Cannabidiol enhancement of exposure therapy in treatment refractory patients with phobias: study protocol of a randomized controlled trial.

BACKGROUND: Phobic anxiety disorders are among the most prevalent psychiatric disorders and are burdensome in terms of loss of quality of life and work productivity. Evidence-based treatments are relatively successful in the majority of patients, especially exposure therapy. However, a substantial subset of patients fails to achieve or stay in remission. Preclinical and genetic research have yielded evidence that the cannabinoid system is involved in the extinction of fear, presumed to underlie the beneficial effects of exposure therapy in phobic disorders. A cannabinoid constituent that may enhance endocannabinoid signaling is cannabidiol (CBD), a non-psychoactive component of cannabis. Hence, the addition of CBD to exposure therapy is expected to strengthen effects of treatment. To determine the added benefit of CBD on exposure therapy, we conduct a randomized controlled trial, in which patients in whom previous treatment as usual has not yielded sufficient response receive either CBD or placebo preceding 8 exposure sessions in a double-blind fashion. A subsidiary aim is to explore which (combination of) clinical, behavioral and genetic profiles of patients are related to treatment response. METHODS/DESIGN: This is an 8-week multicenter, randomized, double-blind, placebo-controlled trial. Seventy-two patients with social phobia or panic disorder with agoraphobia with incomplete response to earlier treatment will be included from outpatient clinics in the Netherlands. Patients are randomized to augmentation of exposure therapy with 300 mg CBD or placebo. The study medication is administered orally, 2 h preceding each of the eight 90 min exposure sessions. Measurements will take place at baseline, first administration of medication, every session, mid-treatment, last administration of medication, post-treatment and at 3 and 6 months' follow-up. The primary outcome measure is the score on the Fear Questionnaire (FQ). In addition, determinants of the expected treatment enhancing effect of CBD will be explored. DISCUSSION: This is the first trial to investigate whether the addition of CBD to exposure therapy is effective in reducing phobic symptoms in treatment refractory patients with social phobia or panic disorder with agoraphobia. TRIAL REGISTRATION: Netherlands Trial Register NTR5100 . Registered 13 March 2015. Protocol version: issue date 17 Jan 2018, protocol amendment number 7.

Abnormalities in metabolite concentrations in tourette's disorder and obsessive-compulsive disorder-A proton magnetic resonance spectroscopy study.

INTRODUCTION: Abnormal glutamatergic transmission in cortico-striato-thalamo-cortical (CSTC) circuits is thought to be involved in the pathophysiology of Tourette's disorder (TD) and obsessive-compulsive disorder (OCD). Using proton magnetic resonance spectroscopy, the current study aimed to investigate regional concentrations of glutamatergic compounds in TD and OCD patients in comparison to healthy control subjects (HC). MATERIAL AND METHODS: Twenty-three TD patients, 20 OCD patients and 22 HC were included. Short echo-time single-voxel 3T MRS was obtained from dorsal anterior cingulate cortex (dACC) and midline bilateral thalamus. RESULTS: The 3-group comparison showed a significant difference in choline concentration in the thalamus. Thalamic choline was highest in OCD patients, showing a significant difference with TD, and a trend compared to HC (post-hoc analyses). Glutamine in dACC correlated negatively with tic severity scores in TD patients, while glutamate in thalamus correlated positively with anxiety severity scores in OCD patients. CONCLUSIONS: These findings suggest subtle differences in metabolites in CSTC areas between TD and OCD. Alterations of choline concentrations seem to be both regional (only in thalamus, not in dACC) and disease specific in OCD pathology. The findings need replication in larger groups, but encourage further research into glutamatergic metabolites in TD and OCD.

Degrading traumatic memories with eye movements: a pilot functional MRI study in PTSD.

BACKGROUND: Eye movement desensitization and reprocessing (EMDR) is an effective treatment for posttraumatic stress disorder (PTSD). During EMDR, the patient recalls traumatic memories while making eye movements (EMs). Making EMs during recall is associated with decreased vividness and emotionality of traumatic memories, but the underlying mechanism has been unclear. Recent studies support a "working-memory" (WM) theory, which states that the two tasks (recall and EMs) compete for limited capacity of WM resources. However, prior research has mainly relied on self-report measures. METHODS: Using functional magnetic resonance imaging, we tested whether "recall with EMs," relative to a "recall-only" control condition, was associated with reduced activity of primary visual and emotional processing brain regions, associated with vividness and emotionality respectively, and increased activity of the dorsolateral prefrontal cortex (DLPFC), associated with working memory. We used a randomized, controlled, crossover experimental design in eight adult patients with a primary diagnosis of PTSD. A script-driven imagery (SDI) procedure was used to measure responsiveness to an audio-script depicting the participant's traumatic memory before and after conditions. RESULTS: SDI activated mainly emotional processing-related brain regions (anterior insula, rostral anterior cingulate cortex (ACC), and dorsomedial prefrontal cortex), WM-related (DLPFC), and visual (association) brain regions before both conditions. Although predicted pre- to post-test decrease in amygdala activation after "recall with EMs" was not significant, SDI activated less right amygdala and rostral ACC activity after "recall with EMs" compared to post-"recall-only." Furthermore, functional connectivity from the right amygdala to the rostral ACC was decreased after "recall with EMs" compared with after "recall-only." CONCLUSIONS: These preliminary results in a small sample suggest that making EMs during recall, which is part of the regular EMDR treatment protocol, might reduce activity and connectivity in emotional processing-related areas. This study warrants replication in a larger sample. HIGHLIGHTS OF THE ARTICLE: Script driven imagery (SDI) before and after recall of traumatic memories is feasible to investigate working mechanisms of degrading of traumatic memories with eye movements (EMs) in PTSD. Right amygdala and rostral ACC activity was significantly lower after "recall with EMs" than after "recall-only". Functional connectivity from amygdala to rostral ACC was decreased after "recall with EMs" vs. "recall-only". This study warrants replication in a larger sample.

Does repeated ticking maintain tic behavior? An experimental study of eye blinking in healthy individuals.

Tics in Tourette Syndrome (TS) are often preceded by 'premonitory urges': annoying feelings or bodily sensations. We hypothesized that, by reducing annoyance of premonitory urges, tic behaviour may be reinforced. In a 2X2 experimental design in healthy participants, we studied the effects of premonitory urges (operationalized as air puffs on the eye) and tic behaviour (deliberate eye blinking after a puff or a sound) on changes in subjective evaluation of air puffs, and EMG responses on the m. orbicularis oculi. The experimental group with air puffs+ blinking experienced a decrease in subjective annoyance of the air puff, but habituation of the EMG response was blocked and length of EMG response increased. In the control groups (air puffs without instruction to blink, no air puffs), these effects were absent. When extrapolating to the situation in TS patients, these findings suggest that performance of tics is reinforced by reducing the subjective annoyance of premonitory urges, while simultaneously preventing habituation or even inducing sensitisation of the physiological motor response.

Tones inferior to eye movements in the EMDR treatment of PTSD.

Eye Movement Desensitization and Reprocessing (EMDR) is an effective treatment for posttraumatic stress disorder (PTSD). During EMDR, patients make eye movements (EMs) while recalling traumatic memories, but recently therapists have replaced EMs by alternating beep tones. There are no outcome studies on the effects of tones. In an earlier analogue study, tones were inferior to EMs in the reduction of vividness of aversive memories. In a first EMDR session, 12 PTSD patients recalled trauma memories in three conditions: recall only, recall + tones, and recall + EMs. Three competing hypotheses were tested: 1) EMs are as effective as tones and better than recall only, 2) EMs are better than tones and tones are as effective as recall only, and 3) EMs are better than tones and tones are better than recall only. The order of conditions was balanced, each condition was delivered twice, and decline in memory vividness and emotionality served as outcome measures. The data strongly support hypothesis 2 and 3 over 1: EMs outperformed tones while it remained unclear if tones add to recall only. The findings add to earlier considerations and earlier analogue findings suggesting that EMs are superior to tones and that replacing the former by the latter was premature.