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Original Article |

Cognitive Enhancers as Adjuncts to Psychotherapy:  Use of D-Cycloserine in Phobic Individuals to Facilitate Extinctionof Fear FREE

Kerry J. Ressler, MD, PhD; Barbara O. Rothbaum, PhD; Libby Tannenbaum, PhD; Page Anderson, PhD; Ken Graap, MEd; Elana Zimand, PhD; Larry Hodges, PhD; Michael Davis, PhD
[+] Author Affiliations

Author Affiliations: Department of Psychiatryand Behavioral Sciences, Center for Behavioral Neuroscience, Emory UniversitySchool of Medicine, Atlanta, Ga (Drs Ressler, Rothbaum, and Davis); YerkesNational Primate Center, Atlanta (Drs Ressler and Davis); Virtually BetterInc, Decatur, Ga (Drs Tannenbaum, Anderson, and Zimand and Mr Graap); andComputing Department, University of North Carolina, Charlotte (Dr Hodges). Financial Disclosure: Drs Davis and Resslerhave submitted a patent for the use of D-cycloserine for the specific enhancementof learning during psychotherapy. The terms of these arrangements have beenreviewed and approved by Emory University, Atlanta, Ga, and Georgia Instituteof Technology, Atlanta, in accordance with their conflict of interest policies.


Arch Gen Psychiatry. 2004;61(11):1136-1144. doi:10.1001/archpsyc.61.11.1136.
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Background  Traditional pharmacological approaches to treating psychiatric disorders focus on correcting presumed biochemical abnormalities. However, some disorders, particularly the anxiety-related disorders exemplified by specific phobia, have an emotional learning component to them that can be facilitated with psychotherapy.

Objective  To determine whether D-cycloserine (DCS), a partial agonist at the N-methyl-D-aspartate receptor that has previously been shown to improve extinction of fear in rodents, will also improve extinction of fear in human phobic patients undergoing behavioral exposure therapy.

Design  Randomized, double-blind, placebo-controlled trial examining DCS vs placebo treatment in combination with a precisely controlled exposure paradigm.

Setting  Participants were recruited from the general community to a research clinic.

Participants  Twenty-eight subjects with acrophobia diagnosed by the Structured Clinical Interview for DSM-IV were enrolled.

Interventions  After we obtained pretreatment measures of fear, subjects were treated with 2 sessions of behavioral exposure therapy using virtual reality exposure to heights within a virtual glass elevator. Single doses of placebo or DCS were taken prior to each of the 2 sessions of virtual reality exposure therapy. Subjects, therapists, and assessors were blind to the treatment condition. Subjects returned at 1 week and 3 months posttreatment for measures to determine the presence and severity of acrophobia symptoms.

Main Outcome Measures  Included were measures of acrophobia within the virtual environment, measures of acrophobia in the real world, and general measures of overall improvement. An objective measure of fear, electrodermal skin fluctuation, was also included during the virtual exposure to heights. Symptoms were assessed by self-report and by independent assessors at approximately 1 week and 3 months posttreatment.

Results  Exposure therapy combined with DCS resulted in significantly larger reductions of acrophobia symptoms on all main outcome measures. Subjects receiving DCS had significantly more improvement compared with subjects receiving placebo within the virtual environment (1 week after treatment, P≤.001; 3 months later, P≤.05). Subjects receiving DCS also showed significantly greater decreases in posttreatment skin conductance fluctuations during the virtual exposure (P≤.05). Additionally, subjects receiving DCS had significantly greater improvement compared with subjects receiving placebo on general measures of real-world acrophobia symptoms (acrophobia avoidance [P≤.02], acrophobia anxiety [P≤.01], attitudes toward heights [P≤.04], clinical global improvement [P≤.01], and number of self-exposures to real-world heights [P≤.01]); the improvement was evident early in treatment and was maintained at 3 months.

Conclusion  These pilot data provide initial support for the use of acute dosing of DCS as an adjunct to exposure-based psychotherapy to accelerate the associative learning processes that contribute to correcting psychopathology.

Figures in this Article

Most pharmacological treatments for anxiety and other mental disordersrely on the hypothesis that there are underlying neurochemical or neurophysiologicalabnormalities that can be corrected with pharmacological treatment.1 However, there may also be a component to some mentaldisorders that responds to the emotional learning that occurs with some formsof psychotherapy, such as behavioral exposure therapy.2 Theseparate successes of pharmacology and psychotherapy have led to the hopethat they can be combined for a more powerful treatment, but to date thishope has not often been realized.2,3 Insome cases, combining these modalities in traditional ways may even decreasethe overall efficacy.4,5

If the learning hypothesis is correct for some mental disorders, thenanother way to approach pharmacological treatment is to enhance the learningthat occurs in psychotherapy. D-cycloserine (DCS), a partial agonist at the N-methyl-D-aspartate (NMDA) glutamatergicreceptor,6,7 has been suggestedto be a putative cognitive enhancer based on preclinical810 andlimited clinical11,12 studies.Recent work in our laboratory and others using rodents has demonstrated thatacute treatment with DCS enhances the learning process underlying extinctionof fear.13,14 The current studywas initiated to determine if similar acute dosing of DCS would enhance learningwhen combined with a simple form of human psychotherapy, behavioral exposuretreatment for specific phobia.

Procedurally, behavioral exposure therapy is very similar to the animalmodel of extinction of conditioned fear.15,16 Experimentalextinction of fear occurs in both humans and animals when a previously conditionedstimulus is repeatedly presented in the absence of the unconditioned aversivestimulus with which it was initially paired. The neural process of extinctionof fear appears to use similar molecular and cellular mechanisms to thoseinvolved in fear conditioning.17 Both fearlearning and extinction are blocked by antagonists at the glutamatergic NMDAreceptor,18,19 a receptor knownto be critically involved in learning and memory. Furthermore, DCS appearsto augment learning in animal models810 andto enhance memory in some human trials.11,12 Werecently found that extinction of conditioned fear in rats was facilitatedby DCS given in a 1-time dose prior to extinction training, which consistsof exposure to a fearful stimulus in the absence of the aversive stimulus.13 Importantly, extinction was measured in a subsequentdrug-free test of conditioned fear, indicating the facilitation of extinctioncould not be attributed to an anxiolytic effect of DCS.

We wished to examine the ability of DCS to enhance extinction learningin humans using the most optimally controlled form of psychotherapeutic learningavailable. Virtual reality exposure (VRE) therapy is ideal for clinical researchassessment because exposure and testing are identical between patients, arewell controlled by the therapist, and occur within the spatial and temporalconfines of the limited therapy environment.20 Thismethod has proven to be successful for the treatment of specific phobias aswell as, more recently, for posttraumatic stress disorder.2022 Inthis study, we directly examined whether acute treatment with DCS would augmentextinction of fear during behavioral exposure therapy for patients with acrophobia.

PARTICIPANTS

We enrolled 28 volunteer participants recruited from the general communitywith no currently active psychiatric disorders except for acrophobia by DSM-III-R.23 The diagnosisof acrophobia (subtype of specific phobia) requires an excessive or unreasonablefear of heights that interferes significantly with the person’s normalroutine and functioning and is characterized by severe anxiety in the presenceof height situations. One participant did not return after the preassessment,thus 27 were randomly assigned, via a predetermined and blinded order of treatmentassignment, to 3 treatment groups: placebo plus VRE therapy (n = 10),50 mg of DCS plus VRE therapy (n = 8), or 500 mg of DCS plus VREtherapy (n = 9). Treatment condition was double-blinded, such thatthe subjects, therapists, and assessors were not aware of the assigned studymedication condition. The blind was maintained throughout the study. Twenty-sevenparticipants (11 men, 16 women) completed pretreatment (Table), both therapy sessions, and the 3-month follow-up assessment.

Table Graphic Jump LocationTable. Baseline Pretreatment Data of Participant Sample
MEASURES

Acrophobia and other psychiatric diagnoses were determined by interviewwith the Structured Clinical Interview for DSM-III-R.24 Participants were examined with the following batteryof screening tests: to examine their fear of heights, the Acrophobia Questionnairewith Avoidance (AAVQ) and Anxiety (AAQ) subscales25 andthe Attitudes Toward Heights Inventory (ATHI)20,26;to examine their general levels of depression and anxiety, the Beck DepressionInventory (BDI)27 and the State-Trait AnxietyInventory (STAI).28 Overall global improvementwas assessed with the Clinical Global Improvement (CGI-I) scale. During theinitial screen, participants also had limited but structured exposure to thevirtual reality height environment during a behavioral avoidance test, inwhich they reported on a 0 to 100 scale (100 being the most intense fear)their subjective units of discomfort (SUDS) for each floor (floors 1-19) ofthe virtual glass elevator.

Electrodermal skin conductance fluctuations were measured as describedpreviously.2931 Fingerelectrodes (ProComp Module; Thought Technology Ltd, Montreal, Quebec) wereworn by the subjects during the initial and posttreatment behavioral assessmenttests. Data are reported as the number of skin conductance fluctuations perminute of exposure. Skin conductance fluctuations were measured as in Grillonand Hill,29 using fluctuation defined as 0.05-μsdeviation in baseline skin conductance. Skin conductance fluctuations wereaveraged over the entire exposure and presented as fluctuations per minute.Each fluctuation was defined as a 2-second or longer deviation of 0.05 μsfrom the local mean (average baseline ± 30 seconds). Follow-up analysesalso examined fluctuations as defined by a 2-second or longer deviation of5% greater or less than the local mean.

MEDICATION

D-cycloserine (Seromycin, 250 mg; Eli Lilly and Co, Indianapolis, Ind)was reformulated into 50 mg or 500 mg with identical placebo capsules. These2 doses of DCS were given acutely prior to psychotherapy for several reasons.The 50-mg dose was based on clinical trials in which 30 to 100 mg per daywere effective for implicit memory12 and subscalesof dementia in Alzheimer disease.32 Furthermore,50 mg per day appeared to be most effective in the treatment of negative symptomsof schizophrenia.33 The 500-mg dose was chosenbecause the efficacy of DCS in the lower dose range (10-250 mg/d) was noteffective in several other trials.3436 Withluteinizing hormone secretion as a measure of NMDA receptor activation, ithas also been shown that although 15 to 150 mg did not increase luteinizinghormone, a single dose of 500 mg did but without adverse effects.37 Thus, single doses as high as 500 mg are likely tobe well tolerated and without adverse effects but with clear neuroendocrineeffects.37

No adverse events occurred during our study. We did not systematicallyobtain reports of adverse effects although the subjects were routinely askedif they were experiencing any difficulties. Upon breaking the blind, we foundno difference between subjects reporting adverse effects with placebo andthose reporting adverse effects with DCS. The research protocol used in thisstudy was approved by the Emory University institutional review board, andall subjects gave written informed consent for participation in the study.

TREATMENT

With VRE for fear of heights, we used a virtual glass elevator in whichparticipants stood while wearing a VRE helmet and were able to peer over avirtual railing. Computerized effects gave a real sense of increase in heightas the elevator rose. Previous work by our group has shown improvements onall acrophobia outcome measures for treated as compared with untreated groupsafter 7 weekly, 35- to 45-minute therapy sessions.20

Participants underwent two 35- to 45-minute therapy sessions, whichis a suboptimal amount of exposure therapy for acrophobia.20 These2 therapy sessions were separated by 1 to 2 weeks (average, 12.9 days). Participantswere instructed to take a single pill of study medication (placebo, 50 mgof DCS, or 500 mg of DCS) 2 to 4 hours before each therapy session, such thatonly 2 pills were taken for the entire study. There were no adverse eventsreported from either group taking placebo or drug prior to exposure therapy.

A midtreatment assessment occurred 1 week after the first treatment(average, 7.2 days), a posttreatment assessment was performed 1 to 2 weeksfollowing the final therapy session (average, 11.5 days), and an additionalfollow-up assessment was performed 3 months after the therapy (average, 107.5days).

ANALYSIS

Patients, therapists, and assessors were kept blind to treatment conditionthroughout the study. All data were entered into the SPSS statistics package(SPSS Inc, Chicago, Ill) by research assistants also blind to condition. Pretreatmentvariables (Table) were analyzed using t tests for independent samples. Posttreatment variables(skin conductance fluctuations, AAQ, AAVQ, ATHI, CGI, and number of self-exposureto heights) were analyzed using 1-way analysis of variance (ANOVA) or repeated-measuresANOVA with time and drug condition as separate factors.

Specific comparisons of different floors and SUDS within treatment sessionswere performed with 1-way ANOVA with the between-subjects factor of drug vsplacebo group. The effect of interaction between drug group and differentfloors or drug group and different time points on the SUDS score (Figure 1) was performed using multivariate analysiswith repeated measures with floor or time as the repeated within-subjectsfactor and drug condition the independent between-subjects factor. The effectof these interactions on SUDS as the outcome variable for the pre-post analysis(Figure 2) was performed with an overallANOVA with pre-post difference and floor as within-subjects factor and druggroup as between-subjects factor.

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Figure 1.

Acrophobia within the virtual environment.A, Level of fear as measured by subjective units of discomfort (1 = nofear, 100 = maximum fear) during the pretreatment assessment ateach successive floor in the virtual glass elevator. B, Subjective units ofdiscomfort during the first treatment session in which subjects were elevatedto successive floors at 5-minute intervals. C, Floor to which the subjectswere elevated at 5-minute intervals during the first treatment session. Therewere no significant differences between the groups during the pretreatmentsubjective units of discomfort measure or either measure during the firsttreatment session. Error bars indicate SEM.

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Figure 2.

Acrophobia within the virtual environmentis improved with D-cycloserine. A, Reduction in fear from pretest to posttestfollowing the 2 therapy sessions measured at the first follow-up assessment.Decrease in subjective units of discomfort level (y-axis) is shown for eachfloor (1-19) of the virtual glass elevator. Overall analysis of variance wasperformed using pre-post difference and floor as within-subjects variablesand drug group as between-subjects variable. Significant overall pre-postchanges were seen: F1,25 = 38, P≤.001.Significant effect of floor was found: F6,150 = 89, P≤.001. Most importantly, significant effect of pre-post × floor × druginteraction was found: F6,150 = 3.8, P≤.001. B, Change in subjective units of discomfort from pretestto posttest at the 3-month long-term follow-up assessment. Statistics wereperformed as above. Significant overall pre-post changes were seen: F1,17 = 21, P≤.001. Significanteffect of floor was found: F6,102 = 81, P≤.001. Most importantly, significant effect of pre-post × floor × druginteraction was found: F6,102 = 2.4, P≤.05. Error bars indicate SEM.

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Twenty-seven participants completed the 2 therapy sessions, with 10subjects randomly assigned to placebo (5 men, 5 women) and 17 subjects randomlyassigned to DCS (6 men, 11 women). At the pretest assessment, there was nodifference in age, number of DSM-IV38 diagnoses,global assessment of functioning, or scores on the BDI, STAI-state, or STAI-traitbetween placebo and drug groups (Table).There was also no difference in initial acrophobia measures (Table) or in SUDS levels at different floors within the virtualelevator environment (Figure 1A).

Following treatment, we found statistically significant differencesbetween placebo and drug groups for almost all of our primary outcome measures.In the results below, statistics are presented for ANOVA measures with thedrug groups both separated and combined. Analysis of our data indicated thatthere were no significant differences between the 50-mg and 500-mg drug groupsfor the primary outcome measures of acrophobia (ANOVA, P>.50); therefore, the data in the figures are presented with druggroups combined.

D-CYCLOSERINE DOES NOT AFFECT BASELINE LEVEL OF FEAR

Because, based on our preclinical studies, no direct anxiolytic effectof DCS was anticipated, and also because there was no retention interval toallow facilitative effects of DCS on extinction learning, no effects of DCSwere anticipated for session 1. Consistent with this, we found no differencesbetween groups in SUDS level during the first therapy session (Figure 1B). During the therapy sessions, participants have somecontrol over how high the elevator is allowed to rise, permitting an analysisof avoidance of heights. During this first session, we also found no differencesin the highest floor attained at different time points (Figure 1C). These findings indicate that the presence of DCS duringthe therapy session did not affect level of fear or avoidance of fear duringthe therapy.

D-CYCLOSERINE ENHANCES EXTINCTION OF FEAR WITHIN THE VIRTUAL ENVIRONMENT

The results of preclinical studies13,14 suggestthat facilitative effects of DCS might develop during the intersession retentioninterval and be evident starting at session 2, and we found this to be thecase. During the second session, participants in the DCS group experiencedlower SUDS than the placebo group (SUDS at 5 minutes, F1,25 = 7.1, P≤.01), and they elevated to higher floors after 20minutes (mean floor for placebo, 13.0; mean floor for DCS, 15.9; F1,25 = 6.3; P≤.01). This suggeststhat during the second session there was less fear and avoidance in the groupthat had received DCS during the first session. This is consistent with thepreclinical studies providing evidence of enhanced extinction after only asingle session of fear exposure in combination with DCS.13,14 TheDCS group also showed more improvement as measured by participant scores onthe CGI scale at the second session (placebo = 2.8 vs DCS = 2.25,F1,25 = 5.2, P≤.05).

One week after the second session, we performed a posttreatment assessmentin the absence of drug and examined the difference scores between posttreatmentand pretreatment. The group that received DCS during the therapy sessionsshowed significantly less fear of heights as determined by SUDS at successiveelevator floors during the behavioral avoidance test virtual reality assessments(Figure 2A) (F6,150 = 3.8, P≤.001). This difference was also seen if the 2 separatedoses of drug were analyzed separately with a repeated-measures ANOVA (F12,144 = 2.7, P≤.01). The continueddecrease in fear within the virtual environment in the absence of DCS demonstratesthat, as in the animal experiments,13,14 theenhancement of extinction in humans with DCS is not state-dependent. Thesedata suggest that 2 sessions of VRE therapy in combination with DCS for fearof heights is sufficient for extinction of fear within the virtual environment(Figure 2A).

ENHANCED EXTINCTION WITH D-CYCLOSERINE IS MAINTAINED AT 3 MONTHS

To evaluate how DCS would affect retention of extinction, as well aswhether it would generalize to real-life situations outside the virtual realityenvironment over time, subjects were asked to return for a follow-up session3 months after their VRE treatment. Twenty-one of the 27 completing participantsreturned for follow-up assessment (8 placebo [80% of enrolled], 13 DCS [77%of enrolled]). Analysis of the pretreatment data and the 1-week posttreatmentassessments showed that there were no significant pretreatment or posttreatmentdifferences on anxiety or fear measures between those who returned for follow-upand the 6 who did not.

At follow-up assessment, subjects were tested again in the absence ofDCS for their level of fear in the virtual elevator environment with the behavioralavoidance test. We found that participants who received DCS maintained thespecific decrease in fear of the virtual environment across the 3-month periodas determined by SUDS during the exposure to virtual heights (Figure 2B) (F6,102 = 2.4, P≤.05). We found no significant differences between the 2 differentdrug doses. This suggests that the extinction of fear that was enhanced inthe drug group during the 2 therapy sessions was relatively robust and lasting.

PHYSIOLOGICAL AROUSAL AND FEARFULNESS DURING VIRTUAL EXPOSURE

The number of spontaneous fluctuations of skin conductance is a commonmeasure of emotional arousal and anxiety, such that those with more fear oranxiety typically show more spontaneous reactivity or fluctuation in theirbaseline skin conductance during provocation.29,31 Consistentwith this, during the posttreatment behavioral assessment tests, we foundthat the number of spontaneous fluctuations correlated with the measures ofsubjective improvement in fear of heights. Those reporting “much”or “very much” improvement at the initial posttreatment assessmenttest showed significantly fewer spontaneous fluctuations than did those whoreported no improvement or worsening (Figure 3A) (F1,19 = 4.5; P≤.05;linear regression, r = 0.44). Additionally,those who showed less avoidance of heights in the real world since treatment,as indicated by increased likelihood of exposing themselves to real-worldheights, also showed fewer spontaneous fluctuations than did those who didnot self-expose since treatment (Figure 3B)(F1,19 = 8.26; P≤.01; linearregression, r = 0.55).

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Figure 3.

Physiological measures of anxietywithin the virtual environment. Spontaneous fluctuations in baseline skinconductance levels are shown as a function of acrophobia treatment responseand treatment condition. A, Subjective improvement in acrophobia symptoms.Those reporting improvement in symptoms show significantly lower posttreatmentspontaneous fluctuations in the virtual environment (F1,19 = 4.5, P≤.05). B, Decreased avoidance (self-reports of whetherthey have self-exposed to heights since treatment) also was associated withsignificantly lower spontaneous fluctuations of skin conductance (F1,19 = 8.26, P≤.01). C, Subjects treatedwith D-cycloserine during exposure therapy showed significant decreases inposttreatment fluctuations (paired t test, P≤.05) compared with those treated with placebo (P≥.5). Error bars indicate SEM.

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We also found that those subjects given DCS during exposure therapyhad a significant decrease in average spontaneous fluctuations from pretreatmentto posttreatment (Figure 3C) (paired t test, P≤.05) compared withthose given placebo during the treatment (P≥.50).Subsequent analysis of skin conductance fluctuations using the criterion ofa 5% change from baseline in skin conductance instead of an absolute 0.05-μsdifference also demonstrated a significant time × treatmenteffect (repeated-measure ANOVA: F1,19 = 8.0, P≤.01). These data suggest that the improvement in extinction offear achieved with DCS augmentation during exposure was evident in both subjectiveand objective physiological measures of fear.

D-CYCLOSERINE AUGMENTS REDUCTION OF GENERAL MEASURES OF ACROPHOBIA

To examine the ability of VRE to heights to reduce symptoms of acrophobiain the real world, we used standard outcome measures of acrophobia that arenot specific to the virtual environment. These measures were taken at thepretreatment assessment, the midtreatment assessment between the 2 therapysessions, 1 to 2 weeks posttreatment, and 3 months posttreatment. These measureswere always taken in the absence of medication, and the questionnaires referredto subjects’ symptoms of acrophobia in the real world not the virtualenvironment. Figure 4 shows the reductionof fear as measured by difference scores between each posttreatment measureand the pretreatment baseline measure for placebo and DCS groups.

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Figure 4.

Maintenance and generalization inreduction of acrophobia. Reduction in fear compared with pretreatment baselineon general measures of acrophobia in the real world 1 week after the firsttherapy session (midtreatment), 1 to 2 weeks after the second therapy session,or at 3-month follow-up. A, Acrophobia Avoidance Questionnaire (repeated-measuresanalysis of variance, D-cycloserine vs placebo: F1,19 = 6.1, P<.02). B, Acrophobia Anxiety Questionnaire (repeated-measuresanalysis of variance, D-cycloserine vs placebo: F1,19 = 7.9, P<.01). C, Attitude Toward Heights Inventory (repeated-measuresanalysis of variance, D-cycloserine vs placebo: F1,19 = 4.9, P<.04). Error bars indicate SEM.

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For all principal outcome measures, we found significant improvementsin the DCS group as compared with the placebo group in this repeated-measureanalysis. This was true for generalized avoidance of heights measures (AAVQ:F1,19 = 6.1, P≤.02), anxietydue to heights (AAQ: F1,19 = 7.9, P≤.01), and general attitudes toward heights (ATHI: F1,19 = 4.9, P≤.04). These significant primary outcomes were alsoseen when the placebo and the 50-mg and 500-mg drug doses were separated (AAVQ:F2,18 = 5.9, P≤.01; AAQ:F2,18 = 4.0, P≤.04; ATHI:F2,18 = 2.5, P≤.10). Thesedata suggest that the enhanced extinction that occurred during the initial2 therapy sessions was robust and lasting and also that it was capable ofgeneralization to real-world height situations during the 3 months that followedthe therapy.

OVERALL SUBJECTIVE AND FUNCTIONAL IMPROVEMENT ENHANCED WITH D-CYCLOSERINEAUGMENTATION

The final analyses examined general measures of overall improvementin acrophobia as well as evidence of functional gains in the subjects’lives at the 3-month follow-up assessment (Figure5). Average scores on the CGI scale were significantly higher atthe 1-week and 3-month follow-up sessions as analyzed with a repeated-measuresANOVA (Figure 5A) (DCS vs placebo: F1,19 = 11.6, P≤.005). Analysisof placebo, 50 mg, and 500 mg separately also revealed significant differences(F2,18 = 5.6, P≤.01). Furthermore,as seen in Figure 5B, the DCS groupshowed significantly greater percentages of subjects reporting “muchimprovement” or “very much improvement” compared with theplacebo group at 1 week and 3 months (Figure 5B) (repeated-measures ANOVA: overall drug effect, F1,19 = 11.5, P≤.005, but no drug × time interaction;when analyzed with drug doses separately, F2,18 = 5.4, P≤.01).

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Figure 5.

Global improvement and self-exposure.Overall improvement in generalized acrophobia. A, Average Clinical GlobalImprovement scores (1 = “very much improved,” 4 = “nochange”) for placebo vs D-cycloserine groups at 1 week and 3 monthsfollowing treatment (repeated-measures analysis of variance, D-cycloserinevs placebo: F1,19 = 11.6, P≤.01).B, Percentage of subjects rating themselves as “very much improved”or “much improved” on the Clinical Global Improvement scale. Subjectsreceiving D-cycloserine during treatment demonstrated significantly greatersubjective improvement compared with those receiving placebo (repeated-measuresanalysis of variance, D-cycloserine vs placebo demonstrating an overall drugeffect but no drug × time interaction: F1,19 = 11.5, P≤.01). C, Reduction in acrophobia as measured by real-worldself-exposures to heights during the 3 months following treatment. Subjectsreceiving D-cycloserine during treatment demonstrated significantly more exposuresto heights at 3 months than did subjects receiving placebo (F1,18 = 7.7, P≤.01). Error bars indicate SEM.

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A critical measure of functional improvement is the actual number oftimes the subjects exposed themselves to previously fear-inducing heightsin the period following the treatment. Previous studies have demonstratedthat subjects successfully treated for acrophobia will expose themselves toheights in the real world following treatment much more frequently than thosewho are still fearful of heights. When we asked subjects to report the numberof significant exposures (eg, peering over a high railing, bridge, etc) thatthey experienced since the completion of treatment, subjects receiving DCSduring treatment reported more than twice as many exposures as those receivingplacebo (Figure 5C) (DCS vs placebo:F1,18 = 7.7, P≤.01; whenanalyzed with drug doses separately, F2,18 = 3.6, P≤.05).

These data demonstrate that DCS facilitates the effects of exposuretherapy for the treatment of acrophobia. Participants in the DCS group showedsome evidence of enhanced extinction after only a single dose of medicationand therapy. Following 2 doses of medication and therapy, they showed significantreductions in levels of fear to the specific exposure environment in bothsubjective and objective physiological measures of fear. Finally, we foundthat 3 months following the 2 treatment sessions, the DCS participants showedsignificant improvements on all general acrophobia measures, their own self-exposuresin the real world, and their impression of clinical self-improvement.

Our data indicate that participants receiving DCS experienced no changein anxiety or fear during the exposure paradigm so that the enhancement ofextinction is not due simply to altered intensity of exposure. Additionally,the placebo and drug groups were evenly matched on all measures prior to thestudy (Table), suggesting that pretreatmentvariables did not contribute to the differential improvement in groups. Theslightly higher but nonsignificant depression scores in the placebo groupcompared with the DCS group (BDI = 7.7 vs 4.2) raised the issueof whether subclinical depression could account for some of the differencesseen. To test this hypothesis, we reanalyzed all the primary outcomes withpretreatment BDI as a covariate. In all cases (1- or 3-week SUDS, skin conductancefluctuations, AAQ, AAVQ, ATHI, CGI, and self-exposure), none of the covariateanalyses were significant (P = .12-.88).Therefore, the data presented here specifically support the role of DCS duringexposure therapy contributing to the resultant enhanced improvement in acrophobia.

It is interesting to note that we did not see an apparent increase inextinction during the treatment session but only between sessions. This findingwas expected in part because preclinical studies13,14 onthe effect of DCS on extinction of fear in rats found that extinction seemedto occur during the postacquisition period. Furthermore, it has also beensuggested that the NMDA-dependent phase of extinction training occurs duringthe postextinction consolidation period.39

What is the mechanism of this enhancement of behavioral extinction inhumans? Although it is possible that DCS somehow specifically enhances extinction,the current literature would suggest that it enhances associative learningin general and thus enhances extinction as a form of learning. The specificevidence that DCS enhances extinction in a learning-specific way again comesfrom preclinical evidence in rodents. When combined with repeated exposureto the conditioned stimulus, the DCS-treated animals showed accelerated extinction.However, this reduction was not seen when the animals were simply placed backin the fear-conditioning context in the absence of the conditioned stimulus.Thus, DCS did not reduce fear by itself but only facilitated the specificprocess of extinction of fear in combination with the exposure.13,14

Evidence suggests that DCS facilitates other forms of learning in animalmodels.8,10,4042 Thisis thought to occur through DCS-mediated enhanced activity of the NMDA receptor,a glutamate receptor known to be critical for multiple forms of learning. N-methyl-D-aspartate antagonists have beenshown to block the formation of fear memories with fear conditioning43,44 as well as to block the process ofextinction of conditioned fear.18,45 Furthermore,a transgenic mouse that overexpressed the most active NMDA receptor subunit,NR2B, showed enhanced learning and memory on numerous spatial tasks as wellas with both fear conditioning and extinction of fear.46 Thedata in our study do not directly address whether DCS is augmenting the cognitivecomponent or associative component of learning. However, based on the animalliterature on mechanisms of extinction, we believe that the most simple andconcise explanation of the data is that DCS primarily enhances the associativecomponent of extinction learning that occurs with exposure therapy.

It is also of interest that we found increased self-exposures in theearly and late postassessment periods in the DCS groups compared with theplacebo group. We cannot rule out the possibility that DCS treatment duringexposure somehow increased the amount of self-exposure in the days and weeksafter treatment (off drug) and that those self-exposures accounted for someof the primary outcome findings. However, we believe that even if this weretrue, it would not detract from the overall finding that only 2 administrationsof drug during exposure-based psychotherapy significantly improved reductionof fear compared with the placebo result. Indeed, it would seem to supportthe idea from the animal literature that the DCS treatment enhanced extinctionso that subjects were less fearful in the real world and less likely to avoidheights, providing further evidence for improvement in the DCS-treated subjects.

In some human trials for the treatment of Alzheimer disease, DCS hasbeen shown to be partially effective on subscales of memory improvement.11,12 However, some studies have failedto find a significant effect on human memory.35,36,47 Wepropose that a principal difference between those studies, our current study,and the animal literature is the frequency and chronicity of drug dosing.The previous human studies used chronic daily dosing for weeks to months comparedwith single dosing in this study and in animals. In fact, Quartermain et al42 explicitly examined acute vs chronic dosing of DCSin mice for improvement of spatial learning. They found that a single doseof drug enhanced learning whereas 15 days of drug had no effect.42 Mostpsychiatric medications have their intended psychotropic effect through chronicmechanisms that often involve receptor, cellular, and systemic regulatorymechanisms that are quite distinct from the acute pharmacological drug effect.Tachyphylaxis, among other regulatory phenomena, is likely to occur with prolongedactivation of the NMDA receptor. Desensitization of the NMDA receptor complexhas been demonstrated in cell culture with prolonged exposure to DCS and otherglycinergic ligands.48 In contrast to othertypes of psychotropic medication, DCS may need to be taken on an acute andnot chronic dosing schedule to achieve the intended effect of functionallyenhancing NMDA receptor activity. This hypothesis remains to be directly testedin an acute vs chronic dosing study in humans.

There are several limitations to this study. First, this is the initialpilot study of the use of DCS to facilitate extinction of fear in humans.As such, the results and interpretations from this study need to be examinedin the context of a pilot study and will depend in part on further replication.Because of the relatively small sample size, the study was not adequatelypowered to demonstrate significant differences between the DCS doses used.Additionally, none of the measures used in this study are without their limitations.All of the psychological measures are by definition subjective, and the physiologicalmeasure of skin conductance fluctuation may also be affected by external stimuliand the subjects’ movements. As outlined in “Methods” and“Results,” we made every attempt to control for these issues andto demonstrate that the physiological and subjective measures of fear werecorrelated. Finally, there are obvious differences in how routine in vivoexposure therapy for phobias is performed compared with VRE therapy that mayimpact effectiveness. Future studies examining the ability of DCS to augmentexposure therapy for different disorders of fear dysregulation are neededand eagerly anticipated.

The use of a medication that is taken only in conjunction with and forthe specific purpose of accelerating learning that occurs in psychotherapywould have important implications. Although specific phobia provides the mosteasily testable disorder that is amenable to behavioral exposure therapy,this form of therapy is also the mainstay of treatment for other anxiety disorders,such as panic disorder, obsessive-compulsive disorder, and posttraumatic stressdisorder. In addition, the process of extinction of conditioned cues is thoughtto be important for recovery from disorders of substance dependence.49 Finally, it is possible that the therapeutic factorof other forms of psychotherapy relies in part on the process of extinctionthrough imaginal exposure. If such future studies prove successful, the useof cognitive enhancers to specifically potentiate the learning that occurswith psychotherapy could significantly alter the theory and practice of psychiatry.Importantly, it suggests new therapeutic approaches for patients with refractoryanxiety disorders that are unresponsive to current treatment options.

Submitted for Publication: February10, 2004; final revision received April 26, 2004; accepted May 2, 2004.

Correspondence: Michael Davis, PhD, Departmentof Psychiatry and Behavioral Sciences, Emory University, Woodruff MemorialBuilding, Suite 4000, 1639 Pierce Dr, Atlanta, GA 30322 (mdavis4@emory.edu).

Funding/Support:This study was supported bygrant IBN-987675 from the Science and Technology Center Program, Center forBehavioral Neuroscience, National Science Foundation, Arlington, Va, and grantsMH-069884 (Dr Ressler) and MH-047840 (Dr Davis) from the National Instituteof Mental Health, Bethesda, Md. Drs Rothbaum and Hodges receive research fundingand are entitled to sales royalty from Virtually Better Inc, Decatur, Ga.

Schatzberg  ANemeroff  CB Textbook of Psychopharmacology.  Washington, DC American Psychiatric Press1998;
Otto  M Learning and “unlearning” fears: preparedness, neural pathways,and patients. Biol Psychiatry 2002;52917- 920
PubMed
Foa  EFranklin  MEMoser  J Context in the clinic: how well do cognitive-behavioral therapies andmedications work in combination? Biol Psychiatry 2002;52987- 997
PubMed
Barlow  DHGorman  JMShear  MKWoods  SW Cognitive-behavioral therapy, imipramine, or their combination forpanic disorder: a randomized controlled trial. JAMA 2000;2832529- 2536
PubMed
Marks  ISwinson  RBasoglu  MKuch  KNoshirvani  HO'Sullivan  GLelliott  PTKirby  MMcNamee  GSengun  S Alprazolam and exposure alone and combined in panic disorder with agoraphobia:a controlled study in London and Toronto. Br J Psychiatry 1993;162776- 787
Sheinin  AShavit  SBenveniste  M Subunit specificity and mechanism of action of NMDA partial agonistD-cycloserine. Neuropharmacology 2001;41151- 158
PubMed
Hood  WCompton  RMonahan  J D-cycloserine: a ligand for the N-methyl-D-aspartate coupled glycinereceptor has partial agonist characteristics. Neurosci Lett 1989;9891- 95
PubMed
Flood  JMorley  JLanthorn  T Effect on memory processing by D-cycloserine, an agonist of the NMDA/glycinereceptor. Eur J Pharmacol 1992;221249- 254
Lelong  VDauphin  FBoulouard  M RS 67333 and D-cycloserine accelerate learning acquisition in the rat. Neuropharmacology 2001;41517- 522
PubMed
Monahan  JBHandelmann  GEHood  WFCordi  AA D-cycloserine, a positive modulator of the N-methyl-D-aspartate receptor,enhances performance of learning tasks in rats. Pharmacol Biochem Behav 1989;34649- 653
PubMed
Tsai  GFalk  WGunther  JCoyle  J Improved cognition in Alzheimer’s disease with short-term D-cycloserinetreatment. Am J Psychiatry 1999;156467- 469
PubMed
Schwartz  BLHashtroudi  SHerting  RLSchwartz  PDeutsch  SI d-Cycloserine enhances implicit memory in Alzheimer patients. Neurology 1996;46420- 424
PubMed
Walker  DLRessler  KJLu  KTDavis  M Facilitation of conditioned fear extinction by systemic administrationor intra-amygdala infusions of D-cycloserine as assessed with fear-potentiatedstartle in rats. J Neurosci 2002;222343- 2351
PubMed
Ledgerwood  LRichardson  RCranney  J Effects of D-cycloserine on extinction of conditioned freezing. Behav Neurosci 2003;117341- 349
PubMed
Rescorla  R Experimental extinction. Klein  SedHandbook of Contemporary LearningTheories. Mahwah, NJ Lawrence Erlbaum Associates2001;119- 154
Bouton  M Context, ambiguity, and unlearning: sources of relapse after behavioralextinction. Biol Psychiatry 2002;52976- 986
PubMed
Myers  KMDavis  M Behavioral and neural analysis of extinction. Neuron 2002;36567- 584
PubMed
Falls  WAMiserendino  MJDavis  M Extinction of fear-potentiated startle: blockade by infusion of anNMDA antagonist into the amygdala. J Neurosci 1992;12854- 863
PubMed
Davis  MMyers  KM The role of glutamate and gamma-aminobutyric acid in fear extinction:clinical implications for exposure therapy. Biol Psychiatry 2002;52998- 1007
PubMed
Rothbaum  BOHodges  LFKooper  ROpdyke  DWilliford  JSNorth  M Effectiveness of computer-generated (virtual reality) graded exposurein the treatment of acrophobia. Am J Psychiatry 1995;152626- 628
PubMed
Rothbaum  BOHodges  LSmith  SLee  JHPrice  L A controlled study of virtual reality exposure therapy for the fearof flying. J Consult Clin Psychol 2000;681020- 1026
PubMed
Rothbaum  BOHodges  LFReady  DGraap  KAlarcon  RD Virtual reality exposure therapy for Vietnam veterans with posttraumaticstress disorder. J Clin Psychiatry 2001;62617- 622
PubMed
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders,Revised Third Edition.  Washington, DC American Psychiatric Association1987;
Spitzer  RLWilliams  JBGibbon  MFirst  MB The Structured Clinical Interview for DSM-III-R (SCID),I: history, rationale, and description. Arch Gen Psychiatry 1992;49624- 629
PubMed
Cohen  D Comparison of self-report and overt-behavioral procedures for assessingacrophobia. Behav Ther 1977;817- 23
Abelson  JCurtis  G Cardiac and neuroendocrine responses to exposure therapy in heightphobics: desynchrony within the “physiological response system”. Behav Res Ther 1989;27561- 567
PubMed
Beck  AWard  CMendelsohn  MMock  JErbaugh  J An inventory for measuring depression. Arch Gen Psychiatry 1961;4561- 571
PubMed
Spielberger  CGorsuch  RLushene  R Manual for the State-Trait Anxiety Inventory (Self-EvaluationQuestionnaire).  Palo Alto, Calif Consulting Psychologists Press1970;
Grillon  CHill  J Emotional arousal does not affect delay eyeblink conditioning. Brain Res Cogn Brain Res 2003;17400- 405
PubMed
Storm  HMyre  KRostrup  MStokland  OLien  MDRaeder  JC Skin conductance correlates with perioperative stress. Acta Anaesthesiol Scand 2002;46887- 895
PubMed
Lader  MH Palmar skin conductance measures in anxiety and phobic states. J Psychosom Res 1967;11271- 281
PubMed
Tsai  GFalk  WGunther  J A preliminary study of D-cycloserine treatment in Alzheimer’sdisease. J Neuropsychiatry Clin Neurosci 1998;10224- 226
PubMed
Goff  DTsai  GLevitt  JAmico  EManoach  DSchoenfeld  DAHayden  DLMcCarley  RCoyle  JT A placebo-controlled trial of D-cycloserine added to conventional neurolepticsin patients with schizophrenia. Arch Gen Psychiatry 1999;5621- 27
PubMed
D'Souza  DCGil  RCassello  KMorrissey  KAbi-Saab  DWhite  JSturwold  RBennett  AKarper  LPZuzarte  ECharney  DSKrystal  JH IV glycine and oral D-cycloserine effects on plasma and CSF amino acidsin healthy humans. Biol Psychiatry 2000;47450- 462
PubMed
Fakouhi  TJhee  SSramek  JBenes  CSchwartz  PHantsburger  GHerting  RSwabb  EACutler  NR Evaluation of cycloserine in the treatment of Alzheimer’s disease. J Geriatr Psychiatry Neurol 1995;8226- 230
PubMed
Randolph  CRoberts  JTierney  MCBravi  DMourandian  MMChase  TN D-cycloserine treatment of Alzheimer’s disease. Alzheimer Dis Assoc Disord 1994;8198- 205
PubMed
van Berckel  BNLipsch  CGispen-de Wied  CWynne  HJBlankenstein  MAvan Ree  JMKahn  RS The partial NMDA agonist D-cycloserine stimulates LH secretion in healthyvolunteers. Psychopharmacology (Berl) 1998;138190- 197
PubMed
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition.  Washington, DC American Psychiatric Association1994;
Santini  EMuller  RUQuirk  GJ Consolidation of extinction learning involves transfer from NMDA-independentto NMDA-dependent memory. J Neurosci 2001;219009- 9017
PubMed
Matsuoka  NAigner  TG D-cycloserine, a partial agonist at the glycine site coupled to N-methyl-D-aspartatereceptors, improves visual recognition memory in rhesus monkeys. J Pharmacol Exp Ther 1996;278891- 897
PubMed
Thompson  LTMoskal  JRDisterhoft  JF Hippocampus-dependent learning facilitated by a monoclonal antibodyor D-cycloserine. Nature 1992;359638- 641
PubMed
Quartermain  DMower  JRafferty  MHerting  RLanthorn  T Acute but not chronic activation of the NMDA-coupled glycine receptorwith D-cycloserine facilitates learning and retention. Eur J Pharmacol 1994;2577- 12
PubMed
Miserendino  MJDSananes  CBMelia  KRDavis  M Blocking of acquisition but not expression of conditioned fear-potentiatedstartle by NMDA antagonists in the amygdala. Nature 1990;345716- 718
PubMed
Kim  JDeCola  JLandeira-Fernandez  JFanselow  M N-methyl-D-aspartate receptor antagonist APV blocks acquisition butnot expression of fear conditioning. Behav Neurosci 1991;105126- 133
PubMed
Baker  JDAzorlosa  JL The NMDA antagonist MK-801 blocks the extinction of Pavlovian fearconditioning. Behav Neurosci 1996;110618- 620
PubMed
Tang  YPShimizu  EDube  GRRampon  CKerchner  GAZhuo  MLiu  GTsien  JZ Genetic enhancement of learning and memory in mice. Nature 1999;40163- 69
PubMed
Laake  KOeksengaard  AR D-cycloserine for Alzheimer's disease. Cochrane Database Syst Rev 2004;32
Boje  KMWong  GSkolnick  P Desensitization of the NMDA receptor complex by glycinergic ligandsin cerebellar granule cell cultures. Brain Res 1993;603207- 214
PubMed
O’Brien  CChildress  AMcLellan  AEhrman  R Classical conditioning in drug-dependent humans. Ann N Y Acad Sci 1992;654400- 415
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Acrophobia within the virtual environment.A, Level of fear as measured by subjective units of discomfort (1 = nofear, 100 = maximum fear) during the pretreatment assessment ateach successive floor in the virtual glass elevator. B, Subjective units ofdiscomfort during the first treatment session in which subjects were elevatedto successive floors at 5-minute intervals. C, Floor to which the subjectswere elevated at 5-minute intervals during the first treatment session. Therewere no significant differences between the groups during the pretreatmentsubjective units of discomfort measure or either measure during the firsttreatment session. Error bars indicate SEM.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Acrophobia within the virtual environmentis improved with D-cycloserine. A, Reduction in fear from pretest to posttestfollowing the 2 therapy sessions measured at the first follow-up assessment.Decrease in subjective units of discomfort level (y-axis) is shown for eachfloor (1-19) of the virtual glass elevator. Overall analysis of variance wasperformed using pre-post difference and floor as within-subjects variablesand drug group as between-subjects variable. Significant overall pre-postchanges were seen: F1,25 = 38, P≤.001.Significant effect of floor was found: F6,150 = 89, P≤.001. Most importantly, significant effect of pre-post × floor × druginteraction was found: F6,150 = 3.8, P≤.001. B, Change in subjective units of discomfort from pretestto posttest at the 3-month long-term follow-up assessment. Statistics wereperformed as above. Significant overall pre-post changes were seen: F1,17 = 21, P≤.001. Significanteffect of floor was found: F6,102 = 81, P≤.001. Most importantly, significant effect of pre-post × floor × druginteraction was found: F6,102 = 2.4, P≤.05. Error bars indicate SEM.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Physiological measures of anxietywithin the virtual environment. Spontaneous fluctuations in baseline skinconductance levels are shown as a function of acrophobia treatment responseand treatment condition. A, Subjective improvement in acrophobia symptoms.Those reporting improvement in symptoms show significantly lower posttreatmentspontaneous fluctuations in the virtual environment (F1,19 = 4.5, P≤.05). B, Decreased avoidance (self-reports of whetherthey have self-exposed to heights since treatment) also was associated withsignificantly lower spontaneous fluctuations of skin conductance (F1,19 = 8.26, P≤.01). C, Subjects treatedwith D-cycloserine during exposure therapy showed significant decreases inposttreatment fluctuations (paired t test, P≤.05) compared with those treated with placebo (P≥.5). Error bars indicate SEM.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Maintenance and generalization inreduction of acrophobia. Reduction in fear compared with pretreatment baselineon general measures of acrophobia in the real world 1 week after the firsttherapy session (midtreatment), 1 to 2 weeks after the second therapy session,or at 3-month follow-up. A, Acrophobia Avoidance Questionnaire (repeated-measuresanalysis of variance, D-cycloserine vs placebo: F1,19 = 6.1, P<.02). B, Acrophobia Anxiety Questionnaire (repeated-measuresanalysis of variance, D-cycloserine vs placebo: F1,19 = 7.9, P<.01). C, Attitude Toward Heights Inventory (repeated-measuresanalysis of variance, D-cycloserine vs placebo: F1,19 = 4.9, P<.04). Error bars indicate SEM.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Global improvement and self-exposure.Overall improvement in generalized acrophobia. A, Average Clinical GlobalImprovement scores (1 = “very much improved,” 4 = “nochange”) for placebo vs D-cycloserine groups at 1 week and 3 monthsfollowing treatment (repeated-measures analysis of variance, D-cycloserinevs placebo: F1,19 = 11.6, P≤.01).B, Percentage of subjects rating themselves as “very much improved”or “much improved” on the Clinical Global Improvement scale. Subjectsreceiving D-cycloserine during treatment demonstrated significantly greatersubjective improvement compared with those receiving placebo (repeated-measuresanalysis of variance, D-cycloserine vs placebo demonstrating an overall drugeffect but no drug × time interaction: F1,19 = 11.5, P≤.01). C, Reduction in acrophobia as measured by real-worldself-exposures to heights during the 3 months following treatment. Subjectsreceiving D-cycloserine during treatment demonstrated significantly more exposuresto heights at 3 months than did subjects receiving placebo (F1,18 = 7.7, P≤.01). Error bars indicate SEM.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Baseline Pretreatment Data of Participant Sample

References

Schatzberg  ANemeroff  CB Textbook of Psychopharmacology.  Washington, DC American Psychiatric Press1998;
Otto  M Learning and “unlearning” fears: preparedness, neural pathways,and patients. Biol Psychiatry 2002;52917- 920
PubMed
Foa  EFranklin  MEMoser  J Context in the clinic: how well do cognitive-behavioral therapies andmedications work in combination? Biol Psychiatry 2002;52987- 997
PubMed
Barlow  DHGorman  JMShear  MKWoods  SW Cognitive-behavioral therapy, imipramine, or their combination forpanic disorder: a randomized controlled trial. JAMA 2000;2832529- 2536
PubMed
Marks  ISwinson  RBasoglu  MKuch  KNoshirvani  HO'Sullivan  GLelliott  PTKirby  MMcNamee  GSengun  S Alprazolam and exposure alone and combined in panic disorder with agoraphobia:a controlled study in London and Toronto. Br J Psychiatry 1993;162776- 787
Sheinin  AShavit  SBenveniste  M Subunit specificity and mechanism of action of NMDA partial agonistD-cycloserine. Neuropharmacology 2001;41151- 158
PubMed
Hood  WCompton  RMonahan  J D-cycloserine: a ligand for the N-methyl-D-aspartate coupled glycinereceptor has partial agonist characteristics. Neurosci Lett 1989;9891- 95
PubMed
Flood  JMorley  JLanthorn  T Effect on memory processing by D-cycloserine, an agonist of the NMDA/glycinereceptor. Eur J Pharmacol 1992;221249- 254
Lelong  VDauphin  FBoulouard  M RS 67333 and D-cycloserine accelerate learning acquisition in the rat. Neuropharmacology 2001;41517- 522
PubMed
Monahan  JBHandelmann  GEHood  WFCordi  AA D-cycloserine, a positive modulator of the N-methyl-D-aspartate receptor,enhances performance of learning tasks in rats. Pharmacol Biochem Behav 1989;34649- 653
PubMed
Tsai  GFalk  WGunther  JCoyle  J Improved cognition in Alzheimer’s disease with short-term D-cycloserinetreatment. Am J Psychiatry 1999;156467- 469
PubMed
Schwartz  BLHashtroudi  SHerting  RLSchwartz  PDeutsch  SI d-Cycloserine enhances implicit memory in Alzheimer patients. Neurology 1996;46420- 424
PubMed
Walker  DLRessler  KJLu  KTDavis  M Facilitation of conditioned fear extinction by systemic administrationor intra-amygdala infusions of D-cycloserine as assessed with fear-potentiatedstartle in rats. J Neurosci 2002;222343- 2351
PubMed
Ledgerwood  LRichardson  RCranney  J Effects of D-cycloserine on extinction of conditioned freezing. Behav Neurosci 2003;117341- 349
PubMed
Rescorla  R Experimental extinction. Klein  SedHandbook of Contemporary LearningTheories. Mahwah, NJ Lawrence Erlbaum Associates2001;119- 154
Bouton  M Context, ambiguity, and unlearning: sources of relapse after behavioralextinction. Biol Psychiatry 2002;52976- 986
PubMed
Myers  KMDavis  M Behavioral and neural analysis of extinction. Neuron 2002;36567- 584
PubMed
Falls  WAMiserendino  MJDavis  M Extinction of fear-potentiated startle: blockade by infusion of anNMDA antagonist into the amygdala. J Neurosci 1992;12854- 863
PubMed
Davis  MMyers  KM The role of glutamate and gamma-aminobutyric acid in fear extinction:clinical implications for exposure therapy. Biol Psychiatry 2002;52998- 1007
PubMed
Rothbaum  BOHodges  LFKooper  ROpdyke  DWilliford  JSNorth  M Effectiveness of computer-generated (virtual reality) graded exposurein the treatment of acrophobia. Am J Psychiatry 1995;152626- 628
PubMed
Rothbaum  BOHodges  LSmith  SLee  JHPrice  L A controlled study of virtual reality exposure therapy for the fearof flying. J Consult Clin Psychol 2000;681020- 1026
PubMed
Rothbaum  BOHodges  LFReady  DGraap  KAlarcon  RD Virtual reality exposure therapy for Vietnam veterans with posttraumaticstress disorder. J Clin Psychiatry 2001;62617- 622
PubMed
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders,Revised Third Edition.  Washington, DC American Psychiatric Association1987;
Spitzer  RLWilliams  JBGibbon  MFirst  MB The Structured Clinical Interview for DSM-III-R (SCID),I: history, rationale, and description. Arch Gen Psychiatry 1992;49624- 629
PubMed
Cohen  D Comparison of self-report and overt-behavioral procedures for assessingacrophobia. Behav Ther 1977;817- 23
Abelson  JCurtis  G Cardiac and neuroendocrine responses to exposure therapy in heightphobics: desynchrony within the “physiological response system”. Behav Res Ther 1989;27561- 567
PubMed
Beck  AWard  CMendelsohn  MMock  JErbaugh  J An inventory for measuring depression. Arch Gen Psychiatry 1961;4561- 571
PubMed
Spielberger  CGorsuch  RLushene  R Manual for the State-Trait Anxiety Inventory (Self-EvaluationQuestionnaire).  Palo Alto, Calif Consulting Psychologists Press1970;
Grillon  CHill  J Emotional arousal does not affect delay eyeblink conditioning. Brain Res Cogn Brain Res 2003;17400- 405
PubMed
Storm  HMyre  KRostrup  MStokland  OLien  MDRaeder  JC Skin conductance correlates with perioperative stress. Acta Anaesthesiol Scand 2002;46887- 895
PubMed
Lader  MH Palmar skin conductance measures in anxiety and phobic states. J Psychosom Res 1967;11271- 281
PubMed
Tsai  GFalk  WGunther  J A preliminary study of D-cycloserine treatment in Alzheimer’sdisease. J Neuropsychiatry Clin Neurosci 1998;10224- 226
PubMed
Goff  DTsai  GLevitt  JAmico  EManoach  DSchoenfeld  DAHayden  DLMcCarley  RCoyle  JT A placebo-controlled trial of D-cycloserine added to conventional neurolepticsin patients with schizophrenia. Arch Gen Psychiatry 1999;5621- 27
PubMed
D'Souza  DCGil  RCassello  KMorrissey  KAbi-Saab  DWhite  JSturwold  RBennett  AKarper  LPZuzarte  ECharney  DSKrystal  JH IV glycine and oral D-cycloserine effects on plasma and CSF amino acidsin healthy humans. Biol Psychiatry 2000;47450- 462
PubMed
Fakouhi  TJhee  SSramek  JBenes  CSchwartz  PHantsburger  GHerting  RSwabb  EACutler  NR Evaluation of cycloserine in the treatment of Alzheimer’s disease. J Geriatr Psychiatry Neurol 1995;8226- 230
PubMed
Randolph  CRoberts  JTierney  MCBravi  DMourandian  MMChase  TN D-cycloserine treatment of Alzheimer’s disease. Alzheimer Dis Assoc Disord 1994;8198- 205
PubMed
van Berckel  BNLipsch  CGispen-de Wied  CWynne  HJBlankenstein  MAvan Ree  JMKahn  RS The partial NMDA agonist D-cycloserine stimulates LH secretion in healthyvolunteers. Psychopharmacology (Berl) 1998;138190- 197
PubMed
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition.  Washington, DC American Psychiatric Association1994;
Santini  EMuller  RUQuirk  GJ Consolidation of extinction learning involves transfer from NMDA-independentto NMDA-dependent memory. J Neurosci 2001;219009- 9017
PubMed
Matsuoka  NAigner  TG D-cycloserine, a partial agonist at the glycine site coupled to N-methyl-D-aspartatereceptors, improves visual recognition memory in rhesus monkeys. J Pharmacol Exp Ther 1996;278891- 897
PubMed
Thompson  LTMoskal  JRDisterhoft  JF Hippocampus-dependent learning facilitated by a monoclonal antibodyor D-cycloserine. Nature 1992;359638- 641
PubMed
Quartermain  DMower  JRafferty  MHerting  RLanthorn  T Acute but not chronic activation of the NMDA-coupled glycine receptorwith D-cycloserine facilitates learning and retention. Eur J Pharmacol 1994;2577- 12
PubMed
Miserendino  MJDSananes  CBMelia  KRDavis  M Blocking of acquisition but not expression of conditioned fear-potentiatedstartle by NMDA antagonists in the amygdala. Nature 1990;345716- 718
PubMed
Kim  JDeCola  JLandeira-Fernandez  JFanselow  M N-methyl-D-aspartate receptor antagonist APV blocks acquisition butnot expression of fear conditioning. Behav Neurosci 1991;105126- 133
PubMed
Baker  JDAzorlosa  JL The NMDA antagonist MK-801 blocks the extinction of Pavlovian fearconditioning. Behav Neurosci 1996;110618- 620
PubMed
Tang  YPShimizu  EDube  GRRampon  CKerchner  GAZhuo  MLiu  GTsien  JZ Genetic enhancement of learning and memory in mice. Nature 1999;40163- 69
PubMed
Laake  KOeksengaard  AR D-cycloserine for Alzheimer's disease. Cochrane Database Syst Rev 2004;32
Boje  KMWong  GSkolnick  P Desensitization of the NMDA receptor complex by glycinergic ligandsin cerebellar granule cell cultures. Brain Res 1993;603207- 214
PubMed
O’Brien  CChildress  AMcLellan  AEhrman  R Classical conditioning in drug-dependent humans. Ann N Y Acad Sci 1992;654400- 415
PubMed

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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
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Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
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