Implementation of a ketamine programme for treatment-resistant depression in the public health system: Lessons from the first Australian public hospital clinic.

One could argue that we are living through a period of innovation and change in psychiatry unlike that seen before, with repurposed medications emerging as novel treatments. However, despite evidence of enhanced clinical outcomes and potential medium-term savings, delivering these promising interventions is resource-intensive and perceived as difficult in the public sector. Consequently, they are generally only available in the private sector, often at great cost, effectively making them inaccessible to the 'Have Nots'. The arrival of these paradigm-shifting treatments has inadvertently highlighted a growing mental health inequity. The Royal Prince Alfred Hospital's Ketamine Treatment Clinic was the first public-sector ketamine treatment clinic for complex mood disorders in Australia. Based on 3 years' experience establishing, developing and running a public-sector ketamine treatment service, we review the progress, perils and pitfalls for clinicians and health services contemplating establishing a public-sector ketamine treatment service of their own.

Evaluating the attitudes of mental health professionals towards trials of MDMA: a randomised vignette trial.

OBJECTIVES: To compare attitudes of mental health (MH) professionals towards trials of methylenedioxymethamphetamine-assisted psychotherapy (MDMA-AP), with a neutrally labelled pharmacotherapy trial. DESIGN: A randomised controlled vignette study design, with experimenters blinded to group condition. SETTING: Participants were recruited online via professional societies. PARTICIPANTS: Psychiatrists, psychologists and MH researchers from across Australia. INTERVENTIONS: Participants were randomly allocated to read a vignette about a trial of either MDMA-AP or a neutrally labelled pharmacotherapy. OUTCOMES: Comparison of the difference in four attitudes towards MDMA-AP and control: How likely they were to (1) recommend participating, or (2) object to participating in the trial; (3) their predicted efficacy; and (4) concerns about the safety of the trial. RESULTS: There were no overall differences between professional's attitudes towards MDMA-AP (n=51) and the control pharmacotherapy (n=43) trial vignettes. Psychiatrists were less likely to recommend participation in the MDMA-AP than the control trial (d=0.72, p=0.02), but did not differ in other attitudes. Psychologists and researchers did not differ in any attitudes. The correlation between professional experience and both: (1) concern about, and (2) strength of objection to, the trial, was higher for MDMA-AP, than control (d=0.60, p=0.01 and d=0.40, p=0.03, respectively). CONCLUSIONS: Psychiatrists, but not psychologists or researchers showed more hesitancy in recommending trials of MDMA-AP versus an unknown pharmacotherapy. Experienced MH professionals were more likely to have negative views about MDMA-AP trials than less experienced MH professionals. This may reflect the experience of prior unfulfilled pharmacotherapy innovation or exuberance associated with fewer years of practice. Research into, and implementation of, MDMA-AP may face barriers with certain MH professionals, which will need be addressed if MDMA-AP continues to show promise as an efficacious treatment. TRIAL REGISTRATION NUMBER: The study design was registered with the ANZCTR (ACTRN12620001068954).

Huntington's Disease: Pathogenic Mechanisms and Therapeutic Targets.

Huntington's disease (HD) is a tandem repeat disorder involving neurodegeneration and a complex combination of symptoms. These include psychiatric symptoms, cognitive deficits culminating in dementia, and the movement disorder epitomised by motor signs such as chorea. HD is caused by a CAG repeat expansion encoding an extended tract of the amino acid glutamine in the huntingtin protein. This polyglutamine expansion appears to induce a 'change of function', possibly a 'gain of function', in the huntingtin protein, which leads to various molecular and cellular cascades of pathogenesis. In the current review, we will briefly describe these broader aspects of HD pathogenesis, but will then focus on specific aspects where there are substantial bodies of experimental evidence, including oxidative stress, mitochondrial dysfunction, glutamatergic dysfunction and neuroinflammation. Furthermore, we will review recent preclinical therapeutic approaches targeting some of these pathogenic pathways, their clinical implications and future directions.

Synaptopathies: synaptic dysfunction in neurological disorders - A review from students to students.

Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in disease-associated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders. In this Review, which was initiated at the 13th International Society for Neurochemistry (ISN) Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer's and Parkinson's diseases), gathered together under the term of synaptopathies. Read the Editorial Highlight for this article on page 783.

N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease.

Glutamatergic dysfunction has been implicated in the pathogenesis of depressive disorders and Huntington's disease (HD), in which depression is the most common psychiatric symptom. Synaptic glutamate homeostasis is regulated by cystine-dependent glutamate transporters, including GLT-1 and system xc- In HD, the enzyme regulating cysteine (and subsequently cystine) production, cystathionine-γ-lygase, has recently been shown to be lowered. The aim of the present study was to establish whether cysteine supplementation, using N-acetylcysteine (NAC) could ameliorate glutamate pathology through the cystine-dependent transporters, system xc- and GLT-1. We demonstrate that the R6/1 transgenic mouse model of HD has lower basal levels of cystine, and showed depressive-like behaviors in the forced-swim test. Administration of NAC reversed these behaviors. This effect was blocked by co-administration of the system xc- and GLT-1 inhibitors CPG and DHK, showing that glutamate transporter activity was required for the antidepressant effects of NAC. NAC was also able to specifically increase glutamate in HD mice, in a glutamate transporter-dependent manner. These in vivo changes reflect changes in glutamate transporter protein in HD mice and human HD post-mortem tissue. Furthermore, NAC was able to rescue changes in key glutamate receptor proteins related to excitotoxicity in HD, including NMDAR2B. Thus, we have shown that baseline reductions in cysteine underlie glutamatergic dysfunction and depressive-like behavior in HD and these changes can be rescued by treatment with NAC. These findings have implications for the development of new therapeutic approaches for depressive disorders.

Avulsion Fracture of the Tibial Tubercle Associated With Patellar Tendon Avulsion.

Avulsion fractures of the tibial tubercle in adolescent athletes are uncommon injuries, believed to be a result of forceful extension of the knee against a fixed leg. Concomitant injury to the ipsilateral patella tendon is even more rare, with few cases reported in the literature. The mechanisms responsible for this association are not well understood. The significance of this double insult to the knee extensor mechanism is the potential deleterious effect of misdiagnosis and/or mismanagement. In this case report, the pathophysiology, mechanism of injury, classification, diagnosis, and management of concomitant injury are reviewed. [Orthopedics. 2016; 39(3):e561-e564.].

Enhancing permanganate chemiluminescence detection for the determination of glutathione and glutathione disulfide in biological matrices.

Acidic potassium permanganate chemiluminescence enables direct post-column detection of glutathione, but its application to assess the redox state of a wider range of biological fluids and tissues is limited by its sensitivity. Herein we show that the simple on-line addition of an aqueous formaldehyde solution not only enhances the sensitivity of the procedure by two orders of magnitude, but also provides a remarkable improvement in the selectivity of the reagent towards thiols such as glutathione (compared to phenols and amino acids that do not possess a thiol group). This enhanced mode of detection was applied to the determination of glutathione and its corresponding disulfide species in homogenised striatum samples taken from both wild type mice and the R6/1 transgenic mouse model of Huntington's disease, at both 8 and 12 weeks of age. No significant difference was observed between the GSH/GSSG ratios of wild type mice and R6/1 mice at either age group, suggesting that the early disease progression had not significantly altered the intracellular redox environment.

Behavioral training increases local astrocytic metabolic activity but does not alter outcome of mild transient ischemia.

Functional neurological outcome after transient ischemia might be improved by timely therapeutic intervention. To determine if restorative behavioral therapy influences damage, improves task learning, or alters astrocyte metabolic activity after ischemia, rats (food-restricted to 85% of free-feeding weight) were (a) first trained to respond on one of two levers under a fixed-ratio 20 schedule of food presentation (FR20), then (b) subjected to sham manipulation of carotid arteries or 10 min ischemia by four-vessel occlusion, followed by (c) 4 days of operant testing or inactivity, (d) then all rats were tested under a FR20 lever reversal task for 4 weeks, and (e) 3 days after the last behavioral session astrocyte metabolism was assayed by local uptake of [2-14C]acetate. Mild loss of hippocampal neurons occurred in ischemic rats with or without training after ischemia. Glial fibrillary acidic protein-positive astrocytes were present in similar numbers throughout brains of sham control and ischemic rats. Mild ischemia did not impair learning, and no changes in FR20 reversal learning were detected in sham vs. ischemic rats. Net [14C]acetate uptake was unaffected by ischemia but [14C]acetate uptake increased 15-24% (P<0.05; n=12-15/group) in specific structures (caudate, primary motor and sensorimotor cortex, CA1 hippocampus, subcortical white matter) in the pooled groups of rats that had 4 days FR20 testing vs. inactivity before reversal learning. 'Behavioral therapy' (operant testing on the 4 days immediately following either sham manipulation or ischemia) did not alter ischemic outcome, but was associated with higher acetate utilization in regions involved in motor activities.