D-cycloserine augmented single-session CBT for panic disorder

All of us are familiar with occasional feelings of panic, but for at least 5 out of every 100 of us, this becomes problematic and can be clinically diagnosed as panic disorder. It is characterised by intense and sudden physical symptoms, such as extreme palpitations or dizziness and is usually accompanied by a fear of death or dying. Half of the patients also develop agoraphobia, where certain situations are avoided for fear of experiencing further attacks, and a patient may become effectively house bound.

Treatment of panic disorder is usually with a psychological intervention such as cognitive-behavioural therapy (CBT) or with a drug treatment like a serotonin reuptake inhibitor (SSRI). These treatments are effective, but for CBT, the courses are long and cost-intensive and access to treatment is difficult. For the drug treatment, symptoms usually return when the patient stops their SSRI medication, and for both interventions there is a subgroup of patients who do not get better at all.

To improve treatments, it is important to identify how they are working and why both psychological and drug treatments can have similar effects. Our recent work suggests that both CBT and drug treatments used for panic disorder affect the way in which the brain processes threatening information and that such effects can be seen very early on in treatment before the patient notices subjectively that anything has changed. Moreover, these early changes on emotional processing are related to how well the patient responds to treatment in the longer term. Interventions which boost these early effects on emotional processing may therefore improve the efficacy of treatment for panic disorder.

This proposal aims to test the effects of a single session CBT approach, which we have shown has clear effects on the response to threatening information, with a pharmacological treatment thought to improve the generalisation and durability of these effects. Research in rodents suggests that the antibiotic d-cycloserine (DCS) improves learning and memory by stimulating a mechanism in the brain which plays a core role in our ability to make new connections and retain information. This study will establish the potential of the novel combination of the single-session CBT treatment with the pharmacological agent DCS as a stand-alone treatment for panic disorder with agoraphobia, and it will determine the basic mechanisms of such an augmentation effect. In particular, we will investigate i) whether the combination treatment improves the impact of single-session CBT on clinical symptom severity, with greater response during a 4-weeks follow-up period, ii) whether such an augmentation effect remains stable over a 6-months follow-up period, and iii) the cognitive and neural mechanisms underlying DCS augmented single-session CBT. The findings will have crucial implications for the development of a new and cost-economic treatment with the potential for low-threshold access for a higher number of patients with anxiety disorders.

Panic disorder (PD) is associated with high disability and economic burden, and conventional treatments are cost-intensive. Understanding the basic mechanisms of treatment action is essential to elucidate key proxy markers for treatment improvement and patient stratification. We have recently shown that hypervigilance to threat is normalised the day after a single session of CBT, highlighting processing change as a key mechanism of CBT action. These early changes were predictive of symptom improvement after a further 4 weeks and led to remission in 30% of treated compared to 0% of untreated patients. The proposed study aims to assess whether this efficacy can be improved by the addition of the NMDA receptor agonist d-cycloserine (DCS), known to improve retention of information by enhancing markers of neural plasticity. This pharmacological strategy has previously been applied to standard CBT and found to double its overall efficacy. We will establish the combination of single-session CBT with DCS as a stand-alone treatment, and we will determine the cognitive and neural basic mechanisms of such an augmentation effect. In a double-blind between-groups design, 50 PD patients will be randomised to a group receiving an acute dose of DCS versus placebo prior to acute CBT. The following day, we will measure automatic threat vigilance, neural response to threat and brain tissue GABA levels. Self-reported clinical symptoms will be recorded the day following treatment and at 1- and 6-months follow-up. We hypothesise that the DCS group will show decreased attentional and neural responses to threat the day after treatment compared to the placebo group, that these changes will lead to greater levels of symptom improvement over the following 4 weeks, and that they will remain stable during the following 6-months. This novel intervention would have wide spread implications for the treatment of a large number of patients in a cost-effective and feasible manner.

IMMEDIATE IMPACT:
Academia: The research will contribute to knowledge in clinical psychology, experimental psychology, pharmacology, and neurobiology and potentially impact the developments of new models of the mechanisms of action of CBT and combination treatment as well as novel treatment approaches for panic disorder and other anxiety disorders.
Patients with panic disorder and agoraphobia: Panic disorder with agoraphobia is associated with significant morbidity and restrictions in life quality. Patients' elaborate and far-reaching safety and avoidance strategies severely affect everyday function including their ability to work and form relationships. SSRIs and CBT are first line approaches, but a significant proportion of patients relapse after medication discontinuation, and CBT courses are cost-intensive and difficult to access. Our single-session CBT approach has been shown to result in improvement of agoraphobic symptoms in all treated patients and full clinical recovery in one third of participants. Therefore, the study is a great opportunity for patients to gain direct and immediate access to a treatment that guarantees at least minimum decrease in agoraphobic avoidance. In combination with the pharmacological agent d-cycloserine, we predict that even more patients will fully benefit from study participation.
Public services: During previous projects, we have been working closely with Oxfordshire GPs, carrying out information campaigns to increase the awareness for panic disorder and treatment options. By recommending participation in our CBT studies and handing out leaflets, GPs were able to immediately refer newly diagnosed patients to approved psychological treatment, increasing the effectiveness of their service. This line of public engagement will be continued throughout the proposed study.
Public: As in our previous projects into panic disorder, we will regularly establish public engagement activities to contribute to the awareness for panic disorder and treatment options, which will not only boost study participant recruitment but will also be useful for undiagnosed people with panic disorder.

POTENTIAL LONG-TERM IMPACT:
Patients with other anxiety disorders: It is estimated that almost 30% of people suffer from an anxiety disorder at some point in their life (Kessler et al., 2005). For all anxiety-disorders, exposure-based cognitive-behavioural treatment has been shown to be effective, and treatment rationales are very similar to the one for panic disorder. It is realistic to expect that a successful outcome of the proposed study will be easily transferable to other forms of anxiety and therefore provoke similar treatment developments.
Health care budgets: Panic disorder has a substantial impact on health care budgets, as it is primarily characterised by intense physical symptoms mirroring those of serious physical illnesses such as angina pectoris. This often results in excessive health care uptake, including unnecessary A&E assessments, GP visits and thorough specialist medical examinations. In addition, currently standard-of-care treatments are long and cost-intensive, and often not immediately available. If successful, our proposed novel treatment approach would bring the onset of clinical improvement forward to allow timely, more cost-effective, and more successful treatment of a higher number of patients (following large-scale clinical trials).
Clinicians and NICE guidelines: The National Institute for Health and Clinical Excellence provides evidence-based guidance regarding the management of panic disorder in primary, secondary and community care. If the proposed study and a follow-up larger-scale clinical trial indicate efficacy and safety of the suggested brief combination treatment in comparison to currently available standard-of-care approaches, this may allow refinement of guidelines and health professionals' clinical judgement.