This is a 5-year double blind, randomized, controlled, trial conducted at three treatment sites, aimed at showing the acute and longer-term effects of DCS augmentation of exposure-based CBT for panic disorder relative to placebo augmentation. 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.

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

Adverse events were monitored and elicited by open questioning of the study clinician, assessing adverse events occurring over the last hour as well as during the week following the last dose of DCS. AEs and SAEs were informally assessed up to the 6-month follow-up.

The investigators did not systematically collect fear estimates across exposure and are therefore unable to examine this factor as a moderator.

Unexpected site effects were observed for several of our outcome variables.