Exposure, Medication May Aid Anxiety Treatment

ST. LOUIS — The experimental concept of improving the treatment of anxiety disorders by combining exposure therapy with a medication has received a boost from two pilot studies presented at the annual conference of the Anxiety Disorders Association of America.

In one study, investigators found that D-cycloserine for obsessive-compulsive disorder (OCD) increases therapeutic learning, accelerates fear extinction in early sessions, and reduces the number of exposure sessions required for a good outcome, reported Matt Kushner, Ph.D., a professor of psychiatry at the University of Minnesota, Minneapolis.

A second, already published study achieved better long-term results in the treatment of social anxiety disorder (Arch. Gen. Psychiatry 2006;63:298–304).

These studies provide preliminary support for the use of short-term dosing of D-cycloserine as an adjunctive intervention to exposure therapy for social anxiety disorder, said Stefan G. Hofmann, Ph.D., lead author of the second study.

“This giving a pill to enhance psychotherapy is a paradigm shift in the treatment of anxiety disorders,” commented Dr. Hofmann, professor of psychology and director of the social anxiety program at the Center for Anxiety and Related Disorders at Boston University.

D-Cycloserine, an agonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor, had been shown to improve the effectiveness of exposure therapy of acrophobia in an earlier pilot study (Arch. Gen. Psychiatry 2004;61:1136–44), and has successfully promoted the extinction of conditioned fear in several other animal studies.

By itself, exposure therapy for OCD has significant limitations, Dr. Kushner said. “It's difficult in that the patient must repeatedly face his or her worst fears. It's time consuming, and it's expensive,” he said, adding that exposure therapy has a refusal/dropout rate approaching 25% and an overall effectiveness rate of less than 50%.

To test the hypothesis that D-cycloserine (DCS) augmentation would raise the effectiveness ceiling of exposure therapy for OCD, Dr. Kushner and his team conducted a double-blind study of 32 subjects with the compulsive rituals of washing or checking.

Half received exposure therapy plus 125 mg DCS twice weekly; the second group received exposure therapy plus placebo. Subjects were allowed to be on a stable dose of psychiatric medications other than benzodiazepines.

All of the subjects received four sessions of exposure and ritual prevention twice weekly.

After four sessions of therapy, the patients were allowed to continue until they had a 50% reduction in symptoms, or until session 10, whichever came first.

This criterion was met by session 10 in 40% of the placebo group and 80% of the DCS group, though the learning effects of the drug diminished after the fourth session.

Dr. Kushner said the most striking finding was that extinction learning from DCS did improve retention, in that less than 7% of those receiving DCS blindly dropped out of the study, compared with one-third of those in the placebo group.

He said he interpreted that to mean that there was a greater effort-to-benefit ratio with dual therapy.

“People tend to stay in therapy and work hard when the early results are good,” he said.

In the social anxiety disorder study, 27 participants received five therapy sessions delivered in either individual or group therapy format. The first session introduced the treatment model and was followed by four sessions emphasizing exposure to increasingly challenging public speaking situations.

An hour before each session, participants received single 50-mg doses of D-cycloserine or placebo.

Symptoms were assessed by patient self-report and by clinicians blind to the rand- omization condition before and after treatment and 1 month after the last session.

Assessments were made using the Social Phobia and Anxiety Inventory, the Liebowitz Social Anxiety Scale, and the Clinical Global Impression Scale. Those receiving D-cycloserine in addition to exposure therapy reported significantly less social anxiety, compared with those in the exposure therapy plus placebo group.

On follow-up, no drop-off was found in fear extinction such as was seen in Dr. Kushner's OCD study.

“It may be that in a dosing regimen such as was used in our study, there's an accumulation of D-cycloserine—which causes it to switch from being an NMDA receptor agonist to an NMDA antagonist, as has been shown in animal studies,” Dr. Kushner said in an interview. “So the drug may be counterproductive at higher doses.”

Dr. Kushner added that his results might have been better had he given the medication as Dr. Hofmann had, 50 mg at weekly intervals.

'People tend to stay in therapy and work hard when the early results are good.' DR. KUSHNER

ST. LOUIS — The experimental concept of improving the treatment of anxiety disorders by combining exposure therapy with a medication has received a boost from two pilot studies presented at the annual conference of the Anxiety Disorders Association of America.

In one study, investigators found that D-cycloserine for obsessive-compulsive disorder (OCD) increases therapeutic learning, accelerates fear extinction in early sessions, and reduces the number of exposure sessions required for a good outcome, reported Matt Kushner, Ph.D., a professor of psychiatry at the University of Minnesota, Minneapolis.

A second, already published study achieved better long-term results in the treatment of social anxiety disorder (Arch. Gen. Psychiatry 2006;63:298–304).

These studies provide preliminary support for the use of short-term dosing of D-cycloserine as an adjunctive intervention to exposure therapy for social anxiety disorder, said Stefan G. Hofmann, Ph.D., lead author of the second study.

“This giving a pill to enhance psychotherapy is a paradigm shift in the treatment of anxiety disorders,” commented Dr. Hofmann, professor of psychology and director of the social anxiety program at the Center for Anxiety and Related Disorders at Boston University.

D-Cycloserine, an agonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor, had been shown to improve the effectiveness of exposure therapy of acrophobia in an earlier pilot study (Arch. Gen. Psychiatry 2004;61:1136–44), and has successfully promoted the extinction of conditioned fear in several other animal studies.

By itself, exposure therapy for OCD has significant limitations, Dr. Kushner said. “It's difficult in that the patient must repeatedly face his or her worst fears. It's time consuming, and it's expensive,” he said, adding that exposure therapy has a refusal/dropout rate approaching 25% and an overall effectiveness rate of less than 50%.

To test the hypothesis that D-cycloserine (DCS) augmentation would raise the effectiveness ceiling of exposure therapy for OCD, Dr. Kushner and his team conducted a double-blind study of 32 subjects with the compulsive rituals of washing or checking.

Half received exposure therapy plus 125 mg DCS twice weekly; the second group received exposure therapy plus placebo. Subjects were allowed to be on a stable dose of psychiatric medications other than benzodiazepines.

All of the subjects received four sessions of exposure and ritual prevention twice weekly.

After four sessions of therapy, the patients were allowed to continue until they had a 50% reduction in symptoms, or until session 10, whichever came first.

This criterion was met by session 10 in 40% of the placebo group and 80% of the DCS group, though the learning effects of the drug diminished after the fourth session.

Dr. Kushner said the most striking finding was that extinction learning from DCS did improve retention, in that less than 7% of those receiving DCS blindly dropped out of the study, compared with one-third of those in the placebo group.

He said he interpreted that to mean that there was a greater effort-to-benefit ratio with dual therapy.

“People tend to stay in therapy and work hard when the early results are good,” he said.

In the social anxiety disorder study, 27 participants received five therapy sessions delivered in either individual or group therapy format. The first session introduced the treatment model and was followed by four sessions emphasizing exposure to increasingly challenging public speaking situations.

An hour before each session, participants received single 50-mg doses of D-cycloserine or placebo.

Symptoms were assessed by patient self-report and by clinicians blind to the rand- omization condition before and after treatment and 1 month after the last session.

Assessments were made using the Social Phobia and Anxiety Inventory, the Liebowitz Social Anxiety Scale, and the Clinical Global Impression Scale. Those receiving D-cycloserine in addition to exposure therapy reported significantly less social anxiety, compared with those in the exposure therapy plus placebo group.

On follow-up, no drop-off was found in fear extinction such as was seen in Dr. Kushner's OCD study.

“It may be that in a dosing regimen such as was used in our study, there's an accumulation of D-cycloserine—which causes it to switch from being an NMDA receptor agonist to an NMDA antagonist, as has been shown in animal studies,” Dr. Kushner said in an interview. “So the drug may be counterproductive at higher doses.”

Dr. Kushner added that his results might have been better had he given the medication as Dr. Hofmann had, 50 mg at weekly intervals.

'People tend to stay in therapy and work hard when the early results are good.' DR. KUSHNER

ST. LOUIS — The experimental concept of improving the treatment of anxiety disorders by combining exposure therapy with a medication has received a boost from two pilot studies presented at the annual conference of the Anxiety Disorders Association of America.

In one study, investigators found that D-cycloserine for obsessive-compulsive disorder (OCD) increases therapeutic learning, accelerates fear extinction in early sessions, and reduces the number of exposure sessions required for a good outcome, reported Matt Kushner, Ph.D., a professor of psychiatry at the University of Minnesota, Minneapolis.

A second, already published study achieved better long-term results in the treatment of social anxiety disorder (Arch. Gen. Psychiatry 2006;63:298–304).

These studies provide preliminary support for the use of short-term dosing of D-cycloserine as an adjunctive intervention to exposure therapy for social anxiety disorder, said Stefan G. Hofmann, Ph.D., lead author of the second study.

“This giving a pill to enhance psychotherapy is a paradigm shift in the treatment of anxiety disorders,” commented Dr. Hofmann, professor of psychology and director of the social anxiety program at the Center for Anxiety and Related Disorders at Boston University.

D-Cycloserine, an agonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor, had been shown to improve the effectiveness of exposure therapy of acrophobia in an earlier pilot study (Arch. Gen. Psychiatry 2004;61:1136–44), and has successfully promoted the extinction of conditioned fear in several other animal studies.

By itself, exposure therapy for OCD has significant limitations, Dr. Kushner said. “It's difficult in that the patient must repeatedly face his or her worst fears. It's time consuming, and it's expensive,” he said, adding that exposure therapy has a refusal/dropout rate approaching 25% and an overall effectiveness rate of less than 50%.

To test the hypothesis that D-cycloserine (DCS) augmentation would raise the effectiveness ceiling of exposure therapy for OCD, Dr. Kushner and his team conducted a double-blind study of 32 subjects with the compulsive rituals of washing or checking.

Half received exposure therapy plus 125 mg DCS twice weekly; the second group received exposure therapy plus placebo. Subjects were allowed to be on a stable dose of psychiatric medications other than benzodiazepines.

All of the subjects received four sessions of exposure and ritual prevention twice weekly.

After four sessions of therapy, the patients were allowed to continue until they had a 50% reduction in symptoms, or until session 10, whichever came first.

This criterion was met by session 10 in 40% of the placebo group and 80% of the DCS group, though the learning effects of the drug diminished after the fourth session.

Dr. Kushner said the most striking finding was that extinction learning from DCS did improve retention, in that less than 7% of those receiving DCS blindly dropped out of the study, compared with one-third of those in the placebo group.

He said he interpreted that to mean that there was a greater effort-to-benefit ratio with dual therapy.

“People tend to stay in therapy and work hard when the early results are good,” he said.

In the social anxiety disorder study, 27 participants received five therapy sessions delivered in either individual or group therapy format. The first session introduced the treatment model and was followed by four sessions emphasizing exposure to increasingly challenging public speaking situations.

An hour before each session, participants received single 50-mg doses of D-cycloserine or placebo.

Symptoms were assessed by patient self-report and by clinicians blind to the rand- omization condition before and after treatment and 1 month after the last session.

Assessments were made using the Social Phobia and Anxiety Inventory, the Liebowitz Social Anxiety Scale, and the Clinical Global Impression Scale. Those receiving D-cycloserine in addition to exposure therapy reported significantly less social anxiety, compared with those in the exposure therapy plus placebo group.

On follow-up, no drop-off was found in fear extinction such as was seen in Dr. Kushner's OCD study.

“It may be that in a dosing regimen such as was used in our study, there's an accumulation of D-cycloserine—which causes it to switch from being an NMDA receptor agonist to an NMDA antagonist, as has been shown in animal studies,” Dr. Kushner said in an interview. “So the drug may be counterproductive at higher doses.”

Dr. Kushner added that his results might have been better had he given the medication as Dr. Hofmann had, 50 mg at weekly intervals.

'People tend to stay in therapy and work hard when the early results are good.' DR. KUSHNER