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.

Evaluation of the pharmacokinetics, safety and clinical efficacy of sertraline used to treat social anxiety.

INTRODUCTION: Social anxiety disorder (SAD) is an emerging, often invalidating, syndrome with deep personal, social and psychological implications. While multiple treatment strategies exist, presently none of them can be considered superior to all others. AREAS COVERED: The aim of this review is to provide the latest information on sertraline (SRT), one of the most important selective serotonin reuptake inhibitors (SSRIs) currently used for the pharmacological therapy of SAD. A literature search was carried out with the keywords 'sertraline', 'social anxiety', 'social phobia' and 'clinical trials'. In this process, particular attention is paid to the pharmacokinetic characteristics of the drug and its safety in clinical use. EXPERT OPINION: SRT is an effective drug in the treatment of SAD, especially when used in combination with some form of psychological support. While it does not seem to be significantly more effective than other SSRIs, SRT could offer some peculiar advantages: for example, it has a long half-life, allowing a single daily administration, and seems to be particularly indicated for the control of specific symptoms of SAD.

Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors.

Oxytocin and vasopressin are regulators of anxiety, stress-coping, and sociality. They are released within hypothalamic and limbic areas from dendrites, axons, and perikarya independently of, or coordinated with, secretion from neurohypophysial terminals. Central oxytocin exerts anxiolytic and antidepressive effects, whereas vasopressin tends to show anxiogenic and depressive actions. Evidence from pharmacological and genetic association studies confirms their involvement in individual variation of emotional traits extending to psychopathology. Based on their opposing effects on emotional behaviors, we propose that a balanced activity of both brain neuropeptide systems is important for appropriate emotional behaviors. Shifting the balance between the neuropeptide systems towards oxytocin, by positive social stimuli and/or psychopharmacotherapy, may help to improve emotional behaviors and reinstate mental health.

Clinical efficacy of Manasamitra Vataka (an Ayurveda medication) on generalized anxiety disorder with comorbid generalized social phobia: a randomized controlled study.

BACKGROUND: Studies on alternative medicines for generalized anxiety disorder (GAD) are few. Manasamitra Vataka (an Ayurveda preparation) is explored for its efficacy in patients with GAD with comorbid generalized social phobia. MATERIALS AND METHODS: Seventy-two (72) patients with GAD with comorbid social phobia meeting DSM IV TR criteria, and who were between the ages of 20 and 55 of either sex, participated in the study. They were randomly divided into three treatment groups: Group 1 (n=24) and Group II (n=24) received Manasamitra Vataka tablets (100 mg twice daily for 30 days). Group II, in addition to Manasamitra Vataka, underwent Shirodhara (therapy involving dripping of medicated oil [Brahmi tail] over the forehead) treatment for the first 7 days. Group III (n=24) received clonazepam 0.75 mg daily in divided dose for 30 days. The assessment of the study was done using the Hamilton Anxiety Rating Scale, Beck Anxiety Inventory, Beck Depression Inventory, Epworth Sleepiness Scale (ESS), World Health Organization Quality of Life BREF, and Clinical Global Impression scales (Improvement and Efficacy). RESULTS: Patients from all the groups showed significant reduction in clinical parameters evaluated. However, improvement in ESS was observed only in Group II. The treatment outcome was comparable between the three groups. CONCLUSIONS: This is the first study conducted on the efficacy of Manasamitra Vataka in anxiety disorders. The results suggest that Manasamitra Vataka is effective in the management GAD with comorbid generalized social phobia. Add-on effect of Shirodhara reduced the daytime sleepiness. Further studies on Manasamitra Vataka need to be carried out to judge its potential as a first-line treatment modality.

Enhanced fear expression in a psychopathological mouse model of trait anxiety: pharmacological interventions.

The propensity to develop an anxiety disorder is thought to be determined by genetic and environmental factors. Here we investigated the relationship between a genetic predisposition to trait anxiety and experience-based learned fear in a psychopathological mouse model. Male CD-1 mice selectively bred for either high (HAB), or normal (NAB) anxiety-related behaviour on the elevated plus maze were subjected to classical fear conditioning. During conditioning both mouse lines showed increased fear responses as assessed by freezing behaviour. However, 24 h later, HAB mice displayed more pronounced conditioned responses to both a contextual or cued stimulus when compared with NAB mice. Interestingly, 6 h and already 1 h after fear conditioning, freezing levels were high in HAB mice but not in NAB mice. These results suggest that trait anxiety determines stronger fear memory and/or a weaker ability to inhibit fear responses in the HAB line. The enhanced fear response of HAB mice was attenuated by treatment with either the α(2,3,5)-subunit selective benzodiazepine partial agonist L-838,417, corticosterone or the selective neurokinin-1 receptor antagonist L-822,429. Overall, the HAB mouse line may represent an interesting model (i) for identifying biological factors underlying misguided conditioned fear responses and (ii) for studying novel anxiolytic pharmacotherapies for patients with fear-associated disorders, including post-traumatic stress disorder and phobias.

Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients.

Generalized Social Anxiety Disorder (SAD) is one of the most common anxiety conditions with impairment in social life. Cannabidiol (CBD), one major non-psychotomimetic compound of the cannabis sativa plant, has shown anxiolytic effects both in humans and in animals. This preliminary study aimed to compare the effects of a simulation public speaking test (SPST) on healthy control (HC) patients and treatment-naïve SAD patients who received a single dose of CBD or placebo. A total of 24 never-treated patients with SAD were allocated to receive either CBD (600 mg; n=12) or placebo (placebo; n=12) in a double-blind randomized design 1 h and a half before the test. The same number of HC (n=12) performed the SPST without receiving any medication. Each volunteer participated in only one experimental session in a double-blind procedure. Subjective ratings on the Visual Analogue Mood Scale (VAMS) and Negative Self-Statement scale (SSPS-N) and physiological measures (blood pressure, heart rate, and skin conductance) were measured at six different time points during the SPST. The results were submitted to a repeated-measures analysis of variance. Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech. The placebo group presented higher anxiety, cognitive impairment, discomfort, and alert levels when compared with the control group as assessed with the VAMS. The SSPS-N scores evidenced significant increases during the testing of placebo group that was almost abolished in the CBD group. No significant differences were observed between CBD and HC in SSPS-N scores or in the cognitive impairment, discomfort, and alert factors of VAMS. The increase in anxiety induced by the SPST on subjects with SAD was reduced with the use of CBD, resulting in a similar response as the HC.

Specific phobias.

Exposure based treatments in which patients are systematically confronted with their feared objects of situations are highly effective in the treatment of specific phobias and produce stable improvement both in reported fear and behavioral avoidance. Exposure in reality is more effective in most cases than exposure in sensu. For situations that are difficult to realize, exposure in virtual environments has become increasingly valuable. Exposure in vivo is clearly superior to pharmacotherapy, although cognitive enhancers have been successfully used recently to increase the effect of exposure therapy. The induction of relaxation is not a necessary precondition for exposure therapy. Rather the current mechanisms of change focus on extinction learning as being the central mechanism both on a cognitive level namely that the feared object is no longer associated with severely threatening consequence but also on an affective level, meaning that feared cue is no longer capable to activate the fear circuit in the brain. Accordingly future diagnostic categorizations of phobic disorders in the DSM-V should rather focus on the pattern of the fear response that needs to be changed than on the eliciting cues or situations that are avoided.

Relaxation and immunity enhancement effects of gamma-aminobutyric acid (GABA) administration in humans.

The effect of orally administrated gamma-aminobutyric acid (GABA) on relaxation and immunity during stress has been investigated in humans. Two studies were conducted. The first evaluated the effect of GABA intake by 13 subjects on their brain waves. Electroencephalograms (EEG) were obtained after 3 tests on each volunteer as follows: intake only water, GABA, or L-theanine. After 60 minutes of administration, GABA significantly increases alpha waves and decreases beta waves compared to water or L-theanine. These findings denote that GABA not only induces relaxation but also reduces anxiety. The second study was conducted to see the role of relaxant and anxiolytic effects of GABA intake on immunity in stressed volunteers. Eight acrophobic subjects were divided into 2 groups (placebo and GABA). All subjects were crossing a suspended bridge as a stressful stimulus. Immunoglobulin A (IgA) levels in their saliva were monitored during bridge crossing. Placebo group showed marked decrease of their IgA levels, while GABA group showed significantly higher levels. In conclusion, GABA could work effectively as a natural relaxant and its effects could be seen within 1 hour of its administration to induce relaxation and diminish anxiety. Moreover, GABA administration could enhance immunity under stress conditions.

The assessment and treatment of specific phobias: a review.

Specific phobia is one of the most common and easily treated mental disorders. In this review, empirically supported assessment and treatment procedures for specific phobia are discussed. Exposure-based treatments in particular are highlighted given their demonstrated effectiveness for this condition. The format and characteristics of exposure-based treatment and predictors of treatment response are outlined to provide recommendations for maximizing outcome. In addition, several other treatments for specific phobia are reviewed and critiqued, including cognitive therapy, virtual reality, eye movement desensitization and reprocessing, applied tension, and pharmacologic treatments. The review concludes with a discussion of future directions for research.

St. John's wort versus placebo in social phobia: results from a placebo-controlled pilot study.

Recognition of social anxiety disorder (social phobia) as a common and disabling condition has led to new advances in its pharmacotherapy. Limitations with selective seroton reuptake inhibitors (side effects) and behavior therapy (scarcity of trained therapists), coupled with the tendency for patients with the disorder to self-medicate with alternative treatments, have led to the interest in Saint John's wort (SJW) (Hypericum perforatum) for this disorder. Although the literature is mixed, SJW has demonstrated efficacy in several double-blind depression trials, and some open-label studies with anxiety disorders. There is pharmacokinetic evidence for the serotonergic, domaminergic, and GABAminergic activity of hypericum, all of which are implicated in social anxiety disorder. This study was designed to generate pilot data to examine the potential efficacy of SJW in generalized social anxiety disorder. Forty subjects were randomized to 12 weeks of treatment with a flexible dose (600-1800 mg) of SJW (n = 20) or placebo (n = 20). Subjects with comorbid depression (clinician HAMD > 16) were excluded. Results found no significant difference between mean change on the Liebowitz Social Anxiety Scale with SJW (11.4) and placebo (13.2), P = 0.27, effect size = -0.09. Post-hoc analyses found larger effects sizes associated with increased baseline severity, omitting patients with variable scores (+/-30%) during the first week, and use of self-report HAMD scores for exclusion. Results of the study fail to provide evidence for the efficacy of SJW in social phobia. The impact of methodologic improvements on signal detection, while suggestive of improvement, remains to be established.

The effect of paroxetine on Taijinkyofusho: a report of three cases.

Taijinkyofusho is a culture-related syndrome conceptualized in Japan. While previous studies suggest its psychopathological similarities to social phobia and obsessive-compulsive disorder, introspection regarding shame and low self-esteem is particularly linked to Japanese culture. We present three cases of Taijinkyofusho: Cases 1 and 2 show neurotic features while Case 3 shows delusional thoughts. Paroxetine was used for treatment but was productive in only the first two cases. Phobic and obsessive thought patterns were altered in Cases 1 and 2, suggesting that the significant core symptoms were responding to the treatment. In the future, large-scale pharmacological studies will be necessary to investigate treatment outcomes Taijinkyofusho. Such studies would contribute to providing information for effective treatment as well as for examining relationships between Taijinkyofusho and related disorders.

Kava kava in the treatment of generalized anxiety disorder, simple phobia and specific social phobia.

A 37-year-old female outpatient with generalized anxiety disorder, a simple phobia and a specific social phobia was treated with phytotherapy (Kava kava). Within 4 weeks, symptoms had improved by 75% and by 6 months an almost total remission of symptoms was observed. The herbal medicine was well tolerated. Kava has considerable potential value in the treatment of anxiety disorders.

Successful management of claustrophobia and depression during allogeneic SCT.

As psychological problems are frequent in SCT patients we report on a patient with chronic myeloid leukemia, claustrophobia and depression. The successful allogeneic stem cell transplant of this patient in a reverse isolation setting required intensive interdisciplinary hematological, psychological and psychiatric collaboration. Psychopharmacologically the patient was treated with lorazepam 1 mg at 10 a.m. and 8 p.m. and after crisis on day +6, and 2.5 mg twice daily i.v. until one day before discharge (total 20 doses). Psychological counseling followed a cognitive-behavioural approach including progressive muscle relaxation and cognitive techniques focusing on the actual coping processes.

Current status of psychotherapeutic interventions for social phobia.

Psychotherapeutic interventions, especially the cognitive-behavioral psychotherapies, have been well studied as treatments for social phobia. The purposes of this article are to (1) enumerate and describe the varieties of cognitive-behavioral therapy (CBT) that have been applied to the treatment of social phobia, (2) provide a meta-analytic overview of the efficacy of these approaches, (3) examine the relative utility of CBT versus that of pharmacotherapy for social phobia, (4) examine the potential utility of multidisciplinary approaches to treatment, and (5) discuss possible future directions in the development of psychotherapeutic strategies for the treatment of social phobia, including the use of computers as adjunctive tools.

[The comparative effect of melatonin and diazepam on shifts in the anxiety-phobia status of rats evoked by damage to the amygdala]. / Sravnitel'noe vliianie melatonina i diazepama na sdvigi v trevozhno-fobicheskom sostoianii krys, vyzvannye povrezhdeniem amigdaly.

Disorders develop in the emotional sphere in the form of increased anxiety and fear in amygdalectomized rats. The pineal hormone melatonin and diazepam (in an equal dose of 0.1 mg/kg) alleviate the state of anxiety and fear in the animals. Despite some differences in behavioral activity, the effect of the drugs appears to be similar. This suggests that melatonin possesses anxiolytic properties which may be related to its effect on the function of the limbic structures.

Practical suggestions for improving MRI throughput and quality.

As the use of MRI increases, radiology managers and healthcare providers will need to use a variety of methods to decrease patient anxiety and minimize on-site cancellations. This article describes some practical methods and devices which can help patients tolerate lengthy exams in confining equipment, inspire return visits from repeat patients, and gain referrals from physicians and patients.

Effects of endorphin blocking on conditioned SCR in humans.

In order to test the hypothesis that low levels of endogenous opioids (endorphins) predispose to strong conditioning effects, female Ss (N = 36) were assigned to a placebo group, a low-dose naltrexone group, or a high-dose naltrexone group and then underwent a classical conditioning procedure. This procedure consisted of an acquisition phase in which all Ss received 5 pairings of a CS+ (neutral picture) and a UCS (100 dB white noise). The CS- (neutral picture) was never followed by a UCS. During extinction, Ss received 4 unreinforced presentations of CS+ and CS-. Throughout the experiment, skin conductance responses (SCRs) to the CSs and UCSs were recorded. Acquisition was successful in that CS+ slides elicited stronger SCRs than CS- slides. However, during acquisition, there was no interaction between drug and differential response (CS+ vs CS-). During extinction, there was no overall remaining effect of conditioning. Again, no evidence was found to suggest that (remaining) effects of conditioning were stronger in the naltrexone treated Ss than in the placebo Ss. If anything, the opposite seemed to be true with especially high-dose naltrexone Ss showing relatively weak conditioning effects.

[A new natural model of elevated anxiety in rats]. / Novaia estestvennaia model' povyshennoi trevozhnosti u krys.

The levels of anxiety were determined in male Wistar rats using a complex multiparameter method for evaluating anxiety-phobic states in rats based on ranged scale. The effects of psychotropic drugs differed in rats with innate high and low levels of anxiety. Anxiolytics sodium valproate (200 mg/kg), phenazepam (0.05 mg/kg) and diazepam (0.1 and 0.6 mg/kg) reduced anxiety in rats with innate high level of anxiety and prevented increase of anxiety induced by saline in rats with innate low level of anxiety. Pentylenetetrazol (10 mg/kg) and haloperidol at a large dose (0.5 mg/kg) increased anxiety in rats with either high or low innate levels of anxiety. However sodium lactate (600 mg/kg) increased anxiety only in rats with innate high level of anxiety. Haloperidol at a small dose (0.01 mg/kg) and melipramin (10 mg/kg) were uneffective in rats with innate high level of anxiety. Results believed the rats with innate high level of anxiety to be used as a new natural animal model of anxiety.