N-acetylcysteine in psychiatry - current therapeutic evidence and potential mechanisms of action

There is an expanding field of research investigating the benefits of alternatives to current pharmacological therapies in psychiatry. N-acetylcysteine (NAC) is emerging as a useful agent in the treatment of psychiatric disorders. Like many therapies, the clinical origins of NAC are far removed from its current use in psychiatry. Whereas the mechanisms of NAC are only beginning to be understood, it is likely that NAC is exerting benefits beyond being a precursor to the antioxidant, glutathione, modulating glutamatergic, neurotropic and inflammatory pathways. This review outlines the current literature regarding the use of NAC in disorders including addiction, compulsive and grooming disorders, schizophrenia and bipolar disorder. N-acetylcysteine has shown promising results in populations with these disorders, including those in whom treatment efficacy has previously been limited. The therapeutic potential of this acetylated amino acid is beginning to emerge in the field of psychiatric research.

Targeting cyclooxygenase-2 in depression is not a viable therapeutic approach and may even aggravate the pathophysiology underpinning depression

Depression is a complex progressive disorder accompanied by activation of inflammatory and Th-1 driven pathways, oxidative and nitrosative stress (O&NS), lowered antioxidant levels, mitochondrial dysfunctions, neuroprogression and increased bacterial translocation. In depression, activation of immuno-inflammatory pathways is associated with an increased risk for cardio-vascular disorder (CVD). Because of the inflammatory component, the use of cyclooxygenase 2 (COX-2) inhibitors, such as celecoxib, has been advocated to treat depression. Electronic databases, i.e. PUBMED, Scopus and Google Scholar were used as sources for this selective review on the effects of COX-2 inhibitors aggravating the abovementioned pathways. COX-2 inhibitors may induce neuroinflammation, exacerbate Th1 driven responses, increase lipid peroxidation, decrease the levels of key antioxidants, damage mitochondria and aggravate neuroprogression. COX-2 inhibitors may aggravate bacterial translocation and CVD through Th1-driven mechanisms. COX-2 inhibitors may aggravate the pathophysiology of depression. Since Th1 and O&NS pathways are risk factors for CVD, the use of COX-2 inhibitors may further aggravate the increased risk for CVD in depression. Selectively targeting COX-2 may not be a viable therapeutic approach to treat depression. Multi-targeting of the different pathways that play a role in depression is more likely to yield good treatment results.

Managing borderline personality disorder and substance use : an integrated approach

Background : Although substance use is a common feature of borderline personality disorder, regular use is associated with greater levels of psychosocial impairment, psychopathology, self harm and suicidal behaviour and leads to poorer treatment outcomes. Management of co-occurring substance use disorder and borderline personality disorder within primary care is further compounded by negative attitudes and practices in responding to people with these conditions, which can lead to a fractured patient-doctor relationship.

Objective : This article provides an overview of how the general practitioner can provide effective support for patients with co-occurring borderline personality disorder and substance use disorder, including approaches to assessment and treatment, the therapeutic relationship, referral pathways and managing risk and chronic suicidality.

Discussion : Despite the complexities associated with this population, GPs are ideally placed to engage patients with co-occurring borderline personality disorder and substance use disorder in a long term therapeutic relationship, while also ensuring timely referral to other key services and health professionals. To provide the most effective responses to this patient group, GPs need to understand borderline personality disorder and its relationship to substance use, develop an ‘explanatory framework’ for challenging behaviours, implement mechanisms for reflective practice to manage negative countertransference, as well as learn skills to respond adequately to behaviours which jeopardise treatment retention.

Religious/spiritual well-being, coping styles and personality dimensions in people with substance use disorders

Religiosity and spirituality have been found to be negatively associated with a range of addictions. It has been suggested that religious/spiritual well-being might play an important role in the development, course and the recovery from addictive disorders. A sample of addiction in-patients (n=389) was assessed using the Multidimensional Inventory for Religious/Spiritual Well-Being (MI-RSWB) and compared with a matched group of non-addicted community controls (n=389). RSWB was found to be substantially lower in people with substance use disorders compared to the normal sample. Discriminate functional analysis showed that Experiences of Sense and Meaning, General Religiosity and Forgiveness were the dimensions of RSWB which strongly distinguished the groups. Within the group of people with substance use disorders, RSWB was strongly positively associated with the personality dimensions of Conscientiousness, Agreeableness and Openness as well as Sense of Coherence and positive Coping styles. The study suggests that therapeutic intervention programs focusing on building a positive and meaningful personal framework, akin to that of a religious/spiritual orientation, may contribute to positive outcomes in addiction treatment.

The use of sensitive chemical antibodies for diagnosis: detection of low levels of Epcam in breast cancer

EpCAM is expressed at low levels in a variety of normal human epithelial tissues, but is overexpressed in 70–90% of carcinomas. From a clinico-pathological point of view, this has both prognostic and therapeutic significance. EpCAM was first suggested as a therapeutic target for the treatment of epithelial cancers in the 1990s. However, following several immunotherapy trials, the results have been mixed. It has been suggested that this is due, at least in part, to an unknown level of EpCAM expression in the tumors being targeted. Thus, selection of patients who would benefit from EpCAM immunotherapy by determining EpCAM status in the tumor biopsies is currently undergoing vigorous evaluation. However, current EpCAM antibodies are not robust enough to be able to detect EpCAM expression in all pathological tissues.

Here we report a newly developed EpCAM RNA aptamer, also known as a chemical antibody, which is not only specific but also more sensitive than current antibodies for the detection of EpCAM in formalin-fixed paraffin-embedded primary breast cancers. This new aptamer, together with our previously described aptamer, showed no non- specific staining or cross-reactivity with tissues that do not express EpCAM. They were able to reliably detect target proteins in breast cancer xenograft where an anti-EpCAM antibody (323/A3) showed limited or no reactivity. Our results demonstrated a more robust detection of EpCAM using RNA aptamers over antibodies in clinical samples with chromogenic staining. This shows the potential of aptamers in the future of histopathological diagnosis and as a tool to guide targeted immunotherapy.

Role of immune-inflammatory and oxidative and nitrosative stress pathways in the etiology of depression: therapeutic implications

Accumulating data have led to a re-conceptualization of depression that emphasizes the role of immuneinflammatory processes, coupled to oxidative and nitrosative stress (O&NS). These in turn drive the production of neuroregulatory tryptophan catabolites (TRYCATs), driving tryptophan away from serotonin, melatonin, and Nacetylserotonin production, and contributing to central dysregulation. This revised perspective better encompasses the diverse range of biological changes occurring in depression and in doing so provides novel and readily attainable treatment targets, as well as potential screening investigations prior to treatment initiation. We briefly review the role that immune-inflammatory, O&NS, and TRYCAT pathways play in the etiology, course, and treatment of depression. We then discuss the pharmacological treatment implications arising from this, including the potentiation of currently available antidepressants by the adjunctive use of immune- and O&NS- targeted therapies. The use of such a frame of reference and the treatment benefits attained are likely to have wider implications and utility for depression-associated conditions, including the neuroinflammatory and (neuro)degenerative disorders.

Is lithium in a class of its own? A brief profile of its clinical use

Lithium is a unique and effective psychotropic agent with a long-standing history of clinical use yet it is increasingly overlooked in lieu of newer agents. The purpose of the present paper was to succinctly review the therapeutic profile of lithium particularly with respect to the treatment of mood disorders and consider its unique properties and clinical utility. A comprehensive literature review pertaining to lithium was undertaken using electronic database search engines to identify relevant clinical trials, meta-analyses and Cochrane reviews. In addition articles and book chapters known to the authors were carefully reviewed, and the authors appraised published guidelines. The evidence from these sources was rated using National Health and Medical Research Council evidence levels and synthesized according to phenotype and mood states. In addition, the authors have drawn upon published guidelines and their own clinical experience. Lithium has specificity for mood disorders with proven efficacy in the treatment of both unipolar depression and bipolar disorder. The recommendations are based predominantly on Level I evidence, but its clinical use has to be tempered against potential side-effects and the need for ongoing monitoring. In practice, lithium should be considered a first-line option in bipolar disorder, especially in prophylaxis and when onset of action is not an imperative. Lithium has been in use in modern medicine for 60 years and as such has been tried and tested across the full range of mood disorders. Arguably, lithium is the only true mood stabilizer and because of its unique properties is in a class of its own.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 1 historical and established therapies

Multiple sclerosis (MS) is a potentially life-changing immune mediated disease of the central nervous system. Until recently, treatment has been largely confined to acute treatment of relapses, symptomatic therapies and rehabilitation. Through persistent efforts of dedicated physicians and scientists around the globe for 160 years, a number of therapies that have an impact on the long term outcome of the disease have emerged over the past 20 years. In this three part series we review the practicalities, benefits and potential hazards of each of the currently available and emerging treatment options for MS. We pay particular attention to ways of abrogating the risks of these therapies and provide advice on the most appropriate indications for using individual therapies. In Part 1 we review the history of the development of MS therapies and its connection with the underlying immunobiology of the disease. The established therapies for MS are reviewed in detail and their current availability and indications in Australia and New Zealand are summarised. We examine the evidence to support their use in the treatment of MS.

Adherence to therapeutic guidelines for patients with community-acquired pneumonia in Australian hospitals

Community-acquired pneumonia (CAP) is a significant cause of morbidity and mortality, particularly in elderly patients, and is associated with a considerable economic burden on the healthcare system. The combination of high incidence and substantial financial costs necessitate accurate diagnosis and appropriate management of patients admitted with CAP. This article will discuss the rates of adherence to clinical guidelines, the use of severity scoring tools and the appropriateness of antimicrobial prescribing for patients diagnosed with CAP. The authors maintain that awareness of national and hospital guidelines is imperative to complement the physicians' clinical judgment with evidence-based recommendations. Increased use of pneumonia severity assessment tools and greater adherence to therapeutic guidelines will enhance concordant antimicrobial prescribing for patients with CAP. A robust and multifaceted educational intervention, in combination with antimicrobial stewardship programs, may enhance compliance of CAP guidelines in clinical practice in Australia.

Nonparametric discovery of learning patterns and autism subgroups from therapeutic data

Autism Spectrum Disorder (ASD) is growing at a staggering rate, but, little is known about the cause of this condition. Inferring learning patterns from therapeutic performance data, and subsequently clustering ASD children into subgroups, is important to understand this domain, and more importantly to inform evidence-based intervention. However, this data-driven task was difficult in the past due to insufficiency of data to perform reliable analysis. For the first time, using data from a recent application for early intervention in autism (TOBY Play pad), whose download count is now exceeding 4500, we present in this paper the automatic discovery of learning patterns across 32 skills in sensory, imitation and language. We use unsupervised learning methods for this task, but a notorious problem with existing methods is the correct specification of number of patterns in advance, which in our case is even more difficult due to complexity of the data. To this end, we appeal to recent Bayesian nonparametric methods, in particular the use of Bayesian Nonparametric Factor Analysis. This model uses Indian Buffet Process (IBP) as prior on a binary matrix of infinite columns to allocate groups of intervention skills to children. The optimal number of learning patterns as well as subgroup assignments are inferred automatically from data. Our experimental results follow an exploratory approach, present different newly discovered learning patterns. To provide quantitative results, we also report the clustering evaluation against K-means and Nonnegative matrix factorization (NMF). In addition to the novelty of this new problem, we were able to demonstrate the suitability of Bayesian nonparametric models over parametric rivals.

The therapeutic alliance and personality dysfunction in offending behaviour programs

 Therapists in offending behaviour programs use a range of strategies to develop the therapeutic alliance to promote treatment collaboration. They described significant difficulties, however, in responding to personality dysfunction. Analysis of treatment sessions revealed therapists often attempted to engage clients but did not often use ruptures in the alliance as therapeutic opportunities or attend to withdrawn clients. Recommendations are made to better support correctional therapists utilise the alliance to maximise treatment

Exergaming as a viable therapeutic tool to improve static and dynamic balance among older adults and people with idiopathic Parkinson's disease: a systematic review and meta-analysis

The use of virtual reality games (known as "exergaming") as a neurorehabilitation tool is gaining interest. Therefore, we aim to collate evidence for the effects of exergaming on the balance and postural control of older adults and people with idiopathic Parkinson's disease (IPD). Six electronic databases were searched, from inception to April 2015, to identify relevant studies. Standardized mean differences (SMDs) and 95% confidence intervals (CI) were used to calculate effect sizes between experimental and control groups. I (2) statistics were used to determine levels of heterogeneity. 325 older adults and 56 people with IPD who were assessed across 11 -studies. The results showed that exergaming improved static balance (SMD 1.069, 95% CI 0.563-1.576), postural control (SMD 0.826, 95% CI 0.481-1.170), and dynamic balance (SMD -0.808, 95% CI -1.192 to -0.424) in healthy older adults. Two IPD studies showed an improvement in static balance (SMD 0.124, 95% CI -0.581 to 0.828) and postural control (SMD 2.576, 95% CI 1.534-3.599). Our findings suggest that exergaming might be an appropriate therapeutic tool for improving balance and postural control in older adults, but more -large-scale trials are needed to determine if the same is true for people with IPD.

The use of mixed methods in drug discovery: integrating qualitative methods into clinical trials

Contemporary methods in clinical trials are pivoted around hypothesis confirmation, not generation. This is a problem for new drug discovery, since the pharmacokinetic or receptor profile of most novel agents do not link to pathophysiology, which is very poorly understood. Therefore, it is difficult to impute the therapeutic potential of a candidate agent. Most psychotropic agents were discovered serendipitously, either through careful clinical observation or by researchers finding unexpected associations in datasets. Methods that increase the ability to detect latent signals in data are needed. These include mixed methods that incorporate qualitative methods into randomized controlled trials.

This chapter proposes a methodology for the integration of mixed methods in clinical trials, fusing qualitative and quantitative methods, and presents an exemplar using this approach.

Mixed methods show potential for signal detection, hypothesis generation, and associations that may be otherwise undetected in traditional clinical trials.

Use of targeted therapy in cancer patients in the end-of-life period: results from an Australian centre

PURPOSE: Data on the use of targeted therapies at the end of life are scarce. This study reviews the pattern of use of targeted and potentially futile, toxic, or costly therapies at an Australian cancer centre. METHODS: This retrospective single-centre review of data from patients who died within 3 months of having targeted therapy examined demographic characteristics, types of cancers, types of therapy, age, and lines of prior therapy. RESULTS: Over 24 months, two groups were analysed. Firstly, 889 patients died with 107 patients who were prescribed targeted therapy. Secondly, 457 patients were treated with targeted therapies with 52 patients, (11 %) dying within 3 months. To focus on the 52 patients: median age was 69 years, 65 % were men and 35 % were women, 50 % had haematologic cancers and 50 % had solid tumours. Ten therapeutic agents were represented: a higher total number of deaths among those prescribed erlotinib, bevacizumab, and rituximab. There were no deaths within 3 months of treatment with trastuzumab, ipilimumab, or vemurafenib. The targeted therapy was the first-line treatment in 54 %, second in 15 %, and third and beyond in 15 %. The patient's sex and type of cancer had no statistically significant influence on death within 3 months of targeted treatment. CONCLUSIONS: The use of targeted therapy at the end of life in this single-centre descriptive study was lower than documented in other studies. There is a need to prospectively document the factors leading to this prescribing behaviour to guide future protocols.

Patient satisfaction with treatment for alcohol use disorders: comparing patients with and without severe mental health symptoms

BACKGROUND: Previous studies suggest patients with co-occurring alcohol use disorders (AUDs) and severe mental health symptoms (SMHS) are less satisfied with standard AUD treatment when compared to patients with an AUD alone. This study compared patient satisfaction with standard AUD treatment among patients with and without SMHS and explored how standard treatment might be improved to better address the needs of these patients.

METHODS: Eighty-nine patients receiving treatment for an AUD either at an inpatient hospital, outpatient clinic, inpatient detoxification, or residential/therapeutic community services were surveyed. Patient satisfaction with treatment was assessed using the Treatment Perception Questionnaire (range: 0-40). Patients were stratified according to their score on the Depression Anxiety Stress Scale. Forty patients scored in the extremely severe range of depression (score >14) and/or anxiety (score >10) (indicating SMHS) and 49 patients did not. An inductive content analysis was also conducted on qualitative data relating to areas of service improvement.

RESULTS: Patients with SMHS were found to be equally satisfied with treatment (mean =25.10, standard deviation =8.12) as patients with an AUD alone (mean =25.43, standard deviation =6.91). Analysis revealed that being an inpatient in hospital was associated with reduced treatment satisfaction. Patients with SMHS were found to be significantly less satisfied with staffs' understanding of the type of help they wanted in treatment, when compared to patients with AUDs alone. Five areas for service improvement were identified, including staff qualities, informed care, treatment access and continuity, issues relating to inpatient stay, and addressing patients' mental health needs.

CONCLUSION: While findings suggest that AUD treatment services adequately meet the needs of patients with SMHS in treatment, patients with SMHS do feel that staff lack understanding of their treatment needs. Findings have important implications as to how current health care practice might be improved according to the patient's perspective of care.