Exposure, D-Cycloserine Enhancement, and Genetic Modulators in Panic Disorder

In this application, the investigators propose to further validate and expand upon one of the
apparent striking successes of translational research. Specifically, basic research on the
neural circuitry underlying fear extinction led to the examination of d-cycloserine (DCS), a
partial agonist of the NMDA receptor in the amygdala, as an agent capable of enhancing
extinction learning (Davis et al., 2006; Davis et al., in press). Following successful
validation of this strategy in the animal laboratory (see Ledgerwood et al., 2005; Richardson
et al., 2004), Ressler et al. (2004) showed that single doses of d-cycloserine (DCS) could
enhance extinction in a human exposure paradigm for height phobic adults. This exciting
initial finding was replicated by this research team for the treatment of social anxiety
disorder (Hofmann et al., 2006), as well as an initial pilot study of the treatment of panic
disorder (Tolin et al., 2006). As discussed by Anderson and Insel (2006), these findings have
the potential to foster significant advances in the treatment of anxiety disorders. The
present study represents the further application of DCS for augmenting the effects of
exposure-based cognitive-behavior therapy (CBT), now applied to the treatment of panic
disorder with or without agoraphobia.

In the current application, the investigators propose a five-year study to show the acute and
longer-term effects of DCS augmentation of exposure-based CBT relative to placebo
augmentation. This study is noteworthy for the use of a brief treatment strategy that has
been shown to be successful in previous trials (e.g., Clark et al., 1999; Roy-Byrne et al.,
2005) and has served as the basis for the DCS augmentation effect seen in a pilot study for
this application. By demonstrating that DCS can enhance the results of even a brief treatment
strategy, the investigators are seeking to validate an approach that fits well with the
practice limitations and applications of CBT in effectiveness studies (e.g., Katon et al.,
2006; Roy-Byrne et al. 2005). Furthermore, by studying the genetic predictors of the overall
response to CBT, and DCS augmentation in particular, the investigators hope to further
elucidate the nature of DCS augmentation and the selection of particularly responsive
subgroups of patients in need. This agenda is in accords with "the ultimate goal of
personalized therapy: identifying individual patterns of pathophysiology that indicate which
pharmacological or behavioral treatment will be most useful for any individual patient"
(Anderson & Insel, 2006, p. 320).

The study design is a double blind, randomized, controlled, trial conducted at three
treatment sites. Patient with panic disorder will randomly receive DCS or placebo 1 hour
prior to sessions 3-5 of a 5-session CBT protocol that includes 2 additional booster sessions
over the course of follow-up. Patients will be enrolled over 5 years with the identical
treatment protocol followed at each of the sites. Sites will nonetheless differ with respect
to study management and analysis procedures.

Inclusion Criteria:

- Male or female outpatients > 18 years of age with a primary psychiatric diagnosis of
panic disorder with or without agoraphobia

- CGI-severity score of 4 or higher

- Physical examination and laboratory findings without clinically significant
abnormalities

- Off concurrent psychotropic medication for at least 2 weeks prior to initiation of
randomized treatment, OR stable on current medication for a minimum of 6 weeks and
willing to maintain a stable dose

- Willingness and ability to comply with the requirements of the study protocol

Exclusion Criteria:

- Agoraphobia sufficiently severe as to limit patient's ability to travel to and
participate in weekly sessions Posttraumatic stress disorder, substance use disorder,
eating disorder, or organic mental disorder within the past 6 months

- Lifetime history of psychotic disorder, bipolar disorder, or developmental disorder

- Significant suicidal ideation or suicidal behaviors within the past 6 months

- Significant personality dysfunction likely to interfere with study participation

- Serious medical illness or instability for which hospitalization may be likely within
the next year

- Patients with a current or past history of seizures (other than febrile seizures in
childhood)

- Pregnant women, lactating women, and women of childbearing potential who are not using
medically accepted forms of contraception

- Concurrent psychotherapy initiated within 3 months of baseline, or ongoing
psychotherapy of any duration directed specifically toward treatment of the panic
disorder other than general supportive therapy initiated at least 3 months prior to
study

- Prior adequate trial of CBT for panic disorder