Patient fibroblast circadian rhythms predict lithium sensitivity in bipolar disorder.

Bipolar disorder is a chronic neuropsychiatric condition associated with mood instability, where patients present significant sleep and circadian rhythm abnormalities. Currently, the pathophysiology of bipolar disorder remains elusive, but treatment with lithium continues as the benchmark pharmacotherapy, functioning as a potent mood stabilizer in most, but not all patients. Lithium is well documented to induce period lengthening and amplitude enhancement of the circadian clock. Based on this, we sought to investigate whether lithium differentially impacts circadian rhythms in bipolar patient cell lines and crucially if lithium's effect on the clock is fundamental to its mood-stabilizing effects. We analyzed the circadian rhythms of bipolar patient-derived fibroblasts (n = 39) and their responses to lithium and three further chronomodulators. Here we show, relative to controls (n = 23), patients exhibited a wider distribution of circadian period (p < 0.05), and that patients with longer periods were medicated with a wider range of drugs, suggesting lower effectiveness of lithium. In agreement, patient fibroblasts with longer periods displayed muted circadian responses to lithium as well as to other chronomodulators that phenocopy lithium. These results show that lithium differentially impacts the circadian system in a patient-specific manner and its effect is dependent on the patient's circadian phenotype. We also found that lithium-induced behavioral changes in mice were phenocopied by modulation of the circadian system with drugs that target the clock, and that a dysfunctional clock ablates this response. Thus, chronomodulatory compounds offer a promising route to a novel treatment paradigm. These findings, upon larger-scale validation, could facilitate the implementation of a personalized approach for mood stabilization.

The True Colours Remote Symptom Monitoring System: A Decade of Evolution.

The True Colours remote mood monitoring system was developed over a decade ago by researchers, psychiatrists, and software engineers at the University of Oxford to allow patients to report on a range of symptoms via text messages, Web interfaces, or mobile phone apps. The system has evolved to encompass a wide range of measures, including psychiatric symptoms, quality of life, and medication. Patients are prompted to provide data according to an agreed personal schedule: weekly, daily, or at specific times during the day. The system has been applied across a number of different populations, for the reporting of mood, anxiety, substance use, eating and personality disorders, psychosis, self-harm, and inflammatory bowel disease, and it has shown good compliance. Over the past decade, there have been over 36,000 registered True Colours patients and participants in the United Kingdom, with more than 20 deployments of the system supporting clinical service and research delivery. The system has been adopted for routine clinical care in mental health services, supporting more than 3000 adult patients in secondary care, and 27,263 adolescent patients are currently registered within Oxfordshire and Buckinghamshire. The system has also proven to be an invaluable scientific resource as a platform for research into mood instability and as an electronic outcome measure in randomized controlled trials. This paper aimed to report on the existing applications of the system, setting out lessons learned, and to discuss the implications for tailored symptom monitoring, as well as the barriers to implementation at a larger scale.

A web-based clinical decision tool to support treatment decision-making in psychiatry: a pilot focus group study with clinicians, patients and carers.

BACKGROUND: Treatment decision tools have been developed in many fields of medicine, including psychiatry, however benefits for patients have not been sustained once the support is withdrawn. We have developed a web-based computerised clinical decision support tool (CDST), which can provide patients and clinicians with continuous, up-to-date, personalised information about the efficacy and tolerability of competing interventions. To test the feasibility and acceptability of the CDST we conducted a focus group study, aimed to explore the views of clinicians, patients and carers. METHODS: The CDST was developed in Oxford. To tailor treatments at an individual level, the CDST combines the best available evidence from the scientific literature with patient preferences and values, and with patient medical profile to generate personalised clinical recommendations. We conducted three focus groups comprising of three different participant types: consultant psychiatrists, participants with a mental health diagnosis and/or experience of caring for someone with a mental health diagnosis, and primary care practitioners and nurses. Each 1-h focus group started with a short visual demonstration of the CDST. To standardise the discussion during the focus groups, we used the same topic guide that covered themes relating to the acceptability and usability of the CDST. Focus groups were recorded and any identifying participant details were anonymised. Data were analysed thematically and managed using the Framework method and the constant comparative method. RESULTS: The focus groups took place in Oxford between October 2016 and January 2017. Overall 31 participants attended (12 consultants, 11 primary care practitioners and 8 patients or carers). The main themes that emerged related to CDST applications in clinical practice, communication, conflicting priorities, record keeping and data management. CDST was considered a useful clinical decision support, with recognised value in promoting clinician-patient collaboration and contributing to the development of personalised medicine. One major benefit of the CDST was perceived to be the open discussion about the possible side-effects of medications. Participants from all the three groups, however, universally commented that the terminology and language presented on the CDST were too medicalised, potentially leading to ethical issues around consent to treatment. CONCLUSIONS: The CDST can improve communication pathways between patients, carers and clinicians, identifying care priorities and providing an up-to-date platform for implementing evidence-based practice, with regard to prescribing practices.

Examining the Effectiveness of Web-Based Interventions to Enhance Resilience in Health Care Professionals: Systematic Review.

BACKGROUND: Internationally, the impact of continued exposure to workplace environmental and psychological stressors on health care professionals' mental health is associated with increased depression, substance misuse, sleep disorders, and posttraumatic stress. This can lead to staff burnout, poor quality health care, and reduced patient safety outcomes. Strategies to improve the psychological health and well-being of health care staff have been highlighted as a critical priority worldwide. The concept of resilience for health care professionals as a tool for negotiating workplace adversity has gained increasing prominence. OBJECTIVE: This systematic review aims to examine the effectiveness of web-based interventions to enhance resilience in health care professionals. METHODS: We searched the PubMed, CINAHL, PsycINFO, and Ovid SP databases for relevant records published after 1990 until July 2021. We included studies that focused on internet-delivered interventions aiming at enhancing resilience. Study quality was assessed with the Risk of Bias 2 tool for randomized controlled trial designs and Joanna Briggs Institute critical appraisal tool for other study designs. The protocol was registered on PROSPERO (International Prospective Register of Systematic Reviews; CRD42021253190). PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. RESULTS: A total of 8 studies, conducted between 2014 and 2020 and involving 1573 health care workers, were included in the review. In total, 4 randomized controlled trial designs and 4 pre- and postdesign studies were conducted across a range of international settings and health care disciplines. All of these studies aimed to evaluate the impact of web-based interventions on resilience or related symptoms in health care professionals involved in patient-facing care. Interventions included various web-based formats and therapeutic approaches over variable time frames. One randomized controlled trial directly measured resilience, whereas the remaining 3 used proxy measures to measure psychological concepts linked to resilience. Three pretest and posttest studies directly measured resilience, whereas the fourth study used a proxy resilience measure. Owing to the heterogeneity of outcome measures and intervention designs, meta-analysis was not possible, and qualitative data synthesis was undertaken. All studies found that resilience or proxy resilience levels were enhanced in health care workers following the implementation of web-based interventions. The overall risk of bias of all 8 studies was low. CONCLUSIONS: The findings indicate that web-based interventions designed to enhance resilience may be effective in clinical practice settings and have the potential to provide support to frontline staff experiencing prolonged workplace stress across a range of health care professional groups. However, the heterogeneity of included studies means that findings should be interpreted with caution; more web-based interventions need rigorous testing to further develop the evidence base. TRIAL REGISTRATION: PROSPERO CRD42021253190; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=253190.

PAX-D: study protocol for a randomised placebo-controlled trial evaluating the efficacy and mechanism of pramipexole as add-on treatment for people with treatment resistant depression.

INTRODUCTION: Clinical depression is usually treated in primary care with psychological therapies and antidepressant medication. However, when patients do not respond to at least two or more antidepressants within a depressive episode, they are considered to have treatment resistant depression (TRD). Previous small randomised controlled trials suggested that pramipexole, a dopamine D2/3 receptor agonist, may be effective for treating patients with unipolar and bipolar depression as it is known to influence motivational drive and reward processing. PAX-D will compare the effects of pramipexole vs placebo when added to current antidepressant medication for people with TRD. Additionally, PAX-D will investigate the mechanistic effect of pramipexole on reward sensitivity using a probabilistic decision-making task. METHODS AND ANALYSIS: PAX-D will assess effectiveness in the short- term (during the first 12 weeks) and in the longer-term (48 weeks) in patients with TRD from the UK. The primary outcome will be change in self-reported depressive symptoms from baseline to week 12 post-randomisation measured using the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). Performance on the decision-making task will be measured at week 0, week 2 and week 12. Secondary outcomes include anhedonia, anxiety and health economic measures including quality of life, capability, well-being and costs. PAX-D will also assess the adverse effects of pramipexole including impulse control difficulties. DISCUSSION: Pramipexole is a promising augmentation agent for TRD and may be a useful addition to existing treatment regimes. PAX-D will assess its effectiveness and test for a potential mechanism of action in patients with TRD. TRIAL REGISTRATION NUMBER: ISRCTN84666271.

Oxford Lithium Trial (OxLith) of the early affective, cognitive, neural and biochemical effects of lithium carbonate in bipolar disorder: study protocol for a randomised controlled trial.

BACKGROUND: Despite lithium's being the most effective drug for bipolar disorder and in clinical use for decades, we still know very little about its early effects relevant to its mode of action. METHODS/DESIGN: The Oxford Lithium Trial is a double-blind, randomised, placebo-controlled study of 6-week lithium treatment in participants with bipolar disorder and mood instability. Its aim is to identify early clinical, neurocognitive and biological effects. Participants (n = 40) will undergo an intensive battery of multi-modal investigations, including remote monitoring of mood, activity and physiology, as well as cognitive testing, fMRI and magnetoencephalography, together with biochemical and gene expression measurements to assess renal, inflammatory and circadian effects. DISCUSSION: The findings derived from this trial may be of value in predicting subsequent therapeutic response or side effects, not only relevant to the use of lithium but also providing a potential signature to help in more rapid evaluation of novel mood stabilisers. In this respect, OxLith is a step towards the development of a valid experimental medicine model for bipolar disorder. TRIAL REGISTRATION: ISRCTN91624955 . Registered on 22 January 2015.

Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial.

BACKGROUND: Depressive symptoms are a major cause of disability in bipolar disorder and there are few safe and effective treatments. The combination of lamotrigine plus quetiapine potentially offers improved outcomes for people with bipolar depression. We aimed to determine if combination therapy with quetiapine plus lamotrigine leads to greater improvement in depressive symptoms over 12 weeks than quetiapine monotherapy plus lamotrigine placebo. METHODS: In this double-blind, randomised, placebo-controlled, parallel group, 2 × 2 factorial trial (CEQUEL), patients with DSM-IV bipolar disorder I or II, who were aged 16 years or older, and required new treatment for a depressive episode, were enrolled from 27 sites in the UK. Patients were randomly assigned (1:1) by an adaptive minimisation algorithm to lamotrigine or placebo and to folic acid or placebo. Participants and investigators were masked to the treatment groups. The primary outcome was improvement in depressive symptoms at 12 weeks with the Quick Inventory of Depressive Symptomatology-self report version 16 (QIDS-SR16). Analysis was by modified intention-to-treat. This trial is registered with EUdraCT, number 2007-004513-33. FINDINGS: Between Oct 21, 2008, and April 27, 2012, 202 participants were randomly assigned; 101 to lamotrigine and 101 to placebo. The mean difference in QIDS-SR16 total score between the group receiving lamotrigine versus the placebo group at 12 weeks was -1·73 ([95% CI -3·57 to 0·11]; p=0·066) and at 52 weeks was -2·69 ([-4·89 to -0·49]; p=0·017). Folic acid was not superior to placebo. There was a significant interaction (p=0·028), with folic acid reducing the effectiveness of lamotrigine at 12 weeks. The mean difference on QIDS-SR16 was -4·14 ([95% CI -6·90 to -1·37]; p=0·004) for patients receiving lamotrigine without folic acid compared with 0·12 ([-2·58 to 2·82]; p=0·931) for those receiving lamotrigine and folic acid. INTERPRETATION: Addition of lamotrigine to quetiapine treatment improved outcomes. Folic acid seems to nullify the effect of lamotrigine. CEQUEL should encourage clinicians and patients to consider lamotrigine for bipolar depression, but also to be aware that concurrent folic acid might reduce its effectiveness. FUNDING: Medical Research Council.

Comparison of the effects of citalopram and escitalopram on 5-Ht-mediated neuroendocrine responses.

Acute oral administration of selective serotonin re-uptake inhibitors (SSRIs) increases plasma cortisol by facilitating brain serotonin activity. Recently, salivary cortisol sampling has grown in popularity as a noninvasive means of assessing HPA axis activity. The aim of the present study was to find out whether acute oral administration of the SSRI, citalopram, increases salivary cortisol in healthy volunteers and whether the increase produced by an equivalent dose of its active isomer, escitalopram, is greater. A total of 15 healthy subjects were tested on three occasions receiving either oral citalopram (20 mg), escitalopram (10 mg), or placebo in a double-blind, randomized, crossover design. Salivary cortisol and plasma cortisol and prolactin were measured for 240 min after each treatment. Relative to placebo, both citalopram and escitalopram increased salivary and plasma cortisol levels with no evidence of consistent differences between them. Plasma prolactin concentration was not altered by either active treatment. Plasma and salivary cortisol responses after citalopram but not escitalopram correlated significantly. The present study does not support an enhanced effect of escitalopram on 5-HT-mediated neuroendocrine responses.

Wake-up call for British psychiatry.

The recent drive within the UK National Health Service to improve psychosocial care for people with mental illness is both understandable and welcome: evidence-based psychological and social interventions are extremely important in managing psychiatric illness. Nevertheless, the accompanying downgrading of medical aspects of care has resulted in services that often are better suited to offering non-specific psychosocial support, rather than thorough, broad-based diagnostic assessment leading to specific treatments to optimise well-being and functioning. In part, these changes have been politically driven, but they could not have occurred without the collusion, or at least the acquiescence, of psychiatrists. This creeping devaluation of medicine disadvantages patients and is very damaging to both the standing and the understanding of psychiatry in the minds of the public, fellow professionals and the medical students who will be responsible for the specialty's future. On the 200th birthday of psychiatry, it is fitting to reconsider the specialty's core values and renew efforts to use psychiatric skills for the maximum benefit of patients.