Youth Depression Alleviation with Anti-inflammatory Agents (YoDA-A): a randomised clinical trial of rosuvastatin and aspirin.

BACKGROUND: Inflammation contributes to the pathophysiology of major depressive disorder (MDD), and anti-inflammatory strategies might therefore have therapeutic potential. This trial aimed to determine whether adjunctive aspirin or rosuvastatin, compared with placebo, reduced depressive symptoms in young people (15-25 years). METHODS: YoDA-A, Youth Depression Alleviation with Anti-inflammatory Agents, was a 12-week triple-blind, randomised, controlled trial. Participants were young people (aged 15-25 years) with moderate to severe MDD (MADRS mean at baseline 32.5 ± 6.0; N = 130; age 20.2 ± 2.6; 60% female), recruited between June 2013 and June 2017 across six sites in Victoria, Australia. In addition to treatment as usual, participants were randomised to receive aspirin (n = 40), rosuvastatin (n = 48), or placebo (n = 42), with assessments at baseline and weeks 4, 8, 12, and 26. The primary outcome was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. RESULTS: At the a priori primary endpoint of MADRS differential change from baseline at week 12, there was no significant difference between aspirin and placebo (1.9, 95% CI (- 2.8, 6.6), p = 0.433), or rosuvastatin and placebo (- 4.2, 95% CI (- 9.1, 0.6), p = 0.089). For rosuvastatin, secondary outcomes on self-rated depression and global impression, quality of life, functioning, and mania were not significantly different from placebo. Aspirin was inferior to placebo on the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) at week 12. Statins were superior to aspirin on the MADRS, the Clinical Global Impressions Severity Scale (CGI-S), and the Negative Problem Orientation Questionnaire scale (NPOQ) at week 12. CONCLUSIONS: The addition of either aspirin or rosuvastatin did not to confer any beneficial effect over and above routine treatment for depression in young people. Exploratory comparisons of secondary outcomes provide limited support for a potential therapeutic role for adjunctive rosuvastatin, but not for aspirin, in youth depression. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12613000112763. Registered on 30/01/2013.

An update on adjunctive treatment options for bipolar disorder.

OBJECTIVES: Bipolar disorder is a complex illness often requiring combinations of therapies to successfully treat symptoms. In recent years, there have been significant advancements in a number of therapies for bipolar disorder. It is therefore timely to provide an overview of current adjunctive therapeutic options to help treating clinicians to inform their patients and work towards optimal outcomes. METHODS: Publications were identified from PubMed searches on bipolar disorder and pharmacotherapy, nutraceuticals, hormone therapy, psychoeducation, interpersonal and social rhythm therapy, cognitive remediation, mindfulness, e-Health and brain stimulation techniques. Relevant articles in these areas were selected for further review. This paper provides a narrative review of adjunctive treatment options and is not a systematic review of the literature. RESULTS: A number of pharmacotherapeutic, psychological and neuromodulation treatment options are available. These have varying efficacy but all have shown benefit to people with bipolar disorder. Due to the complex nature of treating the disorder, combination treatments are often required. Adjunctive treatments to traditional pharmacological and psychological therapies are proving useful in closing the gap between initial symptom remission and full functional recovery. CONCLUSIONS: Given that response to monotherapy is often inadequate, combination regimens for bipolar disorder are typical. Correspondingly, psychiatric research is working towards a better understanding of the disorder's underlying biology. Therefore, treatment options are changing and adjunctive therapies are being increasingly recognized as providing significant tools to improve patient outcomes. Towards this end, this paper provides an overview of novel treatments that may improve clinical outcomes for people with bipolar disorder.

Treatment of bipolar depression.

Depression is usually the predominant phase in bipolar disorder, causes the most psychosocial disability, and carries significant risk of suicide. The management of bipolar depression is relatively under-studied and poses significant challenges for clinicians. There is substantial dissent regarding optimal pharmacotherapy for bipolar depression, particularly around the role of antidepressants. Individual and combination pharmacotherapy should be integrated into a personalised psychosocial and lifestyle package of interventions that considers the person's clinical profile and preferences. The relative lack of evidence relating to optimal strategies, especially when bipolar depression occurs with common comorbidities, poses challenges and requires further research. A flexible approach and evidence-based combinations of treatments can provide effective strategies for improving quality of life and reducing morbidity and mortality.

The role of alprazolam for the treatment of panic disorder in Australia.

OBJECTIVE: To investigate the potential impact of increasing prescription rates of alprazolam for the treatment of panic disorder (PD) in Australia through a review of efficacy, tolerability and adverse outcome literature. METHODS: Data were sourced by a literature search using MEDLINE, Embase, PsycINFO and a manual search of scientific journals to identify relevant articles. Clinical practice guidelines from the American Psychiatric Association, National Institute of Clinical Excellence, Royal Australian and New Zealand College of Psychiatrists and World Federation of Societies of Biological Psychiatry were sourced. Prescription data were sourced from Australian governmental sources. RESULTS: Alprazolam has shown efficacy for control of PD symptoms, particularly in short-term controlled clinical trials, but is no longer recommended as a first-line pharmacological treatment due to concerns about the risks of developing tolerance, dependence and abuse potential. Almost no evidence is available comparing alprazolam to current first-line pharmacological treatment. Despite this, prescription rates are increasing. A number of potential issues including use in overdose and impact on car accidents are noted. conclusion: Although effective for PD symptoms in clinical trials, a number of potential issues may exist with use. Consideration of its future place in PD treatment in Australia may be warranted.

A consensus statement for safety monitoring guidelines of treatments for major depressive disorder.

OBJECTIVE: This paper aims to present an overview of screening and safety considerations for the treatment of clinical depressive disorders and make recommendations for safety monitoring. METHOD: Data were sourced by a literature search using MEDLINE and a manual search of scientific journals to identify relevant articles. Draft guidelines were prepared and serially revised in an iterative manner until all co-authors gave final approval of content. RESULTS: Screening and monitoring can detect medical causes of depression. Specific adverse effects associated with antidepressant treatments may be reduced or identified earlier by baseline screening and agent-specific monitoring after commencing treatment. CONCLUSION: The adoption of safety monitoring guidelines when treating clinical depression is likely to improve overall physical health status and treatment outcome. It is important to implement these guidelines in the routine management of clinical depression.

Youth Depression Alleviation-Augmentation with an anti-inflammatory agent (YoDA-A): protocol and rationale for a placebo-controlled randomized trial of rosuvastatin and aspirin.

AIM: There is growing support for the role of inflammation and oxidative stress in the pathophysiology of major depressive disorder (MDD). This has led to the development of novel strategies targeting inflammation in the treatment of depression. Rosuvastatin and aspirin have well-documented, anti-inflammatory and antioxidant properties. The aim of the Youth Depression Alleviation: Augmentation with an anti-inflammatory agent (YoDA-A) study is to determine whether individuals receiving adjunctive anti-inflammatory agents, aspirin and rosuvastatin experience a reduction in the severity of MDD compared with individuals receiving placebo. METHODS: YoDA-A is a 12-week triple-blind, randomized controlled trial funded by the National Health and Medical Research Council, Australia. Participants aged 15-25, with moderate-to-severe MDD, are allocated to receive either 10 mg/day rosuvastatin, 100 mg/day aspirin, or placebo, in addition to treatment as usual. Participants are assessed at baseline and at weeks 4, 8, 12 and 26. The primary outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. RESULTS: The study is planned to be completed in 2017. At date of publication, 85 participants have been recruited. CONCLUSION: Timely and targeted intervention for youth MDD is crucial. Given the paucity of new agents to treat youth MDD, adjunctive trials are not only pragmatic and 'real-world', but additionally aim to target shortfalls in conventional medications. This study has the potential to first provide two new adjunctive treatment options for youth MDD; aspirin and rosuvastatin. Second, this study will serve as proof of principle of the role of inflammation in MDD.

Clinical diagnosis of skin tumours: how good are we?

BACKGROUND: Few studies have addressed the accuracy of clinical diagnosis of skin malignancies. The present prospective study aims to determine the accuracy with which these lesions are diagnosed and attempts to identify the factors influencing the accuracy of clinical diagnosis. METHODS: All patients undergoing surgical excision of a skin cancer with curative intent from January 2001 to December 2002 at Peter MacCallum Cancer Institute, Melbourne, Australia were prospectively studied. Data were entered into the Filemaker Pro program and analysed using the SPSS software package. RESULTS: A total of 2582 lesions were surgically excised from 1223 patients. Of these 47% were basal cell carcinomas (BCC), 20% were squamous cell carcinomas (SCC), 0.9% were malignant melanomas (MM), and 32.1% were benign or premalignant. Tumours, benign and malignant, were found to be more common in men. The sensitivity for clinical diagnosis of malignancy was 97.5% while the positive predictive value (PPV) for clinical diagnosis of malignancy was 70.3%. BCC and SCC was diagnosed with a sensitivity of 89% and 56.3%, and PPV of 64.5% and 40.3%, respectively (P < 0.001). 23 MM were excised with a sensitivity of clinical diagnosis of 47.8% and PPV of 30.6%. Sensitivity and PPV were also assessed according to clinical experience of the surgeon, site of the lesion and whether surgery was performed for a primary or a recurrent lesion. Sensitivity and PPV were higher for lesions diagnosed by consultant surgeons when compared with surgical trainees (P < 0.001) - MM was diagnosed with a sensitivity of 100% by consultant surgeons. CONCLUSION: The present study shows sensitivity and PPV rates comparable to published figures.

Selective augmentation of striatal functional connectivity following NMDA receptor antagonism: implications for psychosis.

The psychotomimetic effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine is thought to arise from a functional modulation of the brain's fronto-striato-thalamic (FST) circuits. Animal models suggest a pronounced effect on ventral 'limbic' FST systems, although recent work in patients with psychosis and high-risk individuals suggests specific alterations of dorsal 'associative' FST circuits. Here, we used functional magnetic resonance imaging to investigate the effects of a subanesthetic dose of ketamine on measures of functional connectivity as indexed by the temporal coherence of spontaneous neural activity in both dorsal and ventral FST circuits, as well as their symptom correlates. We adopted a placebo-controlled, double-blind, randomized, repeated-measures design in which 19 healthy participants received either an intravenous saline infusion or a racemic mixture of ketamine (100 ng/ml) separated by at least 1 week. Compared with placebo, ketamine increased functional connectivity between the dorsal caudate and both the thalamus and midbrain bilaterally. Ketamine additionally increased functional connectivity of the ventral striatum/nucleus accumbens and ventromedial prefrontal cortex. Both connectivity increases significantly correlated with the psychosis-like and dissociative symptoms under ketamine. Importantly, dorsal caudate connectivity with the ventrolateral thalamus and subthalamic nucleus showed inverse correlation with ketamine-induced symptomatology, pointing to a possible resilience role to disturbances in FST circuits. Although consistent with the role of FST in mediating psychosis, these findings contrast with previous research in clinical samples by suggesting that acute NMDAR antagonism may lead to psychosis-like experiences via a mechanism that is distinct from that implicated in frank psychotic illness.

Hyponatraemia: an audit of aged psychiatry patients taking SSRIs and SNRIs.

OBJECTIVE: Hyponatraemia is a serious adverse event commonly reported in elderly people treated with serotonergic antidepressants. The mechanism, incidence and risk factors for antidepressant induced hyponatraemia are not fully understood. METHOD: In a retrospective chart analysis, depressed patients aged >63 years were investigated for change in serum sodium levels between two time points, separated by a median period of 45.5 days, with the first specimen taken prior to treatment. Patients were grouped into three cohorts; treated with an SSRI or SNRI (n=77), treated with an antidepressant other than an SSRI or SNRI (n=54) and not treated with an antidepressant (n=128). RESULTS: For change in sodium level between measurements and total number of patients with hyponatraemia, there was no significant difference between cohorts. However, the rate of reduction of serum sodium levels between time points was significantly greater for SSRI and SNRI treated patients (p<0.001) and patients treated with other antidepressants (p=0.03) compared to patients not treated with antidepressants. Moreover, the distribution of values of change in serum sodium was skewed towards reduced serum sodium in patients treated with SSRI or SNRIs (skew -0.43) and patients treated with other antidepressants (skew -0.09) but not for patients without antidepressants (skew 0.25). CONCLUSIONS: These data suggest that antidepressant treatment is associated with hyponatraemia affecting a subgroup of individuals only. Generalised linear modelling showed that the risk of hyponatraemia increases with increased age, female gender, and particularly the antidepressant agents sertraline and escitalopram. The findings are of clinical significance as they demonstrate that hyponatraemia can occur rapidly with antidepressants, and SSRI/SNRI medications induce more rapid changes. They support the use of electrolyte monitoring early in antidepressant treatment in patients receiving antidepressants.

Minocycline: therapeutic potential in psychiatry.

Pharmacological interventions to treat psychiatric illness have previously focused on modifying dysfunctional neurotransmitter systems to improve symptoms. However, imperfect understanding of the aetiology of these heterogeneous syndromes has been associated with poor treatment outcomes for many individuals. Growing evidence suggests that oxidative stress, inflammation, changes in glutamatergic pathways and neurotrophins play important roles in many psychiatric illnesses including mood disorders, schizophrenia and addiction. These novel insights into pathophysiology allow new treatment targets to be explored. Minocycline is an antibiotic that can modulate glutamate-induced excitotoxicity, and has antioxidant, anti-inflammatory and neuroprotective effects. Given that these mechanisms overlap with the newly understood pathophysiological pathways, minocycline has potential as an adjunctive treatment in psychiatry. To date there have been promising clinical indications that minocycline may be a useful treatment in psychiatry, albeit from small trials most of which were not placebo controlled. Case reports of individuals with schizophrenia, psychotic symptoms and bipolar depression have shown serendipitous benefits of minocycline treatment on psychiatric symptoms. Minocycline has been trialled in open-label or small randomized controlled trials in psychiatry. Results vary, with findings supporting use in schizophrenia, but showing less benefit for nicotine dependence and obsessive-compulsive disorder. Given the limited data from rigorous clinical trials, further research is required. However, taken together, the current evidence suggests minocycline may be a promising novel therapy in psychiatry.

Ketamine perturbs perception of the flow of time in healthy volunteers.

RATIONALE: Disturbances in the subjective experience of time have been observed both in schizophrenia and following acute administration of ketamine. However, effects of ketamine on more objective timing tasks have not yet been measured in humans, nor has it been established that timing effects are not merely secondary to a more general dysfunction in working memory (WM). OBJECTIVE AND METHODS: In a double-blind placebo-controlled crossover study, we characterised the effects of ketamine (100 ng/ml blood plasma level) on performance of perceptual timing and colour discrimination tasks, which were matched for WM and attentional demands. To test the ubiquity of ketamine's effects on timing, we also examined two distinct measures of temporal predictability. RESULTS: Ketamine significantly distorted the subjective experience of time as measured by the Clinician-Administered Dissociative States Scales. Critically, ketamine also impaired accuracy on the perceptual timing task while having no effect on performance of the colour perception task. Although ketamine did not impair the ability to use prelearned temporal (or spatial) cues to predict target onset (or location), it did slow reaction times at long delays following non-informative neutral cues, suggesting an impaired ability to use the unidirectional flow of time itself to make temporal predictions. CONCLUSIONS: Ketamine induced selective impairments in timing, which could not be explained by more fundamental effects on the ability to hold information in WM. Rather our collected findings suggest that ketamine may disturb timing by selectively impairing the way in which information is temporally manipulated within WM.

Incomplete excision of basal cell carcinoma: a prospective trial.

BACKGROUND: As a measure of the standard of surgical care, incomplete excision of skin malignancy is an important clinical indicator, developed by the Royal Australasian College of Surgeons and the Australian Council on Healthcare Standards. Reported rates of incomplete excision of basal cell carcinoma vary widely (5 to 25 percent) among centers worldwide. This prospective study reports on the incidence of incomplete excision at a tertiary referral public hospital and determines the factors that may influence this. METHODS: From January of 2001 to December of 2002, 1214 basal cell carcinomas were excised at Peter MacCallum Cancer Centre. Data were collected prospectively and analyzed using the FileMaker Pro program and SPSS software. RESULTS: The overall percentage of incomplete excision was 11.2 percent for primary excisions. Risk factors for incomplete excision are the head site; morpheic, superficial, and infiltrative subtypes; lesions larger than 20 mm in diameter; the presence of multiple lesions; repair by skin graft; and recurrent and previously incompletely excised basal cell carcinomas. The type of anesthetic used did not affect outcome. There was no significant difference in the percentage of incomplete excision between consultants, registrars, and the clinical assistant, but this was probably attributable to the small number of cases performed by consultants at Peter MacCallum Cancer Centre. CONCLUSIONS: This is the largest prospective study of incomplete excision of basal cell carcinomas. The authors' result is within the range reported in the current literature but is higher than anticipated. Preoperative "red-flagging" of basal cell carcinomas most at risk of incomplete excision may lead to a better result.

Incomplete excision of squamous cell carcinoma of the skin: a prospective observational study.

BACKGROUND: Squamous cell carcinoma is the second most common cancer of the skin. It behaves differently from basal cell carcinoma. Few large-scale studies have identified risk factors for incomplete excision of cutaneous squamous cell carcinoma. The authors report the largest prospective study to identify the risk factors for incomplete excision of these lesions. METHODS: A total of 517 histopathologically confirmed squamous cell carcinomas were excised from January of 2001 to December of 2002 at the Peter MacCallum Cancer Institute. Of these, 480 primary excisions were analyzed. Data pertaining to patient age, sex, lesion size, margin of excision, recurrence, previous excision, site, anesthetic choice, and repair method were collected prospectively. RESULTS: The overall incomplete excision rate was 6.3 percent. Lesions on the ear (p < 0.003), re-excisions (p < 0.001), and invasive lesions (p < 0.001) were associated with the highest incomplete resection rates. Age (p = 0.61), sex (p = 0.075), tumor size (p = 0.521), surgeon's experience (p = 0.092), and recurrent lesions (p = 0.408) were not statistically significant risk factors. CONCLUSIONS: Statistically significant risk factors were ear lesions, invasive lesions, and previously incompletely excised lesions referred for re-excision. The authors recommend more care with tumor markings, taking margins of at least 5 mm, using deeper margins, and referring patients to more experienced centers.