Trace amine-associated receptor 1 (TAAR1) agonism for psychosis: a living systematic review and meta-analysis of human and non-human data.

Background: Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies. Methods: We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.11.2023), extracted data, and assessed risk of bias. Primary outcomes were standardised mean differences (SMD) for overall symptoms in human studies and hyperlocomotion in animal models. We also examined adverse events and neurotransmitter signalling. We synthesised data with random-effects meta-analyses. Results: Nine randomised trials provided data for two TAAR1 agonists (ulotaront and ralmitaront), and 15 animal studies for 10 TAAR1 agonists. Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Large placebo response was observed in ulotaront phase-III trials. Limited evidence suggested a relatively benign side-effect profile for TAAR1 agonists, although nausea and sedation were common after a single dose of ulotaront. In animal studies, TAAR1 agonists improved hyperlocomotion compared to control (N=13 studies, k=41 experiments, SMD=1.01, 95%CI: 0.74, 1.27), but seemed less efficacious compared to dopamine D 2 receptor antagonists (N=4, k=7, SMD=-0.62, 95%CI: -1.32, 0.08). Limited human and animal data indicated that TAAR1 agonists may regulate presynaptic dopaminergic signalling. Conclusions: TAAR1 agonists may be less efficacious than dopamine D 2 receptor antagonists already licensed for schizophrenia. The results are preliminary due to the limited number of drugs examined, lack of longer-term data, publication bias, and assay sensitivity concerns in trials associated with large placebo response. Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted. Registration: PROSPERO-ID: CRD42023451628.

There is a need for more effective treatments for psychosis, including schizophrenia. Psychosis is a collection of mental health symptoms, such as hearing voices, that can cause distress and impair functioning. These symptoms are thought to be caused by changes in a chemical messenger system in the brain called dopamine. Currently used antipsychotic medications target brain receptors that respond to dopamine. They are not effective in some people and can cause uncomfortable adverse events, such as weight gain and movement disorders, especially with long-term use. A new type of drug is the trace amine-associated receptor 1 (TAAR1) agonists. These drugs act on different brain receptors that can affect the activity of the dopamine system, but do not directly bind to dopamine receptors. We aimed to understand if TAAR1 agonists can reduce symptoms of psychosis, what adverse events they might have, and how they work. We did this by reviewing and collating all available evidence until November 2023. This is a "living" systematic review, so it will be regularly updated in the future. We looked at both human and animal studies investigating TAAR1 agonists. Human studies suggested that two TAAR1 agonists (namely, ulotaront or ralmitaront) might have little to no effect on reducing symptoms of psychosis compared to placebo in people with schizophrenia. They seemed to cause fewer adverse events than current antipsychotics. Data from animal studies suggested that TAAR1 agonists had some positive effects but potentially smaller than other antipsychotics. There were little to no data from both human and animal studies about how TAAR1 agonists actually work. From the current evidence we are uncertain about these results. With the ongoing development of new TAAR1 agonists, more evidence is needed to understand their potential role in the treatment of psychosis.

Resilience in the first year of surviving a stroke in Nigeria.

OBJECTIVES: There is a knowledge gap on resilience and its impact on mental health of Africans who survive a stroke. We describe the trajectory of psychological resilience and its association with depression and quality of life (QoL) across the first poststroke year in Nigeria. METHOD: Prospective observational study of 150 survivors of a first ever stroke. Resilience was ascertained at 3 time-points prospectively over 12 months using the 25-items Resilience Scale (RS). Depression and QoL were also assessed at baseline and follow-up, respectively using the centre for epidemiologic studies depression scale (CES-D 10) and health related quality of life in stroke patients (HRQOLISP-26). Associations were investigated using regression models and presented as adjusted odds ratios (OR) and Wald test coefficients within 95% confidence intervals (CI). RESULTS: Resilience improved across time points of measurement (p < 0.001). In multivariate logistic regression analyses adjusted for the effect of age, education, alcohol use, and hypertension, higher resilience was associated with male sex (OR = 5.3, 95% CI= 1.7, 17.2), younger age (OR = 4.8, 95% CI = 1.5,15.7), and baseline hypertension (OR= 0.2, 95% CI ≤ 0.1,0.8). In similarly adjusted mixed effect linear regression analyses, higher resilience was associated with improvement in depression (months 12= -4.2, 95% CI= -5.6, -2.8) and quality of life (months twelve = 5.2, 95% CI = 2.2, 8.2) overtime. CONCLUSION: Resilience, which was associated with better mental health and wellbeing of stroke survivors, was less likely with hypertension. Results suggest an important role for control of vascular risk factors as part of resilience interventions to promote poststroke recovery.

Participatory development of a home-based depression care model with lived experience older Nigerians and their caregivers: A theory of change.

OBJECTIVES: There is a huge treatment gap for late-life depression in sub-Saharan Africa. Building on prior work to scale-up mental healthcare with the aid of the WHO Mental Health Gap Action Programme Intervention Guide electronic version (emhGAP-IG), this study aims to involve older people in the iterative development of innovations to overcome challenges in the detection and clinical management of late-life depression by frontline non-specialist primary healthcare workers (PHCW) in Nigeria. METHODS: There were 43 participants in the study. We conducted formative qualitative research using 15 in-depth key informant interviews with persons who were 60 years or older and had a recent experience of depression. We also conducted two focus group discussions comprising 13 of their caregivers. Through a full day stakeholders workshop comprising 15 participants, we drew on the results of our qualitative explorations to identify the pathway to impact of an intervention package (emhGAP-Age) appropriate for the specific needs of persons with late-life depression in Nigeria. RESULTS: A Theory of Change (ToC) map was produced. It highlights the expected long-term outcomes of emhGAP-Age to include the potential for improvement of the mental health and wellbeing of older people living in Nigeria and the generation of interest among governmental agencies concerned with policy and planning for mental healthcare. Key resources that serve as preconditions were identified to consist of the availability of PHCW who are skilled in the identification and treatment of depression and have interest in and commitment to providing care to older people. Required community resources include support from immediate family, neighbours, and informal groups. Interventions that are appropriate for depression in old age need to incorporate these community resources and address not only the symptoms of the condition but also comorbid physical health problems. CONCLUSIONS: A participatory ToC process led to the identification of the key components of an age-appropriate version of the emhGAP-IG for delivering care to older persons with depression by PHCW in Nigeria.

Physical restraint in older people: a statement from the Early Career Network of the International Psychogeriatric Association.

The International Psychogeriatric Association (IPA) has expressed significant concerns over the use of physical restraints in older people across diverse aged care settings. Following an extensive analysis of the available literature, the IPA's Early Career Network (ECN) has formulated a collection of evidence-based recommendations aimed at guiding the use of physical restraints within various care contexts and demographic groups. Physical restraints not only infringe upon human rights but also raise significant safety concerns that adversely impact the physical, psychological, social, and functional well-being of older adults. Furthermore, their effectiveness in geriatric settings remains inadequate. Given these considerations, the IPA and its ECN firmly assert that the use of physical restraints should only be considered as a final recourse in the care of older people.

New living evidence resource of human and non-human studies for early intervention and research prioritisation in anxiety, depression and psychosis.

In anxiety, depression and psychosis, there has been frustratingly slow progress in developing novel therapies that make a substantial difference in practice, as well as in predicting which treatments will work for whom and in what contexts. To intervene early in the process and deliver optimal care to patients, we need to understand the underlying mechanisms of mental health conditions, develop safe and effective interventions that target these mechanisms, and improve our capabilities in timely diagnosis and reliable prediction of symptom trajectories. Better synthesis of existing evidence is one way to reduce waste and improve efficiency in research towards these ends. Living systematic reviews produce rigorous, up-to-date and informative evidence summaries that are particularly important where research is emerging rapidly, current evidence is uncertain and new findings might change policy or practice. Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis (GALENOS) aims to tackle the challenges of mental health science research by cataloguing and evaluating the full spectrum of relevant scientific research including both human and preclinical studies. GALENOS will also allow the mental health community-including patients, carers, clinicians, researchers and funders-to better identify the research questions that most urgently need to be answered. By creating open-access datasets and outputs in a state-of-the-art online resource, GALENOS will help identify promising signals early in the research process. This will accelerate translation from discovery science into effective new interventions for anxiety, depression and psychosis, ready to be translated in clinical practice across the world.

Mobile phone intervention to reduce dropout from treatment at an outpatient mental health service for older people in Nigeria.

Background: Half of older Africans drop out of treatment after a single contact with biomedical mental health services. Objective: This study examined the effect of introducing a mobile phone reminder intervention delivered by volunteering health staff to reduce dropout from an outpatient mental health service for older people in Nigeria. Methods: 405 patients were studied using a quasi-experimental design: 169 who attended clinic pre-intervention (2016-2017) and 236 who attended during intervention (2018-2019). We estimated annual dropout rates, reasons for dropout and predictors of drop-out. Results: We found a trend for decreasing dropout rates during intervention (p<0.001). The most common reasons for dropout were distance to the clinic (19.5%) and unavailability of a caregiver (47.6%). Current single status (O.R =2.02, 95% C. I=1.02-3.99) and treatment without adjunctive pharmacotherapy (O. R=2.14, 95% CI; 1.07-4.26) predicted dropout. Conclusion: Mobile phone call reminders improved treatment engagement in this population. Findings are important for policy to improve access to mental healthcare in Africa.

Cross-national harmonization of cognitive measures across HRS HCAP (USA) and LASI-DAD (India).

BACKGROUND: As global populations age, cross-national comparisons of cognitive health and dementia risk are increasingly valuable. It remains unclear, however, whether country-level differences in cognitive function are attributable to population differences or bias due to incommensurate measurement. To demonstrate an effective method for cross-national comparison studies, we aimed to statistically harmonize measures of episodic memory and language function across two population-based cohorts of older adults in the United States (HRS HCAP) and India (LASI-DAD). METHODS: Data for 3,496 HRS HCAP (≥65 years) and 3,152 LASI-DAD (≥60 years) participants were statistically harmonized for episodic memory and language performance using confirmatory factor analysis (CFA) methods. Episodic memory and language factor variables were investigated for differential item functioning (DIF) and precision. RESULTS: CFA models estimating episodic memory and language domains based on a priori adjudication of comparable items fit the data well. DIF analyses revealed that four out of ten episodic memory items and five out of twelve language items measured the underlying construct comparably across samples. DIF-modified episodic memory and language factor scores showed comparable patterns of precision across the range of the latent trait for each sample. CONCLUSIONS: Harmonization of cognitive measures will facilitate future investigation of cross-national differences in cognitive performance and differential effects of risk factors, policies, and treatments, reducing study-level measurement and administrative influences. As international aging studies become more widely available, advanced statistical methods such as those described in this study will become increasingly central to making universal generalizations and drawing valid conclusions about cognitive aging of the global population.

Mild anxiety and depression disorders: Unusual reactions to COVID-19 lockdown in caregivers of older adults attending a psychogeriatric clinic in Southwest Nigeria.

BACKGROUND: Many sub-Saharan African countries have fragile healthcare systems and the mental health care of older adults is in a precarious state. The lockdown that accompanied COVID-19 infection was another monumental event. OBJECTIVE: This study examined the effect of the restriction and lockdown on the mental health of the caregivers of older patients attending a psychogeriatric clinic in Ibadan, Nigeria. MATERIALS AND METHODS: We selected 178 dyads of patients and their caregivers. These caregivers were administered a semi-structured questionnaire that collected demographic information and asked questions on effect of COVID-19 on caregiving. In addition, Patient Health Questionnaire-9 and generalised anxiety disorder-7 item scale were administered. Participants were interviewed through telephone. RESULTS: One hundred and seventy-eight patients' caregivers' dyads were interviewed. About 62.4% of the caregivers were children of the patients. More importantly, 97.2% and 93.8% had neither depressive nor anxiety symptoms and the caregivers expressed little worry about COVID-19. There was no significant difference in the mean depressive and anxiety scores in caregivers of patients with and without dementia (F = 0.28, P = 0.60). Caregivers who were lesser than 50 years in age had significantly higher mean score compared with those who were 50 years and above (F = 5.54, P = 0.03). CONCLUSION: The rate of anxiety and depressive symptoms was very low in this cohort as the lockdown during the pandemic produced little distress to caregivers including those caring for patients with dementia and cognitive impairment. This is a deviation from reports of some other countries and cultures which described psychological implications of COVID-19 on caregivers as severe.

Different Cognitive and Functional Outcomes in Attenuated and Full Delirium Syndromes Among Recent Stroke Survivors.

BACKGROUND: Very little is known about the outcomes of poststroke delirium in relation to its symptom spectrum. We investigated the 3-months cognitive and functional outcomes of attenuated (ADS) and full delirium syndromes in Nigerian survivors of first ever stroke. METHODS: A prospective observational study with repeated assessments conducted in the first week of stroke using the confusion assessment method. Full delirium was diagnosed according to criteria in the fifth edition of the diagnostic and statistical manual of mental disorders (DSM-V). ADS was characterised in survivors who were free of full, but had ≥two core features of, delirium. Baseline and follow-up assessments were conducted using the Mini-Mental state examination (MMSE), 10-words list learning and delayed recall test, Animal naming test and Barthel index. RESULTS: Among 150 participants, ADS was present in 32 (21.3%), full delirium in 29 (19.3%). In linear regression analyses adjusting for age, economic status and systemic hypertension, ADS [(Mean difference (MD) = -3.8, 95% C.I = -7.0, -0.7)] and full delirium (MD = -5.6, 95% C.I = -9.0, -2.1) independently predicted poorer global cognitive functioning at follow-up. Significant declines in memory (MD = -1.9, 95% C.I = -2.8, 0.9), executive (MD = -2.2, 95% C.I = -4.1, -0.3) and physical functioning (MD = -2.8, 95% C.I = -5.5, -0.2), as well as a 4-fold increase in the independent odds (O.R) for dementia (O.R = 4.1, 95% C.I = 1.0,16.1) were also recorded in full, but not attenuated, delirium. CONCLUSION: Attenuated and full delirium are associated with graded risk of poststroke cognitive decline. Reconsideration of poststroke delirium as a spectrum, rather than threshold-based categorical diagnosis will improve detection and prioritization of stroke survivors at increased risk of cognitive decline.