Mechanisms to medicines: elucidating neural and molecular substrates of fear extinction to identify novel treatments for anxiety disorders

The burden of anxiety disorders is growing, but the efficacy of available anxiolytic treatments remains inadequate. Cognitive behavioural therapy for anxiety disorders focuses on identifying and modifying maladaptive patterns of thinking and behaving, and has a testable analogue in rodents in the form of fear extinction. A large preclinical literature has amassed in recent years describing the neural and molecular basis of fear extinction in rodents. In this review, we discuss how this work is being harnessed to foster translational research on anxiety disorders and facilitate the search for new anxiolytic treatments. We begin by summarizing the anatomical and functional connectivity of a medial prefrontal cortex (mPFC)–amygdala circuit that subserves fear extinction, including new insights from optogenetics. We then cover some of the approaches that have been taken to model impaired fear extinction and associated impairments with mPFC–amygdala dysfunction. The principal goal of the review is to evaluate evidence that various neurotransmitter and neuromodulator systems mediate fear extinction by modulating the mPFC–amygdala circuitry. To that end, we describe studies that have tested how fear extinction is impaired or facilitated by pharmacological manipulations of dopamine, noradrenaline, 5-HT, GABA, glutamate, neuropeptides, endocannabinoids and various other systems, which either directly target the mPFC–amygdala circuit, or produce behavioural effects that are coincident with functional changes in the circuit. We conclude that there are good grounds to be optimistic that the progress in defining the molecular substrates of mPFC–amygdala circuit function can be effectively leveraged to identify plausible candidates for extinction-promoting therapies for anxiety disorders.

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This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-20     

Melanoma stem cells in experimental melanoma are killed by radioimmunotherapy

IntroductionIn spite of recently approved B-RAF inhibitors and immunomodulating antibodies, metastatic melanoma has poor prognosis and novel treatments are needed. Melanoma stem cells (MSC) have been implicated in the resistance of this tumor to chemotherapy. Recently we demonstrated in a Phase I clinical trial in patients with metastatic melanoma that radioimmunotherapy (RIT) with 188-Rhenium(¹⁸⁸Re)-6D2 antibody to melanin was a safe and effective modality. Here we investigated the interaction of MSC with RIT as a possible mechanism for RIT efficacy.MethodsMice bearing A2058 melanoma xenografts were treated with either 1.5 mCi ¹⁸⁸Re-6D2 antibody, saline, unlabeled 6D2 antibody or ¹⁸⁸Re-labeled non-specific IgM.ResultsOn Day 28 post-treatment the tumor size in the RIT group was 4-times less than in controls (P < 0.001). The tumors were analyzed by immunohistochemistry and FACS for two MSC markers — chemoresistance mediator ABCB5 and H3K4 demethylase JARID1B. There were no significant differences between RIT and control groups in percentage of ABCB5 or JARID1B-positive cells in the tumor population. Our results demonstrate that unlike chemotherapy, which kills tumor cells but leaves behind MSC leading to recurrence, RIT kills MSC at the same rate as the rest of tumor cells.ConclusionsThese results have two main implications for melanoma treatment and possibly other cancers. First, the susceptibility of ABCB5 + and JARID1B + cells to RIT in melanoma might be indicative of their susceptibility to antibody-targeted radiation in other cancers where they are present as well. Second, specifically targeting cancer stem cells with radiolabeled antibodies to ABCB5 or JARID1B might help to completely eradicate cancer stem cells in various cancers.     

Addition of treatment for trichomoniasis to syndromic management of urethritis in Malawi: a randomized clinical trial

BACKGROUND: Male urethritis is generally treated syndromically, but failure of empirical treatment is common. GOAL: The study goal was to evaluate the addition of metronidazole to the syndromic management of urethritis in Malawi in a randomized clinical trial. STUDY DESIGN: Men with urethritis were randomized to receive either 2 g of metronidazole by mouth or placebo, in addition to standard care for urethritis (i.e., a single intramuscular dose of 240 mg gentamicin and 100 mg doxycycline twice daily for 7 days). The primary endpoints of the study included measurement of the effects of treatment on Trichomonas vaginalis, signs and symptoms of urethritis, and the concentration of HIV RNA in semen in dually infected subjects. RESULTS: The overall prevalence of T vaginalis was 17.3% (71/411), and treatment with metronidazole cleared 95% of culture-positive infections, compared with 54% clearance among men receiving placebo (P = 0.006). Prevalence of persistent urethritis was observed in approximately 16% of both groups at the end of 1 week (29/179 of those receiving metronidazole versus 29/187 in the placebo group; P = 0.86). For a subset of HIV-infected men with trichomoniasis, the seminal plasma HIV RNA concentration was higher than in a group of HIV-positive control subjects (median copies/mL:35,000 vs. 1800 P = 0.06) [correction]. CONCLUSION: In areas with a high prevalence of trichomoniasis, the addition of metronidazole to the syndromic management of male urethritis can eliminate infection with T vaginalis and may help to reduce the transmission of HIV. Such treatment should be strongly considered as part of empirical therapy for urethritis in men in Malawi and places where T vaginalis infection in men is common.     

A0001 in Friedreich ataxia: Biochemical characterization and effects in a clinical trial

This study tested the ability of A0001 (α-tocopheryl quinone; EPI-A0001), a potent antioxidant, to improve in vitro measures, glucose metabolism, and neurological function in Friedreich ataxia. We used an in vitro study of protection from cell toxicity followed by a double-blind, randomized, placebo-controlled trial of 2 doses of A0001 in 31 adults with Friedreich ataxia. The primary clinical trial outcome was the Disposition Index, a measure of diabetic tendency, from a frequently sampled intravenous glucose tolerance test, evaluated 4 weeks into therapy. Secondary neurologic measures included the Friedreich Ataxia Rating Scale. A0001 potently inhibited cell death in Friedreich ataxia models in vitro. For the clinical trial, mean guanine-adenine-adenine repeat length was 699, and mean age was 31 years. Four weeks after treatment initiation, differences in changes in the Disposition Index between subjects treated with A0001 and placebo were not statistically significant. In contrast, a dose-dependent improvement in the Friedreich Ataxia Rating Scale score was observed. Patients on placebo improved 2.0 rating scale points, whereas patients on low-dose A0001 improved by 4.9 points (P = .04) and patients on a high dose improved by 6.1 points (P < .01). Although A0001 did not alter the Disposition Index, it caused a dose-dependent improvement in neurologic function, as measured by the Friedreich Ataxia Rating Scale. Longer studies will assess the reproducibility and persistence of neurologic benefit.     

Preventing compulsory admission to psychiatric inpatient care through psycho-education and crisis focused monitoring

ABSTRACT: BACKGROUND: The high number of involuntary placements of people with mental disorders in Switzerland and other European countries constitutes a major public health issue. In view of the ethical and personal relevance of compulsory admission for the patients concerned and given the far-reaching effects in terms of health care costs, innovative interventions to improve the current situation are much needed. A number of promising approaches to prevent involuntary placements have been proposed that target continuity of care by increasing self-management skills of patients. However, the effectiveness of such interventions in terms of more robust criteria (e.g., admission rates) has not been sufficiently analysed in larger study samples.The current study aims to evaluate an intervention programme for patients at high risk of compulsory admission to psychiatric hospitals. Effectiveness will be assessed in terms of a reduced number of psychiatric hospitalisations and days of inpatient care in connection with involuntary psychiatric admissions as well as in terms of cost-containment in inpatient mental health care. The intervention furthermore intends to reduce the degree of patients' perceived coercion and to increase patient satisfaction, their quality of life and empowerment. METHODS: This paper describes the design of a randomised controlled intervention study conducted currently at four psychiatric hospitals in the Canton of Zurich. The intervention programme consists of individualised psycho-education focusing on behaviours prior to and during illness-related crisis, the distribution of a crisis card and, after inpatient admission, a 24-month preventive monitoring of individual risk factors for compulsory re-admission to hospital. All measures are provided by a mental health care worker who maintains permanent contact to the patient over the course of the study.In order to prove its effectiveness the intervention programme will be compared with standard care procedures (control group). 200 patients each will be assigned to the intervention group or to the control group. Detailed follow-up assessments of service use, psychopathology and patient perceptions are scheduled 12 and 24 months after discharge. DISCUSSION: Innovative interventions have to be established to prevent patients with mental disorders from undergoing the experience of compulsory admission and, with regard to society as a whole, to reduce the costs of health care (and detention). The current study will allow for a prospective analysis of the effectiveness of an intervention programme, providing insight into processes and factors that determine involuntary placement.Trial registrationCurrent Controlled Trials ISRCTN63162737.     

Addictive behavior among young people in Ukraine: a pilot study

The AUDIT-like tests system was created for complex assessment and evaluation of the addictive status of adolescents in a Ukrainian population. The AUDIT-like tests system has been created from the Alcohol Use Disorders Identification Test (AUDIT) developed by the World Health Organization. The AUDIT-like tests were minimally modified from the original AUDIT. Attention was brought to similarities between stages of different addictions (TV, computer games, the Internet, etc.) and alcohol addiction. Seventeen AUDIT-like tests were created to detect the different types of chemical and non-chemical addictions.