AMSTERDAM – The N-methyl-d-aspartate partial agonist d-cycloserine might enhance the results of exposure therapy, especially when it is properly timed and dosed, according to a leading researcher in this field.
Barbara O. Rothbaum, Ph.D., professor of psychiatry at Emory University, Atlanta, discussed the application of d-cycloserine (DCS) to exposure therapy for fear-related conditions at the annual congress of the European College of Neuropsychopharmacology.
DCS has been shown to facilitate exposure therapy in the treatment of obsessive-compulsive disorder, panic disorder, and social phobia, whereas adding “traditional medications” such as alprazolam, imipramine, and fluvoxamine to exposure therapy have shown no advantage over cognitive-behavioral therapy (CBT) alone for these anxiety disorders, according to Dr. Rothbaum.
Pharmacotherapy is aimed at improving the learning that takes place during exposure-based therapy and not at treating the symptoms of anxiety. The glutamatergic N-methyl-d-aspartate (NMDA) receptor is critically involved in learning and memory, and this learning might be augmented by the NMDA partial agonist DCS. In other words, DCS accelerates the associative learning processes that contribute to correcting the psychopathology, she said.
“The use of DCS is a direct attempt to stimulate chemically the NMDA synapses that are thought to be the critical nerve cell mechanisms that support short-term learning and memory at the same moment that CBT is being used to help the patient learn new behaviors,” he said. “DCS is a unique partial agonist for this purpose, because it is thought to work cooperatively with the glutamate that is presumably being released through synaptic activity associated with the patient’s participation in CBT.”
In a double-blind, placebo-controlled study of patients undergoing virtual reality exposure for the treatment of fear of heights, exposure therapy combined with DCS resulted in significantly larger reductions of acrophobia symptoms on all main outcome measures (Arch. Gen. Psych. 2004;61:1136-44). Differences were observed within the virtual environment 1 week and 3 months after treatment. Subjects also showed significantly greater decreases in posttreatment skin conductance fluctuations during the virtual exposure, and had significantly greater improvements on general measures of real world acrophobia symptoms.
The drug did not, however, work by decreasing anxiety during exposure, but it did reduce anxiety, compared with placebo, post treatment (P less than .001) and at 3 months’ follow-up (P less than .05). Its use also was associated with a doubling in the number of height exposures post treatment (P less than .01).
Dr. Rothbaum is now conducting a study in which Iraq war veterans with posttraumatic stress disorder (PTSD) are treated with five sessions of virtual reality exposure therapy plus DCS, alprazolam, or placebo (one pill before each session). Virtual reality exposure therapy (minus the medication) has shown strong efficacy in case studies, one of which showed that PTSD symptoms score dropped from 35 to 10 after four sessions. Currently, 76 subjects have been enrolled in the study, which is still blinded.
Studies in several disorders have evaluated various doses and schedules of DCS when it is given with the exposure therapy. Dr. Rothbaum noted that negative studies have tended to use higher doses administered several hours ahead of the exposure, and she has concluded that dose and timing are critical for this combined approach.
In particular, dosing too early might lead to the peak drug effect’s not being coincident with the emotional learning processes that take place during and immediately after psychotherapy sessions, she maintained. Similarly, too high a dose might activate the antagonist properties of the NMDA partial agonist and the floor effect of subjects improving from a full course of therapy, which could obscure the effects of the drug.
She has concluded – based on these observations and the mechanism of action – that “less d-cycloserine is better than more d-cycloserine, and the timing of the dosing is critical.” She advocates a lower dose that is given approximately once per week and is administered just an hour or so ahead of the exposure therapy session.
Dr. Rothbaum is a consultant to and owns equity in Virtually Better Inc., which is developing products related to virtual reality research.