Ensuring the affordable becomes accessible-lessons from ketamine, a new treatment for severe depression.

In this paper, the case study of ketamine as a new treatment for severe depression is used to outline the challenges of repurposing established medicines and we suggest potential solutions. The antidepressant effects of generic racemic ketamine were identified over 20 years ago, but there were insufficient incentives for commercial entities to pursue its registration, or support for non-commercial entities to fill this gap. As a result, the evaluation of generic ketamine was delayed, piecemeal, uncoordinated, and insufficient to gain approval. Meanwhile, substantial commercial investment enabled the widespread registration of a patented, intranasal s-enantiomeric ketamine formulation (Spravato®) for depression. However, Spravato is priced at $600-$900/dose compared to ~$5/dose for generic ketamine, and the ~AUD$100 million annual government investment requested in Australia (to cover drug costs alone) has been rejected twice, leaving this treatment largely inaccessible for Australian patients 2 years after Therapeutic Goods Administration approval. Moreover, emerging evidence indicates that generic racemic ketamine is at least as effective as Spravato, but no comparative trials were required for regulatory approval and have not been conducted. Without action, this story will repeat regularly in the next decade with a new wave of psychedelic-assisted psychotherapy treatments, for which the original off-patent molecules could be available at low-cost and reduce the overall cost of treatment. Several systemic reforms are required to ensure that affordable, effective options become accessible; these include commercial incentives, public and public-private funding schemes, reduced regulatory barriers and more coordinated international public funding schemes to support translational research.

What clinicians need to know about intranasal esketamine for treatment-resistant depression?

OBJECTIVE: To review the usefulness of esketamine for treatment-resistant depression. METHOD: Pivotal trials of intranasal esketamine in treatment-resistant depression were synthesized as a narrative review. RESULTS: Esketamine is postulated to act through antagonism of N-methyl-D-aspartate (NMDA) glutamate receptors, but opioidergic effects may also be involved. Unlike intravenous ketamine, esketamine is given intranasally (under clinical observation), usually in addition to an oral antidepressant. Trials compared esketamine plus antidepressant versus placebo plus antidepressant. At 4 weeks, remission was 37% higher with esketamine/antidepressant than placebo/antidepressant. Speed of response and improvement in suicidality were comparable. In stable remitters on esketamine/antidepressant, 45% relapsed when esketamine was withdrawn over the following 6 months (whereas 25% relapsed on esketamine/antidepressant). Response appears less likely in patients with multiple antidepressant failures. Adverse effects include dissociation, dizziness, nausea, sedation, and headache but no psychosis. Hypertension affected 13%, especially older patients. Dose frequency is twice-weekly for 4 weeks, then weekly/fortnightly thereafter. No abuse has been reported. Unsubsidised cost may be beyond the reach of many Australians. CONCLUSION: Intranasal esketamine plus antidepressant has been approved by regulators as moderately effective and acceptably tolerable for treatment-resistant depression. Cost is a drawback. Use often needs to be long-term and vigilance for abuse is essential.

Adjunctive Docosahexaenoic Acid in Residual Symptoms of Depression and Anxiety.

OBJECTIVE: The aim of the study is to examine the efficacy of omega-3 fatty acid as an adjunct to ongoing pharmacological treatments in patients with residual symptoms of depression and anxiety. METHODS/PROCEDURES: This randomized, double-blind, placebo-controlled, cross-over trial was conducted at a single private practice site. Participants were drawn from patients attending the practice.Patients meeting criteria had a 4-week run-in period where they continued to receive their prescribed medications and omega-3 supplements. Depression and anxiety ratings were assessed at recruitment and completion of the run-in phase. Patients were randomized to receive an omega-3 supplement (Neurospark) or placebo once daily for 8 weeks then crossed over to the alternative treatment. At the end of the double-blind, cross-over phase, patients received the supplement and were assessed after a 4-week run-out phase.Depression and anxiety symptoms were assessed using the Hamilton scales. Efficacy of treatment was assessed using a linear mixed model analysis with time, order of treatment, diagnosis, and their interaction as factors. Depression and anxiety scales were analyzed as independent measures. RESULTS: The study enrolled 47 patients (mean [SD] age, 46.1 [11.2] years; [59.6%] male). Depression scores did not significantly change across assessments ( P > 0.1); there was no effect of order of treatment ( P > 0.1) or an interaction between time, order of treatment, and psychiatric diagnosis ( P > 0.1). Anxiety scores were similarly unchanged across treatment visits and order of treatment, and there was no interaction between time, order of treatment, and psychiatric diagnosis. CONCLUSIONS: Omega-3 fatty acid supplementation did not significantly alter residual symptoms in this group of patients.

Black cohosh extracts in women with menopausal symptoms: an updated pairwise meta-analysis.

OBJECTIVE: Menopausal symptoms are common in midlife women and have broad impacts on their daily functioning and quality of life. Black cohosh extracts have been widely used to relieve menopausal symptoms. However, the comparative benefits of different combined black cohosh regimens remain inconclusive. The aim of the current updated meta-analysis is to address the comparative efficacies of different black cohosh regimens in improving menopausal symptoms. METHODS: Random-effect model pairwise meta-analysis of randomized controlled trials was conducted to investigate the treatment effect on menopausal symptoms by the black cohosh extract both alone or combined with other related active ingredients. The outcomes studied were changes in menopausal symptoms after treatment with black cohosh extracts in menopausal women. RESULTS: Twenty-two articles including information on 2,310 menopausal women were included in the analyses. Black cohosh extracts were associated with significant improvements in overall menopausal symptoms (Hedges' g = 0.575, 95% CI = 0.283 to 0.867, P < 0.001), as well as in hot flashes (Hedges' g = 0.315, 95% CIs = 0.107 to 0.524, P = 0.003), and somatic symptoms (Hedges' g = 0.418, 95% CI = 0.165 to 0.670, P = 0.001), compared with placebo. However, black cohosh did not significantly improve anxiety (Hedges' g = 0.194, 95% CI = -0.296 to 0.684, P = 0.438) or depressive symptoms (Hedges' g = 0.406, 95% CI = -0.121 to 0.932, P = 0.131). The dropout rate for black cohosh products was similar to that for placebo (odds ratio = 0.911, 95% CI = 0.660 to 1.256, P = 0.568). CONCLUSIONS: This study provides updated evidence regarding the potentially beneficial effects of black cohosh extracts for relieving menopausal symptoms in menopausal women.

Difficult decision-making in major depressive disorder: Practical guidance based on clinical research and experience.

OBJECTIVES: To extend current published guidance regarding the management of major depression in clinical practice, by examining complex cases that reflect real-world patients, and to integrate evidence and experience into recommendations. METHODS: The authors who contributed to recently published clinical practice guidelines were invited to identify important gaps in extant guidance. Drawing on clinical experience and shared knowledge, they then generated four fictional case studies to illustrate the real-world complexities of managing mood disorders. The cases focussed specifically on issues that are not usually addressed in clinical practice guidelines. RESULTS: The four cases are discussed in detail and each case is summarised using a life chart and accompanying information. The four cases reflect important real-world challenges that clinicians face when managing mood disorders in day-to-day clinical practice. To partly standardise the presentation of each case and for ease of reference we provide a Time Line, History Box and Management Chart, along with a synopsis where relevant. Discussion and formulation of the cases illustrate how to manage the complexities of each case and provide one possible pathway to achieving functional recovery. CONCLUSION: These cases draw on the combined clinical experience of the authors and illustrate how to approach diagnostic decision-making when treating major depressive disorder and having to contend with complex presentations. The cases are designed to stimulate discussion and provide a real-world context for the formulation of mood disorders.

Anxiety Symptoms in Patients with Major Depressive Disorder: Commentary on Prevalence and Clinical Implications.

The prevalence of major depressive disorder (MDD) has been increasing, and MDD is now a leading cause of global disability. Depression often coexists with anxiety, and the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) introduced the 'anxious distress' specifier to identify those patients within the MDD category who have anxiety as well. The prevalence of anxious depression is high, with studies suggesting that 50-75% of patients with MDD meet the DSM-5 criteria for anxious depression. However, it can be difficult to discern whether a patient has MDD with anxiety or an anxiety disorder that has triggered an episode of depression. In fact, approximately 60-70% of patients with comorbid anxiety and depression experience anxiety first, but it is often depression that leads the patient to seek treatment. Patients with MDD who also have anxiety have significantly worse psychosocial functioning and poorer quality of life compared with patients with MDD without anxiety. In addition, patients with MDD and anxiety take significantly longer to achieve remission, and are less likely to achieve remission, than patients with MDD without anxiety. Therefore, it is essential that physicians have a high index of suspicion for comorbid anxiety in patients with depression, and that anxiety symptoms in patients with MDD are effectively treated. This commentary is based on a virtual symposium presented at the 33rd International College of Neuropsychopharmacology (CINP) World Congress, Taipei, Taiwan, in June 2022.

Tau, ß-Amyloid, and Glucose Metabolism Following Service-Related Traumatic Brain Injury in Vietnam War Veterans: The Australian Imaging Biomarkers and Lifestyle Study of Aging-Veterans Study (AIBL-VETS).

Traumatic brain injury (TBI) is common among military veterans and has been associated with an increased risk of dementia. It is unclear if this is due to increased risk for Alzheimer's disease (AD) or other mechanisms. This case control study sought evidence for AD, as defined by the 2018 National Institute on Aging - Alzheimer's Association (NIA-AA) research framework, by measuring tau, ß-amyloid, and glucose metabolism using positron emission tomography (PET) in veterans with service-related TBI. Seventy male Vietnam war veterans-40 with TBI (age 68.0 ± 2.5 years) and 30 controls (age 70.1 ± 5.3 years)-with no prior diagnosis of dementia or mild cognitive impairment underwent ß-amyloid (18F-Florbetaben), tau (18F-Flortaucipir), and fluorodeoxyglucose (18F-FDG) PET. The TBI cohort included 15 participants with mild, 16 with moderate, and nine with severe injury. ß-Amyloid level was calculated using the Centiloid (CL) method and tau was measured by standardized uptake value ratios (SUVRs) using the cerebellar cortex as reference region. Analyses were adjusted for age and APOE-e4. The findings were validated in an independent cohort from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DOD ADNI) study. There were no significant nor trending differences in ß-amyloid or tau levels or 18F-FDG uptake between the TBI and control groups before and after controlling for covariates. The ß-amyloid and tau findings were replicated in the DOD ADNI validation cohort and persisted when the Australian Imaging Biomarkers and Lifestyle study of aging-Veterans study (AIBL-VETS) and DOD ADNI cohorts were combined (114 TBI vs. 87 controls in total). In conclusion, no increase in the later life accumulation of the neuropathological markers of AD in veterans with a remote history of TBI was identified.

Positioning of psychodynamic psychotherapy in the treatment of depression: A comparison of the RANZCP 2020 and NICE 2022 guidelines.

OBJECTIVE: To compare the 2022 NICE guidelines (NG222) and 2020 RANZCP clinical practice guidelines (MDcpg2020) recommendations for the treatment of depression using psychodynamic psychotherapy. CONCLUSIONS: Both guidelines recommend psychological interventions first-line. However, only short-term psychodynamic psychotherapy (STPP) is recommended, and in the NG222 it is ranked last for less severe depression and 7th for more severe depression. In contrast, cognitive behavioural therapy and behavioural activation are deemed the more clinically effective and cost-effective psychological therapies. And antidepressants play a significant role - largely in more severe depression.

The management of depression: the evidence speaks for itself.

Comparing the recommendations of two recently published national clinical practice guidelines for depression, this editorial highlights the concordance of advice concerning the selection and sequencing of therapies. Lifestyle and psychological interventions feature prominently and there is broad agreement regarding medication choice and optimisation strategies. The guidelines are therefore a useful resource.

Use of Olanzapine to Treat Agitation in Traumatic Brain Injury: A Series of N-of-One Trials.

Agitation is common during post-traumatic amnesia (PTA) following traumatic brain injury (TBI) and is associated with risk of harm to patients and caregivers. Antipsychotics are frequently used to manage agitation in early TBI recovery despite limited evidence to support their efficacy, safety, and impact upon patient outcomes. The sedating and cognitive side effects of these agents are theorized to exacerbate confusion during PTA, leading to prolonged PTA duration and increased agitation. This study, conducted in a subacute inpatient rehabilitation setting, describes the results of a double-blind, randomized, placebo-controlled trial investigating the efficacy of olanzapine for agitation management during PTA, analyzed as an n-of-1 series. Group comparisons were additionally conducted, examining level of agitation; number of agitated days; agitation at discharge, duration, and depth of PTA; length of hospitalization; cognitive outcome; adverse events; and rescue medication use. Eleven agitated participants in PTA (mean [M] age = 39.82 years, standard deviation [SD] = 20.06; mean time post-injury = 46.09 days, SD = 32.75) received oral olanzapine (n = 5) or placebo (n = 6) for the duration of PTA, beginning at a dose of 5 mg/day and titrated every 3 to 4 days to a maximum dose of 20 mg/day. All participants received recommended environmental management for agitation. A significant decrease in agitation with moderate to very large effect (Tau-U effect size = 0.37-0.86) was observed for three of five participants receiving olanzapine, while no significant reduction in agitation over the PTA period was observed for any participant receiving placebo. Effective olanzapine dose ranged from 5-20 mg. Response to treatment was characterized by lower level of agitation and response to treatment within 3 days. In group analyses, participants receiving olanzapine demonstrated poorer orientation and memory during PTA with large effect size (olanzapine, mean = 9.32, SD = 0.69; placebo, M = 10.68, SD = 0.30; p = .009, d = -2.16), and a trend toward longer PTA duration with large effect size (olanzapine, M = 71.96 days, SD = 20.31; placebo, M = 47.50 days, SD = 11.27; p = 0.072, d = 1.26). No further group comparisons were statistically significant. These results suggest that olanzapine can be effective in reducing agitation during PTA, but not universally so. Importantly, administration of olanzapine during PTA may lead to increased patient confusion, possibly prolonging PTA. When utilizing olanzapine, physicians must therefore balance the possible advantages of agitation management with the possibility that the patient may never respond to the medication and may experience increased confusion, longer PTA and potentially poorer outcomes. Further high-quality research is required to support these findings and the efficacy and outcomes associated with the use of any pharmacological agent for the management of agitation during the PTA period.

Effectiveness of Pharmacotherapy for Depression after Adult Traumatic Brain Injury: an Umbrella Review.

Symptoms of depression are common following traumatic brain injury (TBI), impacting survivors' ability to return to work, participate in leisure activities, and placing strain on relationships. Depression symptoms post TBI are often managed with pharmacotherapy, however, there is little research evidence to guide clinical practice. There have been a number of recent systematic reviews examining pharmacotherapy for post TBI depression. The aim of this umbrella review was to synthesize systematic reviews and meta-analyses of the effectiveness of pharmacotherapy for the management of post TBI depression in adults. Eligible reviews examined any pharmacotherapy against any comparators, for the treatment of depression in adults who had sustained TBI. Seven databases were searched, with additional searching of online journals, Research Gate, Google Scholar and the TRIP Medical Database to identify published and unpublished systematic reviews and meta-analyses in English up to May 2020. A systematic review of primary studies available between March 2018 and May 2020 was also conducted. Evidence quality was assessed using Joanna Briggs Institute Critical Appraisal Instruments. The results are presented as a narrative synthesis. Twenty-two systematic reviews were identified, of which ten reviews contained a meta-analysis. No new primary studies were identified in the systematic review. There was insufficient high quality and methodologically rigorous evidence to recommend prescribing any specific drug or drug class for post TBI depression. The findings do show, however, that depression post TBI is responsive to pharmacotherapy in at least some individuals. Recommendations for primary studies, systematic reviews and advice for prescribers is provided. Review Registration PROSPERO (CRD42020184915).

Key features of adolescent inpatient units and development of a checklist to improve consistency in reporting of settings.

WHAT IS KNOWN ON THE SUBJECT?: Little is known about adolescent inpatient units, key features which define them, and how these essential services operate and deliver care. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: Adolescent inpatient unit studies are limited in their descriptions of settings in terms of how they operate and key features. The proposed preliminary checklist is a practical tool to assist clinicians, policy makers, and researchers when reporting to ensure comprehensive descriptions of adolescent inpatient settings. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: This could be used to inform service design processes for inpatient and other mental health service models which is of critical importance in the context of reforms and implementation of these in Australia currently. Greater attention to operational models, services, and philosophies of practice will improve reporting and allow for the advancement of knowledge, comparison of study results, and a clearer direction for mental health nursing clinicians and researchers. ABSTRACT: Introduction Adolescent inpatient units care for vulnerable population groups; however, little is known about how these essential services operate and deliver care. Aims To examine the descriptions of adolescent mental health inpatient units in Australian and international research publications and to identify key features which were used to define them. A secondary aim was to develop a checklist to improve consistency when reporting on the operations and services delivered within adolescent mental health inpatient units (both public and private). Methods Five electronic databases (CINAHL, MEDLINE, ERIC, EMBASE, and PsycINFO) were systematically searched. We included studies that provided descriptions of operations and services within adolescent inpatient units where participants had a mean age between 12 and 25. Narrative synthesis was used to explore the similarities and differences between descriptions of settings. Results Twenty-eight studies were identified, which varied in their descriptions of adolescent inpatient units, providing inconsistent information to inform best practice. Discussion Studies lack consistency and comprehensive detail when describing the operational models within inpatient units, making interpretation challenging. Consequently, a preliminary checklist is proposed to improve reporting of adolescent inpatient units.

A Qualitative Study of the Expectations, Experiences, and Perceptions That Underpin Decisions Regarding PTSD Treatment in Help-seeking Veterans.

INTRODUCTION: A range of evidence-based treatments are available for PTSD. However, many veterans with PTSD do not engage in these treatments. Concurrently, various novel PTSD treatments with little or no evidence based are increasingly popular among veterans. This qualitative study explored the expectations, experiences, and perceptions of help-seeking veterans with PTSD to improve understanding of how these veterans make treatment decisions. MATERIALS AND METHODS: Fifteen treatment-seeking veterans with PTSD participated in the study. Participants took part in semi-structured interviews. Data were analyzed using interpretative phenomenological analysis. RESULTS: A number of themes and subthemes emerged from the data, providing a detailed account of the factors that influenced participants' treatment decisions. Most participants were in an acute crisis when they made the initial decision to seek treatment for their PTSD. In choosing a specific treatment, they tended to follow recommendations made by other veterans or health professionals or orders or directions from their superiors, health providers, or employers. Few participants actively considered the scientific evidence supporting different treatments. Participants had a strong preference for treatment provided by or involving other veterans. They reported finding PTSD treatments helpful, although some were not convinced of the value of evidence-based treatments specifically. Many participants reported negative experiences with treatment providers. CONCLUSIONS: These findings will inform strategies to improve engagement of veterans in evidence-based PTSD treatments and advance progress toward veteran-centered care.

The Potential Impact of a Public Health Approach to Improving the Physical Health of People Living with Mental Illness.

With already wide disparities in physical health and life expectancy, COVID-19 presents people with mental illness with additional threats to their health: decreased access to health services, increased social isolation, and increased socio-economic disadvantage. Each of these factors has exacerbated the risk of poor health and early death for people with mental illness post-COVID-19. Unless effective primary care and preventative health responses are implemented, the physical illness epidemic for this group will increase post the COVID-19 pandemic. This perspective paper briefly reviews the literature on the impact of COVID-19 on service access, social isolation, and social disadvantage and their combined impact on physical health, particularly cancer, respiratory diseases, heart disease, smoking, and infectious diseases. The much-overlooked role of poor physical health on suicidality is also discussed. The potential impact of public health interventions is modelled based on Australian incidence data and current research on the percentage of early deaths of people living with mental illnesses that are preventable. Building on the lessons arising from services' response to COVID-19, such as the importance of ensuring access to preventive, screening, and primary care services, priority recommendations for consideration by public health practitioners and policymakers are presented.

Open innovation: the key to advancing brain health.

With the exponential growth in investment attention to brain health-solutions spanning brain wellness to mental health to neurological disorders-tech giants, payers, and biotechnology companies have been making forays into this field to identify technology solutions and pharmaceutical amplifiers. So far, their investments have had mixed results. The concept of open innovation (OI) was first coined by Henry Chesbrough to describe the paradigm by which enterprises allow free flow of ideas, products, and services from the outside to the inside and vice versa in order to remain competitive, particularly in rapidly evolving fields where there is abundant, relevant knowledge outside the traditional walls of the enterprise. In this article, we advocate for further exploration and advancement of OI in brain health.

Using an ecological momentary assessment protocol to understand problem anger in veterans.

BACKGROUND AND OBJECTIVES: Problem anger is highly destructive, and is one of the most commonly reported issues in military and veteran populations. The goal of this study was to use ecological momentary assessment (EMA) to explore and characterize moment-to-moment experiences of problem anger in a sample of Australian veterans. METHODS: Sixty veterans with problem anger (measured on the Dimensions of Anger Reactions Scale) completed measures of anger and anger rumination, before and after a 10-day EMA period which assessed the frequency, intensity, and expression of momentary anger experiences. RESULTS: Findings showed that 75% of respondents indicated some level of anger during EMA monitoring. In 25% of cases, anger was reported as severe. Moreover, anger was expressed verbally in 43% of cases, and expressed physically in 27% of cases. While anger fluctuated frequently during the day, more severe anger was more likely to be reported in the late afternoon/early evening. Problem anger symptoms decreased significantly over time, from pre-EMA to post EMA (p < .001). LIMITATIONS: The generalizability of findings is limited to a predominantly male sample, with low levels of risk of harm or violence. The study was also limited in the selection of outcome variables assessed and the lack of a control group; other momentary factors could influence experience of problem anger and provide further explanation of study results. CONCLUSIONS: EMA is a valuable assessment tool for individuals with problem anger, and the potential for EMA as an intervention needs to be explored further.

An Evidence-Based Perspective on The 2020 Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines.

OBJECTIVE: To rebut the claims made in an opinion piece by Anaf and colleagues regarding the recommendations for psychotherapy within the 2020 RANZCP Mood Disorders Clinical Practice Guidelines (CPG). CONCLUSIONS: The CPG attaches importance to psychological interventions and recommends their administration as first-line in the treatment of depression. The concerns raised by Anaf and colleagues have no basis and are readily dismissed by referring to the guidelines. Therefore, we strongly encourage clinicians to formulate their own views by reading the guidelines for themselves.