In the past decade, there has been a burgeoning interest in the potential use of D-cycloserine (DCS; Cycloserine, King Pharmaceuticals Ltd., Herts) to facilitate the reduction of fear and avoidance through enhancement of extinction learning (see , glossary) in exposure-based behavioural treatment. DCS is an antibiotic used in the UK in the treatment of drug resistant tuberculosis40
and currently not listed in the formulary for the treatment of anxiety. At the glycine binding site, DCS is a partial agonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor that affects brain processes involved in fear, specifically in the amygdala.41
Initial animal research testing the use of DCS in expediting extinction learning arose deductively from theories of brain circuitry, as well as empirical data that showed that NMDA antagonists inhibit extinction learning. Existing compounds that were NMDA agonists were identified as potentially impacting extinction, and so were tested with animals. Positive findings from animal work about DCS then led to limited human trials, an excellent example of translational research.42
Use of DCS in the treatment of anxiety
DCS does not act directly as an anxiolytic. Rather, it expedites learning by impacting the neural circuitry that is involved in extinction, which is the basis for behavioural treatments to reduce fears. Ressler and colleagues43
found that 28 individuals with acrophobia (fear of heights) showed greater anxiety reduction, as measured by self-report ratings and skin conductance, after exposure therapy (see , glossary) with DCS versus participants treated with a placebo. DCS was taken orally by capsule two to four hours prior to exposure therapy. A 500mg dose of DCS was no more effective than a 50mg dose with regard to extinction. Prior research by this group demonstrated through a drug-free extinction trial that DCS has no anxiolytic properties of its own.44
DCS typically is dosed at 50 to 500mg in isolated, rather than chronic, dosing to enhance the effects of exposure treatment for anxiety and fear.41
DCS is generally well tolerated.40
It is important to note that DCS does not appear to make standard behaviour therapy more effective. Rather, it seems to expedite the reduction of fear and anxiety, making behaviour therapy more efficient. This research suggests that administering DCS during a practice session prior to sedation treatment may help the patient decrease his or her fear more quickly than with exposure therapy alone. For example, patients may undergo a brief practice session, during which they ‘rehearse’ the placement of the cannula while practising relaxation strategies. Administration of DCS in conjunction with this rehearsal session would help expedite fear and anxiety reduction, leading to less fear and anxiety during the cannulisation. In this type of learning, reinforcement of fear (e.g. temporary relief of fear by escaping the situation: see glossary) is avoided in order to extinguish the fear response through exposure. Systematic practice by the patient of the steps involved in dental treatment (e.g. sitting in the dental chair, relaxing one’s limbs and torso, opening one’s mouth) substitutes for the earlier fear response.
Directions for future research in DCS
To date, clinical studies of DCS’s enhancement of exposure treatment and other cognitive-behavioural treatments have been limited to acrophobia,43
social phobia/social anxiety disorder,41
and obsessive-compulsive disorder.45
Since DCS has been found to enhance exposure treatment, in both animals and humans with regards to several different anxiety conditions, the use of DCS has promise to facilitate extinction learning (see , glossary) in dental anxiety, fear and phobia as well.
At present, use of DCS in dentistry is theoretically promising, and studies of the enhancement efficacy of DCS in dentistry are at an early stage of development at King’s College London Dental Institute to determine its appropriateness for routine use in clinical care. While it cannot be assumed that DCS will enhance exposure treatment for all phobic or other anxiety disorders, there is considerable promise for using DCS as an aid for dental fear exposure treatment, which ultimately may allow affected patients to utilise dental services more comfortably with improved attendance. In testing its effectiveness, as DCS acts to enhance memory, it is critical that any dental experiences in which DCS is used be positive. Short-term behavioural preparation of patients involves controlled exposure to fearful stimuli, so use during clinical care should be carefully considered and planned to maximise a positive experience throughout. This novel pharmacological adjunct shows promise in its ability to combine with behavioural methods to reduce anxiety and fear in dental patients.