Protocol for a randomised controlled trial of ketamine versus ketamine and behavioural activation therapy for adults with treatment-resistant depression in the community.

INTRODUCTION: Although short-term benefits follow parenteral ketamine for treatment-resistant major depressive disorder (TR-MDD), there are challenges that prevent routine use of ketamine by clinicians. These include acute dissociative effects of parenteral ketamine, high relapse rates following ketamine dosing and the uncertain role of psychotherapy. This randomised controlled trial (RCT) seeks to establish the feasibility of evaluating repeated oral doses of ketamine and behavioural activation therapy (BAT), compared with ketamine treatment alone, for TR-MDD. We also aim to compare relapse rates between treatment arms to determine the effect size of adding BAT to oral ketamine. METHODS AND ANALYSIS: This is a prospectively registered, two-centre, single-blind RCT. We aim to recruit 60 participants with TR-MDD aged between 18 and 65 years. Participants will be randomised to 8 weeks of oral ketamine and BAT, or 8 weeks of oral ketamine alone. Feasibility will be assessed by tracking attendance for ketamine and BAT, acceptability of treatment measures and retention to the study follow-up protocol. The primary efficacy outcome measure is the Montgomery-Asberg Depression Rating Scale (MADRS) measured weekly during treatment and fortnightly during 12 weeks of follow-up. Other outcome measures will assess the tolerability of ketamine and BAT, cognition and activity (using actigraphy). Participants will be categorised as non-responders, responders, remitters and relapsed during follow-up. MADRS scores will be analysed using a linear mixed model. For a definitive follow-up RCT study to be recommended, the recruitment expectations will be met and efficacy outcomes consistent with a >20% reduction in relapse rates favouring the BAT and ketamine arm will be achieved. ETHICS AND DISSEMINATION: Ethics approval was granted by the New Zealand Central Health and Disability Ethics Committee (reference: 2023 FULL18176). Study findings will be reported to participants, stakeholder groups, conferences and peer-reviewed publications. TRIAL REGISTRATION NUMBER: UTN: U1111-1294-9310, ACTRN12623000817640p.

The Aotearoa New Zealand doctor shortage: current context and strategies for retention.

The international migration of health professionals has been an ongoing issue with the medical workforce in Aotearoa New Zealand. There are many reasons why New Zealand-trained doctors choose to leave. Often it has been to gain overseas experience, with many eventually returning to New Zealand; however, this has now changed, with increasing numbers not returning. Little has been done to combat this developing problem, amidst an increasingly competitive global market for health professionals. There is public and political concern about the current shortage and uneven distribution of doctors, particularly because this has fostered unsustainable working conditions, which diminishes the provision of safe healthcare in this country. This article examines the context behind the migration of New Zealand-trained doctors and proposes several strategies for retention as potential solutions to the underlying problem.

Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force.

BACKGROUND: Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD. METHODS: We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials. RESULTS: Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias. CONCLUSIONS: Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.

The effect of age on emotion processing in individuals with mood disorders and in healthy individuals.

Introduction: Emotion processing is an essential part of interpersonal relationships and social interactions. Changes in emotion processing have been found in both mood disorders and in aging, however, the interaction between such factors has yet to be examined in detail. This is of interest due to the contrary nature of the changes observed in existing research - a negativity bias in mood disorders versus a positivity effect with aging. It is also unclear how changes in non-emotional cognitive function with aging and in mood disorders, interact with these biases. Methods and results: In individuals with mood disorders and in healthy control participants, we examined emotional processing and its relationship to age in detail. Data sets from two studies examining facial expression recognition were pooled. In one study, 98 currently depressed individuals (either unipolar or bipolar) were compared with 61 healthy control participants, and in the other, 100 people with bipolar disorder (in various mood states) were tested on the same facial expression recognition task. Repeated measures analysis of variance was used to examine the effects of age and mood disorder diagnosis alongside interactions between individual emotion, age, and mood disorder diagnosis. A positivity effect was associated with increasing age which was evident irrespective of the presence of mood disorder or current mood episode. Discussion: Results suggest a positivity effect occurring at a relatively early age but with no evidence of a bias toward negative emotions in mood disorder or specifically, in depressed episodes. The positivity effect in emotional processing in aging appears to occur even within people with mood disorders. Further research is needed to understand how this fits with negative biases seen in previous studies in mood disorders.

Measuring memory: A survey of neuropsychological practice amongst New Zealand psychologists.

This study sought to explore patterns of memory assessment in neuropsychological practice within New Zealand (NZ), to compare it to that previously described in Europe, North America and Australia, and to consider the implications for neuropsychology training in NZ. 80 NZ-registered psychologists completed an online survey asking them how frequently they utilized 50 commonly used tests of memory. Participants were also asked about their main areas of specialty, work context and demographic information. Whilst participants appeared, broadly, to utilize a similar set of 'core' tests to their colleagues in Europe, Australia and North America, there were a number of tests and test domains that were rarely utilized by NZ psychologists, in contrast to overseas samples. Furthermore, several of the tests in common usage have been shown to have significant validity issues for use with an NZ population. Overall, this study suggests that most NZ psychologists employ a similar approach to memory assessment, typically relying upon a small number of well-known tests. This appears to contrast with a greater variability of practice shown in studies of European, North American and Australian psychologists and raises several interesting questions for the future development of neuropsychology in NZ.

UNITE Project: understanding neurocognitive impairment after trauma exposure-study protocol of an observational study in Christchurch, New Zealand.

INTRODUCTION: Our previous research has demonstrated significant cognitive effects of earthquake exposure 2-3 years following the Canterbury earthquake sequence of 2011. Such impairment has major implications for a population trying to recover, and to rebuild, a devastated city. This study aims to examine psychological, cognitive and biological factors that may contribute to subjective cognitive difficulties in a large group of individuals exposed to the Canterbury earthquake sequence. METHODS AND ANALYSIS: Two-hundred earthquake-exposed participants from an existing large cohort study (Christchurch Health and Development Study, CHDS) will be recruited. Inclusion is based on results of online screening of the CHDS cohort, using the Cognitive Failures Questionnaire. Individuals scoring the highest (n=100) and lowest (n=100), representing the highest and lowest levels of subjective cognitive impairment, are selected. Exclusions are: psychotic/bipolar disorders, serious substance/alcohol dependence, chronic medical conditions, pregnancy and previous serious head injury. Participants will undergo a half-day assessment including clinician-rated interviews, self-report measures, objective and subjective cognitive assessments, blood sample collection and physical measurements. The primary analysis will compare cognitive, psychological and biological measures in 'high' and 'low' subjective cognitive impairment groups. The study will have power (p<0.05, α=0.8) to show a difference between groups of 0.4 SD on any variable. ETHICS AND DISSEMINATION: Ethical approval for this study was granted by the New Zealand Health and Disability Ethics Committee. The online screening component of the study received ethical approval on 1 April 2021 (16/STH/188, PAF 7), and the main study (subsequent to screening) received approval on 16 August 2021 (Northern A 21/NTA/68). All participants provide written informed consent. Findings will be disseminated initially to the CHDS cohort members, the wider Canterbury community, and then by publication in scientific journals and conference presentations. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05090046).

Barriers to and facilitators of success for early and Mid-Career professionals focused on bipolar disorder: A global needs survey by the International Society for Bipolar Disorders.

INTRODUCTION: The International Society for Bipolar Disorders created the Early Mid-Career Committee (EMCC) to support career development of the next generation of researchers and clinicians specializing in bipolar disorder (BD). To develop new infrastructure and initiatives, the EMCC completed a Needs Survey of the current limitations and gaps that restrict recruitment and retention of researchers and clinicians focused on BD. METHODS: The EMCC Needs Survey was developed through an iterative process, relying on literature and content expertise of workgroup members. The survey included 8 domains: navigating transitional career stages, creating and fostering mentorship, research activities, raising academic profile, clinical-research balance, networking and collaboration, community engagement, work-life balance. The final survey was deployed from May to August 2022 and was available in English, Spanish, Portuguese, Italian, and Chinese. RESULTS: Three hundred participants across six continents completed the Needs Survey. Half of the participants self-identified as belonging to an underrepresented group in health-related sciences (i.e., from certain gender, racial, ethnic, cultural, or disadvantaged backgrounds including individuals with disabilities). Quantitative results and qualitative content analysis revealed key barriers to pursuing a research career focused on BD with unique challenges specific to scientific writing and grant funding. Participants highlighted mentorship as a key facilitator of success in research and clinical work. CONCLUSION: The results of the Needs Survey are a call to action to support early- and midcareer professionals pursuing a career in BD. Interventions required to address the identified barriers will take coordination, creativity, and resources to develop, implement, and encourage uptake but will have long-lasting benefits for research, clinical practice, and ultimately those affected by BD.

Ketamine and psychotherapy for the treatment of psychiatric disorders: systematic review.

BACKGROUND: Ketamine is an effective short-term treatment for a range of psychiatric disorders. A key question is whether the addition of psychotherapy to ketamine treatment improves outcomes or delays relapse. AIM: To identify all studies combining psychotherapy with ketamine for the treatment of psychiatric disorders to summarise their effects and make recommendations for future research. METHOD: The review protocol was prospectively registered with PROSPERO (registration number CRD42022318120). Potential studies were searched for in MEDLINE, Embase, PsycINFO, SCOPUS, the Cochrane library and Google Scholar. Eligible studies combined ketamine and psychotherapy for the treatment of psychiatric disorders and did not use case reports or qualitative designs. Key findings relating to psychotherapy type, diagnosis, ketamine protocol, sequencing of psychotherapy and study design are reported. Risk of bias was assessed using modified Joanna Briggs critical appraisal tools. RESULTS: Nineteen studies evaluating 1006 patients were included in the systematic review. A variety of supportive individual and group, manualised and non-manualised psychotherapies were used. The majority of studies evaluated substance use disorders, post-traumatic stress disorder and treatment-resistant depression. Ketamine protocols and sequencing of ketamine/psychotherapy treatment varied substantially between studies. Outcomes were largely positive for the addition of psychotherapy to ketamine treatment. CONCLUSION: The combination of psychotherapy and ketamine offers promise for the treatment of psychiatric disorders, but study heterogeneity prevents definitive recommendations for their integration. Larger randomised controlled trials using manualised psychotherapies and standardised ketamine protocols are recommended to clarify the extent to which the addition of psychotherapy to ketamine improves outcomes over ketamine treatment alone.

Childhood trauma and cognitive functioning in mood disorders: A systematic review.

BACKGROUND: Cognitive impairment is a core feature of mood disorders and has been identified as an important treatment target. A better understanding of the factors contributing to cognitive impairment in mood disorders would be beneficial in developing interventions to address cognitive impairment. One key factor is childhood trauma. The aim of this review was to systematically synthesise and review research examining associations between reported childhood trauma and cognitive functioning in mood disorders. METHODS: Studies in adult samples examining the relationship between objective cognitive function and reported childhood trauma in major depressive disorder and/or bipolar disorder (in-episode or euthymia) were identified. Searches were conducted on PubMed, Embase and PsycINFO until January 2022. A narrative review technique was used due to the heterogeneity of group comparisons, cognitive tests and data analysis across studies. RESULTS: Seventeen studies met the criteria for inclusion (mood disorders N = 1723, healthy controls N = 797). Evidence for childhood trauma being related to poorer cognitive functioning was consistent across global cognitive functioning and executive function domains for euthymic patients and psychomotor speed for in-episode patients. There was mixed evidence for verbal learning and memory and executive function for in-episode patients. Identification of patterns within other domains was difficult due to limited number of studies. CONCLUSION: Findings from this review suggest childhood trauma is associated with poorer cognitive functioning in people with mood disorders. Targeted interventions to improve cognition may be warranted for this group.

Validation of the Longitudinal Interval Follow-Up Evaluation for the Long-Term Measurement of Mood Symptoms in Bipolar Disorder.

The long-term burden of symptoms is an important outcome in bipolar disorder (BD). A method which has minimal burden of assessment uses a retrospective interview, the Longitudinal Interval Follow-up Examination (LIFE), although this may be subject to problems with recall. This study examines the relationship between the retrospective LIFE scale and concurrently-rated mood rating scales in two clinical trials of 18 months of psychotherapy for patients with BD. The Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) were administered every eight to nine weeks and the LIFE was carried out every 6 months. Correlations between scores on mood rating scales and at equivalent times on the LIFE were examined, as well as of potential clinical moderators. There were significant correlations between LIFE depression ratings and concurrent MADRS score (r = 0.57) and between LIFE mania ratings and YMRS score (r = 0.40). In determining "mild depression" on the MADRS, a receiver operating characteristics (ROC) analysis showed an AUC of 0.78 for LIFE scores. Correlations, particularly for depression scores, were high even when the LIFE rating was several months before the interview, suggesting that the LIFE has validity in examining the burden of mood symptoms over time, with relatively little burden of assessment. Future research should examine the relationship between symptom burden and quality of life measured in this way.

Changes in Mood, Anxiety, and Cognition with Polycystic Ovary Syndrome Treatment: A Longitudinal, Naturalistic Study.

Purpose: Individuals with polycystic ovary syndrome (PCOS) are at increased risk of depression and anxiety symptoms and impairment in aspects of cognitive function. However, there is little evidence regarding effects of standard treatment for PCOS on these features of the syndrome. The aim of this study was to examine the effect of 12 weeks of naturalistic treatment of PCOS, with usual medications, on depression symptoms, anxiety symptoms and cognitive function. Patients and Methods: Thirty-three participants with PCOS received 12 weeks of individualised treatment based on clinical presentation. Changes in depression and anxiety symptoms were assessed with the self-report Hospital Anxiety and Depression Scale at baseline and 12 weeks, and cognitive function was assessed at the same time-points with a battery of tests spanning cognitive domains of verbal learning and memory, visuospatial learning and memory, psychomotor speed, attention and executive function. Outcomes were compared with a control group of 40 healthy participants. Results: Participants with PCOS (mean age = 29.2 years; mean Body Mass Index = 27.4) were treated with a variety of medications, predominantly spironolactone (n = 22) and oral contraceptives (n = 16). Depression and anxiety symptoms improved significantly over the course of treatment, with moderate effect sizes (Cohen's d 0.43-0.55, p < 0.05). Effect sizes of the difference in change from that of the control group were moderate but did not reach statistical significance. Women undergoing PCOS treatment demonstrated significant improvements in aspects of cognitive function, but improvement did not differ significantly from controls and effect size changes were similar, suggesting practise effects in both groups. Conclusion: Our study provides preliminary evidence that treatment of PCOS may be associated with improvement in psychiatric aspects of the syndrome, particularly depressive symptoms.

Relationship between baseline cognition and 18-month treatment response in bipolar disorder.

BACKGROUND: To date, few studies have examined baseline cognitive function as a predictor of clinical outcome following treatment in bipolar disorder (BD). The aim of this analysis was therefore to examine the relationship between baseline cognitive function and treatment outcome in a sample of young adults with BD receiving Interpersonal Social Rhythm Therapy (IPSRT) or Specialist Supportive Care (SSC) with adjunctive pharmacotherapy. METHODS: Eighty-six BD patients underwent baseline cognitive testing and completed 18 months of IPSRT or SCC. Univariate analyses examined the relationship between baseline cognitive function (global and individual cognitive domains) and change in mood symptom burden, and psychosocial functioning, from baseline to treatment-end. RESULTS: Baseline global cognition was not predictive of change in mood symptom burden over 18 months of treatment. However, poorer baseline psychomotor speed performance was associated with less improvement in mood symptom burden at treatment-end. Neither baseline global cognition nor individual cognitive domain scores were associated with change in psychosocial functioning. LIMITATIONS: Due to the exploratory nature of the study, correction was not made for multiple comparisons. Data was obtained from a relatively small sample and has been the subject of prior analysis, thereby increasing the likelihood of chance findings. CONCLUSION: Although global cognition was not associated with outcome, when examining individual domains, poorer baseline psychomotor speed predicted less change in mood symptom burden following 18-months of psychotherapy and pharmacotherapy. This suggests that pre-treatment measures of psychomotor speed may help to identify those who require additional, and more targeted, intervention. Further large-scale research is required.

Can magnetic resonance imaging enhance the assessment of potential new treatments for cognitive impairment in mood disorders? A systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Developing treatments for cognitive impairment is key to improving the functioning of people with mood disorders. Neuroimaging may assist in identifying brain-based efficacy markers. This systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force examines the evidence from neuroimaging studies of pro-cognitive interventions. METHODS: We included magnetic resonance imaging (MRI) studies of candidate interventions in people with mood disorders or healthy individuals, following the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE, Cochrane Library, and Clinicaltrials.gov from inception to 30th April 2021. Two independent authors reviewed the studies using the National Heart, Lung, Blood Institutes of Health Quality Assessment Tool for Controlled Intervention Studies and the quality of neuroimaging methodology assessment checklist. RESULTS: We identified 26 studies (N = 702). Six investigated cognitive remediation or pharmacological treatments in mood disorders (N = 190). In healthy individuals, 14 studies investigated pharmacological interventions (N = 319), 2 cognitive training (N = 73) and 4 neuromodulatory treatments (N = 120). Methodologies were mostly rated as 'fair'. 77% of studies investigated effects with task-based fMRI. Findings varied but most consistently involved treatment-associated cognitive control network (CCN) activity increases with cognitive improvements, or CCN activity decreases with no cognitive change, and increased functional connectivity. In mood disorders, treatment-related default mode network suppression occurred. CONCLUSIONS: Modulation of CCN and DMN activity is a putative efficacy biomarker. Methodological recommendations are to pre-declare intended analyses and use task-based fMRI, paradigms probing the CCN, longitudinal assessments, mock scanning, and out-of-scanner tests.