A randomized placebo controlled multi-center study

The difficult to treat anxiety patient: New treatment approaches

​Approximately 30-40% of patients with anxiety disorders respond poorly to the documented effective exposure-based psychological treatments and are not helped by traditional pharmacological interventions1-2. This group of Difficult to treat anxiety patients (DTAP) exceeds in number patients with psychosis or bi-polar affective disorders3, and is overrepresented among the increase in the number of young disability cases seen in Norway the recent years. Thus, improved help to the DTAP would have immense consequences for the individual patient as well as for the health care system and the society. An obvious, but nearly unexplored possibility for the sub-optimal response to exposure-based treatments seen in the DTAP is that the variability in treatment response reflects fundamental differences in neural processing of emotional learning, and fear processing in particular. Fear-processing is dependent on N-methyl-D-aspartate (NMDA) receptors in amygdala and prefrontal cortex.   

The aim of the current study is to investigate if the combination of concentrated, prolonged exposure-based treatment (The Bergen 4-day treatment) and the NMDA agonist d-cyloserine (DCS), enhance and stabilize treatment effects for this group of patients.

The study includes 160 difficult to treat anxiety patients (DTAP) who all receive The Bergen 4-day treatment and are randomly assigned to receive an addition of either DCS or a pill placebo. In order to reduce unwanted variability associated with diagnostic heterogeneity and at the same time target perhaps the most debilitating and complex anxiety disorder, Obsessive Compulsive Disorder (OCD) was chosen as the model disorder. If the approach is successful, it will be extended to panic disorder, generalized anxiety disorder and Post Traumatic Stress Disorder (PTSD), as well as to children and adolescents.

The study is lead by Haukeland University Hospital (Bergen) with professor Gerd Kvale (PI) and Bjarne Hansen (co-PI). The following persons are leaders/ representatives of the partner-sites: Psychiatrist Gunvor Launes (Sørlandet Hospital), Psychologist Svein Haseth (St. Olavs University Hospital), Psychiatrist Unn Beate Kristensen (Oslo University Hospital) and Psychologist Kristen Hagen (Molde Hospital).

The core research group: Gerd Kvale (PI), Bjarne Hansen (co-PI), Professor emeritus Lars-Göran Öst (Stockholm University), Professor Emeritus Michael Davis, Robert W. Woodruff Professor of Psychiatry, Behavioral Sciences and Psychology, Department of Psychiatry, Emory University School of Medicine, Professor Joseph Himle, University of Michigan at Ann Arbor, Professor Jonathan Abramowitz, Universtity of North Carolina at Chapel Hill and Associate Professor Martin Franklin, University of Pennsylvania.

Scientific advisory board: Professor Ole Andreassen, Oslo Universitetssykehus/UiO; Professor Gunnar Morken, NTNU/St.Olavs Hospital; Professor Hans Nordahl, St. Olavs Hospital/NTNU; Professor Egil Martinsen, Oslo Universitetssykehus/UiO; Professor Ketil Ødegaard, Haukeland Universitetssykehus/ UiB; Førsteamanuensis Vegar Haaland, Sykehuset Sørlandet/ UiO; Leader of ANANKE (patient organization), Arne Strand.

The inclusion of patients in this study was completed August 2017.


1. Abramowitz, J., B. Deacon, J. and S. Whiteside, P.J. (2011). Exposure Therapy for Anxiety: Principles and Practice New York, Guilford Press.
2. Kvale, G., O. E. Havik, E. R. Heiervang, B. S. M. Haugland and T. Tangen (2013). Hvordan sikre angstpasienter kunnskapsbasert behandling? Oslo, Universitetsforlaget.
3. Perala, J., J. Suvisaari, S. I. Saarni, K. Kuoppasalmi, E. Isometsa, S. Pirkola, T. Partonen, A. Tuulio-Henriksson, J. Hintikka, T. Kieseppa, T. Harkanen, S. Koskinen and J. Lonnqvist (2007). "Lifetime prevalence of psychotic and bipolar I disorders in a general population." Arch Gen Psychiatry 64(1): 19-28.
4. Knudsen, A. K., S. Overland, M. Hotopf and A. Mykletun (2012). "Lost working years due to mental disorders: an analysis of the Norwegian disability pension registry." PLoS One 7(8): e42567.

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