D-cycloserine Research Articles

A placebo-controlled randomized trial of D-cycloserine augmentation of cue exposure therapy for smoking cessation

ABSTRACTRecent studies underscore the importance of studying d-cycloserine (DCS) augmentation under conditions of adequate cue exposure treatment (CET) and protection from reconditioning experiences. In this randomized trial, we evaluated the efficacy of DCS for augmenting CET for smoking cessation under these conditions.Sixty-two smokers attained at least 18 hours abstinence following 4 weeks of smoking cessation treatment and were randomly assigned to receive a single dose of DCS (n=30) or placebo (n=32) prior to each of two sessions of CET. Mechanistic outcomes were self-reported cravings and physiologic reactivity to smoking cues. The primary clinical outcome was 6-week, biochemically-verified, continuous tobacco abstinence.DCS, relative to placebo, augmentation of CET resulted in lower self-reported craving to smoking pictorial and in vivo cues (d = 0.8 to 1.21) in a relevant subsample of participants who were reactive to cues and free from smoking-related reconditioning experiences. Select craving outcomes were correlated with smoking abstinence, and DCS augmentation was associated with a trend toward a higher continuous abstinence rate (33% vs. 13% for placebo augmentation).DCS augmentation of CET can significantly reduce cue-induced craving, supporting the therapeutic potential of DCS augmentation when applied under appropriate conditions for adequate extinction learning.

Learn to forget: Does post-exposure administration of d-cycloserine enhance fear extinction in agoraphobia?

The use of d-cycloserine (DCS) to augment exposure based therapy for anxiety disorders has shown mixed, although overall positive effects. Aim of the present study was to examine post-exposure administration of DCS in patients with agoraphobia with or without panic disorder. 73 patients with agoraphobia (with or without panic disorder) were treated with 12 sessions of cognitive behavioral therapy (CBT) including 3 exposures. Following successful exposure patients were given double blind either placebo or 50 mg of DCS. Primary outcome criterion was change in the Panic and Agoraphobia Scale (PAS) between CBT session t1, t4 (+∼2 months), t10 (+∼3 months) und t11 (+∼4 months). During the course of CBT the patients' symptomatology decreased significantly as measured by primary and secondary outcome criteria, however, without an additional benefit for DCS treated patients. Exploratory sub-group analyses for severely ill patients and patients with high anxiety and strong habituation during exposure showed that DCS administration was associated with increased improvement during the 1-month follow-up period (t10 - t11) with medium to large effect sizes (range in effect size η2p from .06 to .25). Our study results are consistent with recent research on DCS, indicating a beneficial augmentative effect for sub-groups of anxiety patients. The lack of an overall DCS effect for the whole patient sample might be explained by a dual mechanism in fear conditioning and extinction with different cognitive processes being involved during exposure depending on the degree of anxiety experienced by the patient.

N-methyl-D-aspartate Partial Agonist Enhanced Intensive Cognitive-Behavioral Therapy of Panic Disorder in Adolescents.

Panic disorder (PD) can result in significant functional impairment. Studies of cognitive behavioral therapy (CBT) for PD have demonstrated response rates ranging between 38 and 65%. D-cycloserine (DCS), a partial NMDA agonist, may enhance the effects of exposure-based therapy for PD in adults; however, no studies have examined its effect in adolescents with PD. This study examined the feasibility and acceptability of the use of DCS to augment intensive CBT for PD in adolescents. Twenty-four adolescents (ages 12-17) participated in this randomized, double-blinded, placebo-controlled trial, to compare CBT + DCS to CBT + placebo. The results demonstrated the feasibility and acceptability of the treatment to participants. No significant differences were found between the two groups, but both groups showed significant improvement. This is the first investigation of DCS in the treatment of PD in adolescents and it provides initial support for a more extensive study of DCS augmentation of CBT among adolescents with PD.

Therapeutic drug monitoring of cycloserine and linezolid during anti-tuberculosis treatment in Beijing, China.

Plasma concentrations of cycloserine (CS) and linezolid (LZD) in tuberculosis (TB) patients are largely unknown. To measure the plasma concentrations of CS and LZD after drug ingestion in drug-resistant TB patients. Patients who received CS and LZD as part of their treatment between 1 July 2012 and 1 July 2016 were studied retrospectively. CS and LZD plasma levels were determined using high-pressure liquid chromatography-tandem mass spectrometry. Plasma drug concentration, age, sex, liver disease, renal disease, administered doses and diabetes mellitus status were recorded. Based on 390 samples, CS plasma concentrations were below the lower limit of normal (54.87%, 214/390). There was a statistically significant difference between the low concentration group (14.0 ± 3.71 μg/ml) and the target concentration group (25.2 ± 3.73 μg/ml, P < 0.01). The mean plasma concentration of LZD was 15.6 ± 4.91 μg/ml, which was within the target concentration (12-26 μg/ml) in 65 patients. Variables that correlated with CS and LZD concentrations were not found in this retrospective study. Low plasma CS concentrations were common, while 83.1% (54/65) of plasma LZD concentrations were within the target range. Therapeutic drug monitoring is essential to maintain appropriate plasma drug concentrations in the era of precision medicine.

D-Cycloserine augmentation of cognitive behavior therapy for pediatric OCD: Predictors and moderators of outcome

BackgroundOver half of children receiving cognitive behavioral therapy (CBT) for obsessive compulsive disorder (OCD) do not fully remit. To improve response rates and enhance extinction learning, d-cycloserine (DCS) has been examined as an augmenting agent of CBT. To direct children with OCD towards treatments with the highest likelihood of success, the current study evaluated the conditions under which DCS augmentation works best (i.e., moderators) and the baseline characteristics associated with outcome, irrespective of treatment type (i.e., predictors). MethodsData came from a two-site randomized controlled trial (N = 142) in which children received either DCS + CBT (n = 70) or placebo + CBT. ResultsNo baseline variables moderated the effects of DCS augmentation on CBT outcome. However, several predictor variables were associated with a decreased likelihood of achieving remission status, including higher family accommodation scores, higher impairment scores, higher depression scores, and higher externalizing scores. Furthermore, better insight at pre-treatment was associated with more improvement longitudinally on a clinician-rated summary measure of illness severity. LimitationsThe current study did not examine all variables that had previously been shown to moderate or predict treatment outcome (e.g., family history of OCD or cognitive profile). ConclusionsThe absence of significant moderators suggests that baseline factors cannot yet be used to determine who benefits most from DCS. To maximize treatment benefits for children presenting with identified predictors of worse treatment outcome, clinicians might need to adapt existing CBT protocols and administer additional interventions that address patients’ specific problem areas.

D-cycloserine nasal formulation development for anxiety disorders by using polymeric gels.

D-cycloserine (DCS), a partial agonist at N-methyl-D-aspartate (NMDA) receptors, is used as an enhancer of exposure therapy for anxiety disorders. The purpose of the present study was to investigate the feasibility of using polymeric gels to increase the viscosity of the formulation and thereby increase the nasal residence time and sustained release of DCS in vitro. Hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and methyl cellulose (MC) were prepared at concentrations of 0.5 to 5% w/v. Pluronic F-127 (PF-127) was prepared at concentrations of 15 to 35% w/v. pH, viscosity and in vitro DCS release behavior of the formulated gels were analyzed. All four gels that were tested, demonstrated sustained DCS release behavior over a 24-hour period, but with different rates. Based on the results of this study, HPMC, HPC, MC, and PF-127 are capable of increasing the viscosity of nasal gel formulations and of releasing DCS in sustained manner. Therefore, these polymeric gels can be suitable carriers for DCS nasal gel formulation.

D-Cycloserine facilitates fear extinction in adolescent rats and differentially affects medial and lateral prefrontal cortex activation

Adolescent humans and rodents are impaired in extinguishing learned fear relative to younger and older groups. This impairment could be due to differences in recruitment of medial prefrontal cortex (PFC), orbitofrontal cortex (OFC), or amygdala during extinction. For example, unlike juveniles and adults, adolescent rats do not express extinction-induced increases in phosphorylated mitogen activated protein kinase (pMAPK), a marker of synaptic plasticity, in the medial PFC. The NMDA receptor partial agonist d-cycloserine (DCS) improves extinction retention in adolescent rats. We investigated whether DCS affected recruitment of the PFC and amygdala during extinction by measuring pMAPK-immunoreactive (IR) neurons. Adolescent rats were trained to fear a conditioned stimulus in one context followed by extinction in a second context or equivalent context exposure only (i.e., no extinction). DCS (15 mg/kg, s.c.) or saline was administered systemically immediately after extinction training or context exposure. DCS enhanced extinction learning and this was associated with increased activation of the MAPK signaling pathway in the OFC after extinction training and increased activation in the medial PFC and amygdala at extinction retention. These findings suggest that DCS improves extinction learning in adolescents because it augments OFC contributions to extinction learning, enabling better medial prefrontal contributions to extinction retention.

Estradiol-induced enhancement of fear extinction in female rats: The role of NMDA receptor activation

Converging cross-species evidence indicates that fear extinction (the laboratory basis of exposure therapy for anxiety disorders) in females is modulated by endogenous and exogenous estradiol. The mechanisms underlying estradiol's influences on fear extinction are largely undefined. However, one likely candidate is the NMDA-receptor (NMDAr), activation of which is necessary for estradiol-mediated enhancements in structural and functional neural plasticity, as well as extinction consolidation in males. Here, we demonstrate that systemic co-administration of the non-competitive NMDAr antagonist, MK801, blocked the enhancement of fear extinction by systemic estradiol in ovariectomized rats. In intact rats, MK801 during diestrus (rising estradiol) prevented the enhancement in extinction recall in rats that received extinction training during proestrus (peak estradiol). Systemic administration of the partial NMDAr agonist D-cycloserine (DCS) prior to extinction training facilitated extinction in ovariectomized rats, mimicking the effects of estradiol. In intact rats, DCS administered on the afternoon of proestrus and the morning of estrus (declining estradiol) facilitated extinction in rats that received extinction training during metestrus (low estradiol). Finally, DCS also facilitated extinction in ovariectomized rats when administered immediately after extinction training. Combined, these findings suggest that endogenous and exogenous estradiol enhance fear extinction via NMDAr-dependent mechanisms. Moreover, these findings raise the possibility that fear extinction deficits during periods of low endogenous estradiol levels can be reversed by increasing NMDAr activation via DCS administration, either well prior to, or immediately after, extinction training.

T13. D-Cycloserine Facilitates Fear Extinction in Adolescent Rats and Differentially Affects Medial and Lateral Prefrontal Cortex Activation

Adolescents, both humans and rodents, exhibit a marked impairment in extinction of learned fear relative to both younger (i.e., juveniles) and older (i.e., adults) groups. This impairment could be due to the medial or lateral prefrontal cortex (PFC) not being efficiently recruited during extinction. For example, unlike juveniles and adults, adolescent rats do not express extinction-induced increases in phosphorylated mitogen activated protein kinase (pMAPK), a marker of synaptic plasticity, in the medial PFC. The NMDA receptor partial agonist D-cycloserine (DCS), which enhances exposure therapy in humans with anxiety disorders, overcomes the extinction retention deficit in adolescent rats. The present experiments investigated the effects of DCS on the PFC and amygdala by measuring pMAPK-immunoreactive (IR) neurons.

T14. Individual Differences in Extinction and Relapse: Who, Why, and What Can We Do?

We have recently demonstrated that vulnerability to relapse of fear is related to individual differences in the rate of extinction (with slow extinguishers being more vulnerable). Here we examined the molecular basis for these individual differences in rate of extinction and found differences between “fast” and “slow” extinguishers in NMDA receptor protein levels. We then examined whether this translated to differences in responding to an NMDA receptor partial-agonist, D-cycloserine (DCS).

D-Cycloserine Facilitates Reversal in an Animal Model of Post-traumatic Stress Disorder

Many psychiatric disorders are associated with cognitive dysfunction that is ineffectively treated by existing pharmacotherapies and which may contribute to poor real-world functioning. D-cycloserine (DCS) is a partial N-methyl-D-aspartate (NMDA) agonist that has attracted attention because of its cognitive enhancing properties, including in people with post-traumatic stress disorder (PTSD). Here, we examined the effect of DCS on reversal learning - a type of cognitive flexibility – following exposure to single prolonged stress (SPS), a rodent model of PTSD. Male Sprague Dawley rats (n = 64) were trained to press levers in an operant chamber, matched for performance and assigned to SPS or control (unstressed) groups. Following SPS, rats received three additional lever press sessions, followed by a side bias test on day three. One day later they learned a response discrimination rule (press left or right lever, opposite to side bias) and on a subsequent day were trained (and tested) for reversal to the opposite lever. DCS (15 mg/kg) or vehicle was administered 30 minutes prior to the reversal session. No between-group differences were found in acquisition or retrieval of the initial rule, but a significant drug x stress interaction on response discrimination reversal indicated that DCS had a greater beneficial effect on SPS rats’ cognitive flexibility than it did on performance in controls. These findings add to a growing literature on the beneficial effects of DCS for treating a wide variety of deficits that develop following exposure to extreme stress and may have implications for the development of novel pharmacotherapies for PTSD.

The relationship between posttraumatic and depressive symptoms during virtual reality exposure therapy with a cognitive enhancer

Two studies suggest that reductions in posttraumatic symptoms (Aderka et al., 2013) and cognitions (Zalta et al., 2014) precede reductions in depressive symptoms during prolonged exposure (PE) therapy for posttraumatic stress disorder (PTSD) in female assault survivors. The present study explored the temporal relationship between posttraumatic and depressive symptoms in a randomized trial of D-Cycloserine (DCS) versus placebo augmented virtual reality exposure (VRE) therapy for chronic World Trade Center-related PTSD following the September 11, 2001 terrorist attacks. Twenty-five male and female participants were randomly assigned to receive either 100 mg DCS (N = 13) or placebo (N = 12) 90 min before 12 weekly VRE sessions. Participants contributed a total of 280 weekly PTSD Checklist (PCL; Weathers et al., 1993) and Beck Depression Inventory-second edition (BDI-II; Beck et al., 1996) symptom scores. Two sets of mediation analyses for longitudinal mixed models assessed the effects of 1) lagged PCL on BDI-II (Model 1), and 2) lagged BDI-II on PCL (Model 2) in the VRE-DCS and VRE-Placebo treatment groups, respectively. Results revealed reciprocal relations between posttraumatic and depressive symptoms during VRE treatment, although reductions in posttraumatic symptoms led to subsequent reductions in depressive symptoms to a greater extent than the converse. These effects were stronger in the DCS-enhanced group. Findings suggest that VRE primarily decreases posttraumatic symptoms, which in turn leads to decreased depressive symptoms, and that DCS may strengthen these effects.

Prognostic factors for treatment success in patients with multidrug-resistant tuberculosis in China.

To examine the clinical outcomes and associated prognostic factors among patients with multidrug-resistant tuberculosis (MDR-TB) in China. This retrospective study involved 243 patients with MDR-TB. All patients received standard regimens containing para-amino salicylic acid (PAS) and/or cycloserine (CS). The demographic, social and clinical characteristics of patients were recorded and the patients were followed up for 24 months. Treatment success was closely associated with young age, non-farming occupations, shorter history or smoking, normal urine results, initial MDR-TB treatment regimen, increased haemoglobin, direct bilirubin, uric acid and thyroid stimulating hormone (TSH) levels, and lower white blood cell, neutrophil and blood platelet counts (all P < 0.05). On multivariable analysis, increased haemoglobin (hazard ratio [HR] 1.019, 95%CI 1.007-1.032, P = 0.002) and TSH levels (HR 1.002, 95%CI 1.006-1.039, P = 0.008), normal urine results (HR 1.541, 95%CI 1.008-2.358, P = 0.046) and initial MDR-TB treatment regimen (HR 2.238, 95%CI 1.090-4.597, P = 0.028) were prognostic factors for treatment success in MDR-TB. Higher haemoglobin and TSH levels, normal urine results and initial MDR-TB treatment regimen might predict successful treatment of MDR-TB.

Intra-hippocampal D-cycloserine rescues decreased social memory, spatial learning reversal, and synaptophysin levels in aged rats.

Aging is characterized by a decrease in N-methyl-D-aspartate receptors (NMDARs) in the hippocampus, which might be one of the factors involved in the age-dependent cognitive decline. D-Cycloserine (DCS), a partial agonist of the NMDAR glycine recognition site, could improve memory deficits associated to neurodegenerative disorders and cognitive deficits observed in normal aging. The aim of the present study was to explore whether DCS would reverse age-dependent memory deficits and decreases in NMDA receptor subunits (GluN1, GluN2A, and GluN2B) and the presynaptic protein synaptophysin in Wistar rats. We investigated the effects of pre-training infusions of DCS (10 μg/hemisphere) in the ventral hippocampus on two hippocampal-dependent learning tasks, the social transmission of food preference (STFP), and the Morris water maze (MWM). The results revealed that infusions of DCS administered before the acquisition sessions rescued deficits in the STFP retention and MWM reversal learning in old rats. DCS also significantly increased the hippocampal levels of synaptophysin in old rats, which correlated with STFP and MWM performance in all tests. Moreover, although the levels of the GluN1 subunit correlated with the MWM acquisition and reversal, DCS did not enhance the expression of such synaptic protein. The present behavioral results support the role of DCS as a cognitive enhancer and suggest that enhancing the function of NMDARs and synaptic plasticity in the hippocampus may be related to improvement in social memory and spatial learning reversal in aged animals.

Correction: D-cycloserine improves synaptic transmission in an animal mode of Rett syndrome.

[This corrects the article DOI: 10.1371/journal.pone.0183026.].

Construction of an overexpression library for Mycobacterium tuberculosis.

There is a pressing need to develop novel anti-tubercular drugs. High-throughput phenotypic screening yields chemical series that inhibit bacterial growth. Target identification for such series is challenging, but necessary for optimization of target engagement and the development of series into clinical drugs. We constructed a library of recombinant Mycobacterium tuberculosis strains each expressing a single protein from an inducible promoter as a tool for target identification. The library of 1733 clones was arrayed in 96-well plates for rapid screening and monitoring growth. The library contains the majority of the annotated essential genes as well as genes involved in cell wall and fatty acid biosynthesis, virulence factors, regulatory proteins, efflux, and respiration pathways. We evaluated the growth kinetics and plasmid stability over three passages for each clone in the library. We determined expression levels (mRNA and/or protein) in 396 selected clones. We screened the entire library and identified the Alr-expressing clone as the only recombinant strain, which grew in the presence of d-cycloserine (DCS). We confirmed that the Alr-expressing clone was resistant to DCS (7-fold shift in minimum inhibitory concentration). The library represents a new tool that can be used to screen for compound resistance and other phenotypes.

Does d-cycloserine facilitate the effects of homework compliance on social anxiety symptom reduction?

BackgroundPrior studies examining the effect of d-cycloserine (DCS) on homework compliance and outcome in cognitive-behavior therapy (CBT) have yielded mixed results. The aim of this study was to investigate whether DCS facilitates the effects of homework compliance on symptom reduction in a large-scale study for social anxiety disorder (SAD). Methods169 participants with generalized SAD received DCS or pill placebo during 12-session exposure-based group CBT. Improvements in social anxiety were assessed by independent raters at each session using the Liebowitz social anxiety scale (LSAS). ResultsControlling for LSAS at the previous session, and irrespective of treatment condition, greater homework compliance in the week prior related to lower LSAS at the next session. However, DCS did not moderate the effect of homework compliance and LSAS, LSAS on homework compliance, or the overall augmenting effect of DCS on homework compliance. Furthermore, LSAS levels were not predictive of homework compliance in the following week. ConclusionThe findings support the general benefits of homework compliance on outcome, but not a DCS-augmenting effect. The comparably small number of DCS-enhanced sessions in this study could be one reason for the failure to find a facilitating effect of DCS.

No Effects of D-Cycloserine Enhancement in Exposure With Response Prevention Therapy in Panic Disorder With Agoraphobia: A Double-Blind, Randomized Controlled Trial.

D-cycloserine (DCS) is a partial N-methyl-D-aspartate receptor agonist that potentially augments response to exposure therapy in anxiety disorders by enhancing extinction learning. This randomized, double-blinded, placebo-controlled augmentation trial examined (1) the effectiveness of adding 125 mg of DCS to exposure therapy (before or directly after the first 6 treatment sessions) in patients with panic disorder with agoraphobia and (2) the effectiveness of DCS augmentation preceding exposure relative to DCS augmentation directly postexposure. Fifty-seven patients were allocated to 1 of 3 medication conditions (placebo and pre-exposure and postexposure DCS) as an addition to 6 exposure sessions within a 12-session exposure and response prevention protocol. The primary outcome measure was the mean score on the "alone" subscale of the Mobility Inventory (MI). No differences were found in treatment outcome between DCS and placebo, administered either pre-exposure or postexposure therapy, although at 3-month follow-up, the DCS postexposure group compared with DCS pre-exposure, exhibited greater symptom reduction on the MI-alone subscale. Ancillary analyses in specific subgroups (responders vs nonresponders, early vs late responders, severely vs mildly affected patients) did not reveal any between-group DCS versus placebo differences. Finally, the study did not find an effect of DCS relative to placebo to be specific for successful exposure sessions. This study does not find an effect of augmentation with DCS in patients with severe panic disorder and agoraphobia administered either pretreatment or directly posttreatment sessions. Moreover, no preferential effects are revealed in specific subgroups nor in successful exposure sessions. Yet, a small effect of DCS administration postexposure therapy cannot be ruled out, given the relatively small sample size of this study.

D-cycloserine improves synaptic transmission in an animal mode of Rett syndrome

Rett syndrome (RTT), a leading cause of intellectual disability in girls, is predominantly caused by mutations in the X-linked gene MECP2. Disruption of Mecp2 in mice recapitulates major features of RTT, including neurobehavioral abnormalities, which can be reversed by re-expression of normal Mecp2. Thus, there is reason to believe that RTT could be amenable to therapeutic intervention throughout the lifespan of patients after the onset of symptoms. A common feature underlying neuropsychiatric disorders, including RTT, is altered synaptic function in the brain. Here, we show that Mecp2tm1.1Jae/y mice display lower presynaptic function as assessed by paired pulse ratio, as well as decreased long term potentiation (LTP) at hippocampal Schaffer–collateral-CA1 synapses. Treatment of Mecp2tm1.1Jae/y mice with D-cycloserine (DCS), an FDA-approved analog of the amino acid D-alanine with antibiotic and glycinergic activity, corrected the presynaptic but not LTP deficit without affecting deficient hippocampal BDNF levels. DCS treatment did, however, partially restore lower BDNF levels in the brain stem and striatum. Thus, treatment with DCS may mitigate the severity of some of the neurobehavioral symptoms experienced by patients with Rett syndrome.

D-Cycloserine facilitates extinction learning and enhances extinction-related brain activation

Extinction learning is modulated by N-methyl d-aspartate receptors (NMDAR) particularly in prefrontal and hippocampal brain regions. The use of of NMDA agonists in exposure therapy of anxiety disorders has been investigated in various patient groups. Behavioral results showed beneficial effects of pre-learning administration of the partial NMDAR agonist d-Cycloserine (DCS) on therapy success. However, the impact of DCS upon non-fear-related contextual extinction, and associated recruitment of extinction-relevant brain regions is as yet unknown. In the present fMRI study, healthy human participants performed a context-related associative learning and extinction task. A single dose of DCS, administered prior to extinction learning, enhanced extinction learning performance in an identical context, and increased activation in prefrontal, temporal as well as hippocampal/insular regions, compared to placebo controls. In contrast, DCS did not affect extinction learning in a novel context, nor the renewal effect, which describes the recovery of an extinguished response if the context of extinction differs from the context of recall. Our findings demonstrate a specific involvement of prefrontal and hippocampal NMDAR in the modification of established stimulus-outcome associations in identical contexts and thus their role in behavioral flexibility, underlining their potential for enhancing AAA extinction learning.