-0001-7014-8121 Eduardo Cinosi http://orcid.org/0000-0002-8903-181X Naomi Fineberg http://orcid.org/0000-0003-1158-6900 Edna Grünblatt http://orcid.org/0000-0001-8505-7265 Marek Jarema http://orcid.org/0000-0001-5267-5315 Yong-Ku Kim http://orcid.org/0000-0001-5694-7840 Vasileios Masdrakis http://orcid.org/0000-0003-0197-9583 David Nutt http://orcid.org/0000-0002-1286-1401 Stefano Pallanti http://orcid.org/0000-0001-5828-4868 Stefano Pini http://orcid.org/0000-0001-9092-9144 Florence Thibaut http://orcid.org/0000-0002-0204-5435 Matilde M. Vaghi http://orcid.org/0000-0002-0999-9055 Eunsoo Won http://orcid.org/0000-0001-6825-032X Peter Zwanzger http://orcid.org/0000-0002-5385-8188 Bandelow et al. Page 2 Human Physiology, University of Zurich, Zurich, Switzerland nThird Department of Psychiatry, Institute of Psychiatry and Neurology, Warszawa, Poland oDepartment of Psychiatry College of Medicine, Korea University, Seoul, Republic of Korea pDepartment of Psychiatry, North Estonia Medical Centre, Tallinn, Estonia qDepartment of Psychiatry, University of Tartu, Estonia rAthens Europe PMC Funders Author Manuscripts University Medical School, First Department of Psychiatry, Eginition Hospital, Athens, Greece sFoundation Biological Psychiatry, Sofia, Bulgaria tFaculty of Medicine Department of Medicine, Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, UK uUC Davis Department of Psychiatry and Behavioural Sciences, Sacramento, CA, USA vDepartment of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité – University Medica Center Berlin, Berlin, Germany wFaculty of Medicine Paris Descartes, University Hospital Cochin, Paris, France xDepartment of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK ykbo-Inn-Salzach-Klinikum Wasserburg am Inn, Germany zDepartment of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany Abstract Objective—Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD). Methods—Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network. Europe PMC Funders Author Manuscripts Results—The present article (Part II) summarises findings on potential biomarkers in neurochemistry (neurotransmitters such as serotonin, norepinephrine, dopamine or GABA, neuropeptides such as cholecystokinin, neurokinins, atrial natriuretic peptide, or oxytocin, the HPA axis, neurotrophic factors such as NGF and BDNF, immunology and CO2 hypersensitivity), neurophysiology (EEG, heart rate variability) and neurocognition. The accompanying paper (Part I) focuses on neuroimaging and genetics. Conclusions—Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high quality research has accumulated that should improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD. Keywords Anxiety disorders; neuroimaging; genetic; neurochemistry; neurobiology; review Introduction This consensus statement on biological markers of anxiety disorders was organised by members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the Anxiety Disorders Research Network (ADRN) within the World J Biol Psychiatry. Author manuscript; available in PMC 2017 April 01. Bandelow et al. Page 3 European College of Neuropsychopharmacology Network Initiative (ECNP-NI; Baldwin et al. 2010), an initiative intended to meet the goal of extending current understanding of the causes of central nervous system (CNS) disorders, thereby contributing to improvements in clinical outcomes and reducing the associated societal burden. Europe PMC Funders Author Manuscripts The present article (Part II) summarises the findings on potential biomarkers in neurochemistry, neurophysiology, and neurocognition. Part I (Bandelow et al. 2016) focuses on neuroimaging and genetics. Neurochemistry Plasma appears to be a rational source for proteomic and metabolomic measurements in psychiatric conditions because it is easily accessible, and several molecules from the brain are transported across the blood–brain barrier and reach the peripheral circulation. However, it is difficult to draw inferences from the neurochemical composition of plasma on the situation in brain cells. Lumbar puncture is an invasive method, and the composition of cerebrospinal fluid (CSF) does not reflect exactly the neurochemistry in brain cells. Nevertheless, as a biomarker measure, such recourses are highly valuable, and several examples of evidence in the literature points to possible links between CNS and periphery. In the following sections, some of these findings are listed and described. Neurotransmitters Monoaminergic systems have long been suggested to play a major role in depression and anxiety disorders. While the “reward system” is modulated by endogenous dopamine and opioids (Barbano & Cador 2007; Berridge & Aldridge 2008; Le Merrer et al. 2009; Bandelow & Wedekind 2015), the “punishment system” is mainly driven by serotonin (5- Europe PMC Funders Author Manuscripts HT; Stein 1971; Daw et al. 2002). Goal-directed behaviours are stimulated by dopamine (DA), and dopamine neurons have been suggested to be a substrate for intracranial self- stimulation (Wise & Bozarth 1982; Mason & Angel 1984; Aboitiz 2009). Norepinephrine (noradrenaline; NE) has been connected to “emotional memory” and the consolidation and retrieval of the emotional arousal induced by particular behaviours (van Praag et al. 1990; Goddard et al. 2010). NE neurons regulate vulnerability to social defeat through inhibitory control of ventral tegmental area DA neurones (Isingrini et al. 2016). Serotonergic system—Findings on brain imaging and genetics of the serotonin system are summarised in Part I (Bandelow et al. 2016). 5-HT is a monoamine, found in the CNS, in blood platelets, and the gastrointestinal tract. The principal source of serotonin release in the brain are the raphe nuclei in the brainstem. They are hypothesised to have a dual role in aversive contingencies (Deakin & Graeff 1991; Deakin 2013). 5-HT can inhibit periaqueductal grey matter-medicated fight/flight responses from threats, while it can also facilitate amygdala-mediated anxiety responses. The latter mechanism has been demonstrated both in animals (Deakin & Graeff 1991; Deakin 2013) and humans (Blanchard et al. 2001; Mobbs et al. 2007; Feinstein et al. 2013). Such differences may explain partly