bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/615757

Neurocognitive mechanisms of d-cycloserine augmented single-session exposure therapy for anxiety

Reinecke, A.·Nickless, A.·Browning, M.·Harmer, C.
View original source ↗Export metadata ↓

Abstract

ObjectiveDrugs targeting the N-Methyl-D-aspartic acid (NMDA) system and the ability to learn new associations have been proposed as potential adjunct treatments to boost the success of exposure therapy for anxiety disorders. However, the effects of the NMDA partial agonist d-cycloserine on psychological treatment have been mixed. We investigated potential neurocognitive mechanisms underlying the clinical effects of d-cycloserine-augmented exposure, to inform the optimal combination of this and similar agents with psychological treatment. MethodsUnmedicated patients with panic disorder were randomised to single-dose d-cycloserine (250mg; N=17) or matching placebo (N=16) 2hrs before one session of exposure therapy. Neurocognitive markers were assessed one day after treatment, including reaction-time based threat bias for fearful faces and amygdala response to threat. Clinical symptom severity was measured using self-report and clinician-rated scales the day before and after treatment, and at 1- and 6-months follow-up. Analysis was by intention-to-treat. ResultsOne day after treatment, threat bias for fearful faces and amygdala threat response were attenuated in the drug compared to the placebo group. Lower amygdala magnitude predicted greater clinical improvement during follow-up across groups. D-cycloserine led to greater clinical recovery at 1-month follow-up (d-cycloserine 71% versus placebo 25%). DiscussionD-cycloserine-augmented single-session exposure therapy reduces amygdala threat response, and this effect predicts later clinical response. These findings highlight a neurocognitive mechanism by which d-cycloserine may exert its augmentative effects on psychological treatment and bring forward a marker that may help understand and facilitate future development of adjunct treatments with CBT for anxiety disorders. (D-cycloserine Augmented CBT for Panic Disorder; clinicaltrials.gov; NCT01680107)

Explore related subjects

clinical trialsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Reinecke, A., Nickless, A., Browning, M., Harmer, C.. 2019-04-26. Neurocognitive mechanisms of d-cycloserine augmented single-session exposure therapy for anxiety. https://doi.org/10.1101/615757

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2019

Quadruplex qPCR for qualitative and quantitative analysis of the HIV-1 latent reservoir

HIV-1 infection requires life-long therapy with anti-retroviral drugs due to the existence of a latent reservoir of transcriptionally inactive integrated proviruses. The goal of HIV-1 cure research is to eliminate or functionally silence this reservoir. To this end there are numerous ongoing studies to evaluate immunologic approaches including monoclonal antibody therapies. Evaluating the results of these studies requires sensitive and specific measures of the reservoir. Here we describe a relatively high throughput combined quantitative polymerase chain reaction (qPCR) and next generation sequencing method. Four different qPCR probes covering the packaging signal (PS), group-specific antigen (gag), polymerase (pol), and envelope (env) are combined in a single multiplex reaction to detect the HIV-1 genome in limiting dilution samples followed by sequence verification of individual reactions that are positive for combinations of any 2 of the 4 probes (Q4PCR). This sensitive and specific approach allows for an unbiased characterization of the HIV-1 latent reservoir. SummaryHIV-1 cure research seeks to decrease or eliminate the latent reservoir. The evaluation of such curative strategies requires accurate measures of the reservoir. Gaebler et al. describe a combined multicolor qPCR and next generation sequencing method that enables the sensitive and specific characterization of the HIV-1 latent reservoir.

clinical trials↗
bioRxiv2019

11β-Hydroxysteroid Dehydrogenase Type 1 inhibition in Idiopathic Intracranial Hypertension: a double-blind randomized controlled trial.

Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11{beta}-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability, and investigate indicators of in vivo efficacy of the 11{beta}-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared to placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-weeks treatment with AZD4017 or placebo was conducted. Women aged 18 to 55 years with active idiopathic intracranial hypertension (>25cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400mg twice daily of oral AZD4017 compared to matching placebo over 12-weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropological measures. In vivo efficacy was evaluated in the central nervous system and systemically. 31 subjects (mean age 31.2 (SD=6.9) years and BMI 39.2 (SD=12.6) kg/m2) were randomized to AZD4017 (n=17) or placebo (n=14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmH2O) compared with placebo (31.3 cmH2O), but the difference between groups was not statistically significant (mean difference: -2.8, 95% confidence interval: -7.1-1.5; p=0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group (mean change: -4.3 cmH2O (SD=5.7); p=0.009) but not in the placebo group (mean change: -0.3 cmH2O (SD=5.9); p=0.8). AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). In vivo biomarkers of 11{beta}-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation and CSF cortisone to cortisol ratios) demonstrated significant enzyme inhibition. This is the first phase 2 randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe, well-tolerated and inhibited 11{beta}-hydroxysteroid dehydrogenase type 1 activity in vivo. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.

clinical trials↗
bioRxiv2019

Integrated meditation and exercise therapy: A randomized controlled trial of a combined non-pharmacological intervention reduces disability and pain in patients with chronic low back pain

Integrative and complementary non-pharmacological treatments have proven efficacious in treating both the physiological and psychological symptoms of chronic pain conditions but the potential of many combined therapies is unknown. This study examined the effects of a combined intervention of mindfulness meditation followed by aerobic walking exercise in chronic low back pain (cLBP) patients. We hypothesized that meditation before exercise would reduce disability and pain by increasing mindfulness prior to physical activity. Thirty-eight adults completed either meditation and exercise treatment (MedExT) (n=18) or an audiobook control condition (n=20). Over a 4-week period, participants in the MedExT group performed 12-17 minutes of guided meditation followed by 30 minutes of moderate intensity walking exercise 5 days per week. Measures of disability, pain, mindfulness and anxiety were taken at baseline and post-intervention. Ratings of pain were also assessed by participant self-report, before and after each intervention session. Following MedExT, participants showed significant improvement in our primary outcome of disability compared to the control group (p<0.05). From pre to post-intervention, MedExT also increased mindfulness (p<0.05), but had no significant effect on quantitative sensory testing on the low back. Mean ratings of low back pain intensity and unpleasantness significantly improved with MedExT from before the study to during participation, respectively (intensity p<0.05; unpleasantness p<0.05). Overall, four weeks of MedExT produced substantive changes in disability, mindfulness and measures of pain intensity and unpleasantness.

clinical trials↗