PANIK-Netz: Teilprojekt P4

Experimental pharmacology of exposure treatment and relearning
in panic disorder

Principal Investigator
Priv.-Doz. Dr. med. Andreas Ströhle
Department of Psychiatry and Psychotherapy
Campus Charité Mitte
Charité – University Medicine Berlin
Schumannstr. 20/21
10117 Berlin, Germany
Phone: 030 450517034
Fax: 030 450517934

Duration applied for
3 years

Project Description
Introduction/state of the art
The success of some antidepressants and CBT in the treatment of anxiety disorders such as panic disorder have led to the hope that these two approaches can be combined for a more powerful treatment. However, until now this hope is not unequivocally supported by empirical data and some studies suggest that combining treatment strategies in this way may even decrease the overall efficacy (Barlow et al. 2000). An alternative strategy to use both pharmacological and psychotherapeutic treatment may be to pharmacologically enhance relearning in psychotherapy.
Within cognitive behavioral therapy relearning is a central mechanism by which behavioral changes are thought to occur. Behavioral exposure as a key component of this psychological treatment bears procedural similarities to extinction of conditioned fear in animal models. The neural processes of underlying fear extinction have recently been found to be mediated in similar (fear network) brain regions as the ones implicated in fear conditioning. Both processes may even depend on the same or closely related molecular and cellular mechanisms. Both fear learning and extinction are blocked by antagonists at the NMDA receptor, whereas D-cycloserine, a partial agonist at the NMDA receptor augments learning in animal and human models of anxiety (Walker et al. 2002; Ressler et al. 2004). Preclinical studies suggest that the cannabinoid (CB) receptor 1 is critically involved in fear extinction as well (Marsicano et al. 2002). Additionally, the GABAA receptor and the cholinergic neurotransmission play important roles for fear, anxiety modulation and relearning. In patients with acrophobia D-cycloserine facilitated the clinical effects of virtual reality exposure (Ressler et al. 2004). “Cognitive enhancers” may be effective in exposure therapy of other anxiety disorders like panic disorder or posttraumatic stress disorder as well. Clinical and preclinical studies have provided substantial evidence that stress response alterations play a major role in the pathophysiology and therapy of major depression, panic disorder and posttraumatic stress disorder (Ströhle and Holsboer 2003). The hypothalamic pituitary adrenocortical (HPA) system and its modulation by CRH, corticosteroids and their receptors have been characterized in panic disorder patients and a role of central CRH in panic attacks has been suggested. However, no empirical data could demonstrate this release directly. In the context of exposure therapy, situationally triggered panic attacks were not accompanied by an increase in cortisol concentrations. CCK-4-induced panic attacks however, are accompanied by an exaggerated ACTH secretion, providing evidence for an enhanced pituitary ACTH secretion during panic attacks despite unchanged cortisol concentrations and points to a possible role of CRH in these attacks (Ströhle et al. 2000). Recent data further suggest a major role of 3α-reduced neuroactive steroids in panic attacks and panic disorder patients (Ströhle et al. 2002 & 2003).
The use of panicogenic challenges like sodium lactate, CO2 or cholecystokinin tetrapeptide (CCK-4) in panic disorder is unique in that the clinical phenomenon of central interest (i.e., the panic attack) can readily be provoked and assessed in the clinical laboratory setting. Uses of this approach allow for the generation and testing of hypotheses regarding the underlying neurobiology of the disorder, the identification of pathophysiologically distinct diagnostic subtypes, and the delineation of the effects and mechanisms of action of various treatments, the study of new treatment approaches, and clinical applications as a diagnostic test, as a means of assessing treatment adequacy (Ströhle 2003). Interestingly, repeated exposure to induced panic attacks can be used in the treatment of panic disorder as well and may therefore serve as a standardized model of exposure therapy. Recently, we could describe a central role of GABAA receptor modulating neuroactive steroids in induced panic attacks of patients with panic disorder (Ströhle et al. 2002, 2003). These findings seem to be unique in that patients with panic disorder respond qualitatively, not only quantitatively, different from healthy control subjects. However, the role of neuroactive steroids in spontaneous or situational panic attacks has not been studied.
Although exposure to agoraphobic situations and panic attacks is a central part of cognitive behavioral treatment of panic disorder and agoraphobia, the physiological and neuroendocrine correlates and the relationship to clinical response as well as the effects of a pharmacological modulation have not been studied in panic disorder patients.

Exposure during cognitive behavioral treatment of panic disorder will be studied accompanied by pharmacological modulation. In this randomized placebo-controlled pilot study the following questions will be addressed:
1. Does the additional administration of D-cycloserine increase the effectiveness of exposure during cognitive behavioral treatment in panic disorder?
2. How does pharmacological support of exposure therapy affect the neuroendocrine changes?
3. What are the neuroendocrine correlates of exposure during cognitive behavioral treatment in panic disorder?

Own previous work and resources
Over the past ten years the principal investigator has performed multiple studies on the neurobiology, neuroendocrinology and neuropsychopharmacology of panic disorder as head of the research group Neurobiology of Anxiety at the Max Planck Institute of Psychiatry. Since 2002 at the Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Berlin, he has established the largest panic disorder outpatient clinic in the city. Within this outpatient clinic he has established and evaluated a standardized 4-week group CBT treatment for patients with panic disorder containing repeated therapist-guided exposure exercises in-vivo.

Ströhle A., Kellner M., Yassouridis A., Holsboer F., Wiedemann K. (1998) Effect of flumazenil in lactatesensitive patients with panic disorder. American Journal of Psychiatry 155:610-612.
Ströhle A., Kellner M., Holsboer F., Wiedemann K. (2001) Anxiolytic activity of atrial natriuretic peptide in patients with panic disorder. American Journal of Psychiatry 158:1514-1516.
Ströhle A., Romeo E., di Michele F., Pasini A., Yassouridis A., Holsboer F., Rupprecht R. (2002) GABAA receptor modulatory neuroactive steroid composition in panic disorder before and during paroxetine treatment. American Journal of Psychiatry 159:145-147.
Ströhle A., Romeo E., di Michele F., Pasini A., Hermann B., Gajewsky G., Holsboer F, Rupprecht R. (2003) Induced panic attacks shift GABAA receptor modulatory neuroactive steroid composition in patients with panic disorder. Archives of General Psychiatry 60:161-168.
Ströhle A., Feller C., Onken M., Godemann F., Heinz A., Dimeo F (2005) Acute antipanic activity of aerobic exercise. American Journal of Psychiatry 162(12).

The Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Berlin, has all equipment necessary for studying pharmacological modulation of exposure therapy in patients with panic disorder. The core group consists of Priv.-Doz. Dr. med. A. Ströhle, Dr. med. F. Godemann, Dipl. Psych. A. Siegmund, Dr. med. J. Winterer, C. Feller and M. Scheel. For the statistical analysis support can be obtained from Dr. A. Yassouridis (Max Planck Institute of Psychiatry, Munich).

Work program
Exposure during cognitive behavioral treatment in panic disorder will be studied clinically and physiologically within a randomized placebo-controlled design and the additional administration of D-cycloserine. Within a standardized 4-week CBT treatment four therapist-guided exposure exercises in-vivo will be performed. Two to four hours before exposure treatment patients receive either 500 mg D-cycloserine or placebo. The primary outcome measures are: the number of panic attacks, severity of agoraphobic avoidance, the Hamilton-A total score and the overall severity of panic disorder measured with the Panic and Agoraphobia Scale. Clinical follow-up data of the patients will be collected 1 and 3 months after the end of treatment. From our previous experience we expect a drop-out rate of 10%. With complete data of 20 panic disorder patients per group, the effects of a pharmacological cotreatment are expected with alpha=5% and a power of 80% (1-beta).
We hypothesize that D-cycloserine treated patients will have a more pronounced clinical improvement following in-vivo exposure treatment. This clinical improvement is also expected at follow-up one and three months after the end of treatment. Blood samples for HPA system hormones (ACTH and cortisol) and the GABAA receptor modulatory neuroactive steroid 3α,5α-tetrahydroprogesterone (3α,5α-THP) and ist stereoisomers 3α,5β-THP and 3β,5α-THP as well as their precursor progesterone will be taken at baseline and after therapist guided exposure treatment in-vivo. Neuroactive steroid determinations will be performed by means of a highly sensitive combined gas chromatography/mass spectrometry analysis (GC/MS) (Ströhle et al. 2003). After extraction and separation by thin layer chromatography (TLC), the eluate containing 3α,5α-THP, 3α,5β- THP, 3β,5α-THP and progesterone will lyophilized and derivatized with heptafluorobutyric acid anhydride (HFBAA). A Finningham Trace GC/MS equipped with a capillary column is used to analyze the derivatized steroids in the negative ion chemical ionization mode, in the single ion monitoring. ACTH plasma immunoreactivity will be measured using a commercially available immunoradiometric assay. For cortisol a commercial radioimmunoassay kit will be employed. Exposure induced anxiety is hypothesized to be accompanied by changes in neuroactive steroid composition that may result in decreased GABAA receptor mediated neuronal activity. A decrease in positive allosteric modulators of GABAA receptors (3α,5α-THP, 3α,5β-THP) and an increase in the functional antagonist for GABAA-agonistic steroids 3β,5α-THP is expected. Repeated exposure in-vivo will be accompanied by changes in neuroactive steroid composition that may result in increased GABAA receptor mediated neuronal activity. These changes will be more pronounced in D-cycloserine treated patients. We further hypothesize that during repeated exposure the HPA system response habituates and that this habituation is faster in D-cycloserine treated patients.

Time frame:
Recruiting, treating and studying patients: Year 1-2; Cortisol, ACTH and neuroactive steroid determinations and data analysis: Year 3.