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Dr. Jane Walker, Department of Psychiatry, is the 2018 recipient of the Don R. Lipsitt award.
Absolute and relative risks of mental disorders in families: a Danish register-based study
Background: Relative risk estimates of familial aggregation of many types of mental disorders are available, but absolute risk estimates of familial aggregation of mental disorders remain sparse. The proportion of individuals who develop a mental disorder in the absence of the same disorder in a relative (non-familial cases) has not been examined. We aimed to create comprehensive risk estimates of the familial aggregation of mental disorders. Methods: In this prospective cohort study, we followed people of Danish origin between Jan 1, 1970, and Dec 31, 2021. We used Danish population-based registers to link individuals and their mental health across extended family pedigrees. These registers include the Danish Civil Registration System, the Danish Multi Generation Register, the Danish Psychiatric Central Research Register, and the Danish National Patient Register. Mental disorders investigated were substance use disorder, cannabis use disorder, alcohol use disorder, schizophrenia and related disorders, schizophrenia, schizoaffective disorder, mood disorders, bipolar disorder, single and recurrent depressive disorders (depression), personality disorder, borderline personality disorder, and antisocial personality disorder. We estimated lifetime risk (risk up to age 60 years), age-specific absolute risk, and relative risk for each mental disorder and type of affected relative (eg first, second, or third-degree relatives). We calculated heritability estimates and the proportion of non-familial cases. We involved people with related lived experience in the study design and implementation. Findings: A total of 3 048 583 individuals (1 486 132 [48·75%] females and 1 562 451 [51·25%] males) were followed up for 80 425 971 person-years. Individuals with a family member with a specific type of mental disorder had higher lifetime and relative risks of developing the same type of mental disorder. Both lifetime and relative risks were higher the closer the affected kinship. For example, the lifetime risk of depression was 15·48% (95% CI 15·31–15·65) in individuals with affected first-degree relatives, 13·50% (13·25–13·75) in individuals with affected second-degree relatives, 7·80% (7·76–7·84) in the general population, and 4·68% (4·65–4·71) in individuals without affected first-degree and second-degree relatives. The heritability for depression was 45·4% (95% CI 44·8–46·0) and the proportion of non-familial cases constituted 60·0% (95% CI 59·8–60·2). Interpretation: Individuals with family members with a mental disorder face increased risks of the same disorder. From a population perspective, most mental disorders occur in individuals without affected close relatives, thus highlighting the need for prevention strategies which target the entire population. Funding: Novo Nordisk Foundation. Translation: For the Danish translation of the abstract see Supplementary Materials section.
The Psychiatric Genomics Consortium: discoveries and directions.
Research by the Psychiatric Genomics Consortium (PGC) has advanced the discovery of common and rare genetic variations that contribute to the susceptibility to many psychiatric disorders and neurodevelopmental conditions. This Review reflects on major findings from the past 5 years of research by the PGC in five priority areas: discovery of common variants using genome-wide association studies; rare variation and its interplay with polygenic risk; using genetics to go beyond diagnostic boundaries; ascribing functional attributes to genomic discoveries; and developing and implementing processes for data sharing, outreach to various communities, and training. The insights gained in these domains frame the agenda for the next phase of PGC research. In addition to accelerating integrative findings of common and rare variants within, and across, multiple psychiatric disorders and neurodevelopmental conditions, the next phase will use multiple populations to elucidate genetic causes, integrate results with rapidly accumulating multimodal functional genomics data to gain mechanistic understanding, convert genetic findings to clinically actionable phenotypes, such as treatment response, and address the emerging use of polygenic scores. Together, these next steps will highlight the biological underpinnings of psychiatric disorders and neurodevelopmental conditions, which continue to contribute to global morbidity and mortality.
Using scores from the 4AT delirium detection tool as an indicator of possible dementia: a study of 75 221 older adult hospital admissions.
INTRODUCTION: Overall dementia diagnosis rates are substantially below true rates. Hospital admissions of older people involve cognitive and functional assessments relevant to dementia diagnosis. These assessments could be harnessed to contribute to identifying patients for further assessment. Yet relationships of inpatient cognitive tests with known dementia are unclear. The 4AT (www.the4AT.com) assesses for delirium (Scores 4-12) and also cognitive impairment via embedded cognitive tests (Scores 1-3). We investigated relationships between 4AT scores and clinical dementia diagnoses. METHODS: We included participants aged ≥65 years admitted as a medical emergency to three hospitals from 4 January 2016 to 4 January 2020, who had the 4AT performed on admission. Clinical dementia diagnosis was ascertained from linked primary care, hospital discharge and community prescribing data. RESULTS: Of 75 221 admissions, 62 188 (82.7%; 33 625 unique patients; mean age 80.2 years; 55.8% female) had a 4AT on admission. Of these, 9948 (16.0%) had a recorded clinical dementia diagnosis at the time of admission, with a further 1197 (1.9%) receiving a new diagnosis at discharge. Of admissions with dementia, 9669/11 145 (86.8%) had a 4AT score ≥1 on admission, compared to 14 994/51 043 (29.4%) without dementia.4AT ≥1 had a sensitivity of 0.87 (95% CI 0.86-0.87) and a specificity of 0.71 (0.70-0.71) in relation to clinical dementia diagnosis. 4AT ≥4 showed sensitivity of 0.50 (0.50-0.51) and a specificity of 0.88 (0.88-0.88). CONCLUSIONS: 4AT scores were associated with clinically diagnosed dementia. These results suggest that routinely collected 4AT scores could be leveraged in conjunction with other clinical indicators to identify patients with possible undiagnosed dementia who could undergo further inpatient diagnostic assessment and/or post-discharge specialist follow-up.
Working Memory Predicts Long-Term Recognition of Auditory Sequences: Dissociation Between Confirmed Predictions and Prediction Errors.
Memory is a crucial cognitive process involving several subsystems: sensory memory (SM), short-term memory (STM), working memory (WM), and long-term memory (LTM). While each has been extensively studied, the interaction between subsystems, particularly in relation to predicting temporal sequences, remains largely unexplored. This study investigates the association between WM and LTM, and how these relate to aging and musical training. Using three datasets with a total of 243 healthy volunteers across various age groups, we examined the impact of WM, age, and musical training on LTM recognition of novel and previously memorized musical sequences. Our results show that WM abilities are positively associated with the identification of novel sequences, but not with the recognition of memorized sequences. Additionally, musical training has a similar positive impact on the identification of novel sequences, while increasing age is associated with reduced memory performance. Different cognitive processes are involved in handling prediction errors compared to confirmatory predictions, and WM contributes to these processes differently. Future research should extend our investigation to populations with memory impairments and explore the underlying neural substrates.
Evaluating a brief imagery-based intervention for adolescent depression: study protocol for a Phase IIB randomised control trial (INDIGO) in secondary schools.
BACKGROUND: There is an urgent need for psychological interventions that can target depression in late adolescence and prevent it from having lifelong implications. Schools have been identified as a promising setting to enhance access to interventions and offer support earlier. We have co-developed a novel intervention, IMAGINE, that targets key cognitive mechanisms implicated in depression across the lifespan. Depression has been associated with distressing negative mental images, a deficit in positive future images and overgeneral autobiographical memories. Interventions targeting these factors have shown clinical promise in adults. Here, we combine techniques targeting these cognitive processes into a novel, brief psychological intervention for adolescent depression. This Phase IIb randomised controlled trial will evaluate IMAGINE compared to an active psychological intervention. METHODS/DESIGN: One hundred sixty adolescents (aged 16-18) with high levels of depressive symptoms will be recruited from schools. Participants will be randomly allocated to IMAGINE or the active psychological control intervention, non-directive support (NDS). Assessment will take place at baseline, 8-, 16- and 24-week post randomisation. The primary objective is to establish whether IMAGINE reduces symptoms of depression, relative to NDS, at 8 weeks following randomisation. Secondary objectives include whether changes in depression are maintained at 16- and 24-week follow-up, the efficacy of IMAGINE on secondary clinical outcomes and key cognitive mechanisms and, finally, to assess outcomes around acceptability, safety and adherence. DISCUSSION: If IMAGINE is shown to be safe and clinically effective, an effectiveness-implementation hybrid RCT will be indicated. If rolled out as an intervention, IMAGINE would significantly extend the range of effective therapies available for adolescent depression. TRIAL REGISTRATION: ISRCTN, ISRCTN14015295. Registered 11 September 2023, https://doi.org/10.1186/ISRCTN14015295 .
Brain network dynamics following induced acute stress: a neural marker of psychological vulnerability to real-life chronic stress.
BACKGROUND: Stress leads to neurobiological changes, and failure to regulate these can contribute to chronic psychiatric issues. Despite considerable research, the relationship between neural alterations in acute stress and coping with chronic stress is unclear. This longitudinal study examined whole-brain network dynamics following induced acute stress and their role in predicting chronic stress vulnerability. METHODS: Sixty military pre-deployment soldiers underwent a lab-induced stress task where subjective stress and resting-state functional magnetic resonance imaging were acquired repeatedly (before stress, after stress, and at recovery, 90 min later). Baseline depression and post-traumatic stress symptoms were assessed, and again a year later during military deployment. We used the Leading Eigenvector Dynamic Analysis framework to characterize changes in whole-brain dynamics over time. Time spent in each state was compared across acute stress conditions and correlated with psychological outcomes. RESULTS: Findings reveal significant changes at the network level from acute stress to recovery, where the frontoparietal and subcortical states decreased in dominance in favor of the default mode network, sensorimotor, and visual states. A significant normalization of the frontoparietal state activity was related to successful psychological recovery. Immediately after induced stress, a significant increase in the lifetimes of the frontoparietal state was associated with higher depression symptoms (r = 0.49, p
The lifetime accumulation of multimorbidity and its influence on dementia risk: a UK Biobank study.
The number of people living with dementia worldwide is projected to reach 150 million by 2050, making prevention a crucial priority for health services. The co-occurrence of two or more chronic health conditions, termed multimorbidity, occurs in up to 80% of dementia patients, making multimorbidity an important risk factor for dementia. However, we lack an understanding of the specific health conditions, and their age of onset, that drive the link between multimorbidity and dementia. Using data from 282 712 participants of the UK Biobank, we defined the sequential patterns of accumulation of 46 chronic conditions over the life course. By grouping individuals based on their life history of chronic illness, we show here that the risk of incident dementia can be stratified by both the type and timing of their accumulated chronic conditions. We identified several distinct clusters of multimorbidity throughout the lifespan (cardiometabolic, mental health, neurovascular, peripheral vascular, eye diseases and low/no multimorbidity). We observed that the odds of developing dementia varied based on when these comorbidities were diagnosed. Until midlife (age 55), the accumulation of cardiometabolic conditions, such as coronary heart disease, atrial fibrillation, and diabetes, was most strongly associated with dementia risk. However, from 55 to 70 years, the accumulation of mental health conditions, such as anxiety and depression, as well as neurovascular conditions, such as stroke and transient ischaemic attack, was associated with an over 2-fold increase in dementia risk compared with low multimorbidity. Importantly, individuals who continuously and sequentially accumulate cardiometabolic, mental health, and neurovascular conditions were at greatest risk. The age-dependent role of multimorbidity in predicting dementia risk could be used for early stratification of individuals into high- and low-risk groups and could inform targeted prevention strategies based on a person's prior history of chronic disease.
Clinical and cost-effectiveness of lithium versus quetiapine augmentation for treatment-resistant depression in adults: LQD a pragmatic randomised controlled trial.
BACKGROUND: Lithium and several atypical antipsychotics are the recommended first-line augmentation options for treatment-resistant depression; however, few studies have compared them directly, and none for longer than 8 weeks. Consequently, there is little evidence-based guidance for clinicians when choosing an augmentation option for patients with treatment-resistant depression. OBJECTIVES: This trial examined whether it is more clinically and cost-effective to prescribe lithium or quetiapine augmentation therapy for patients with treatment-resistant depression over 12 months. DESIGN: This was a parallel group, multicentre, pragmatic, open-label superiority trial comparing the clinical and cost-effectiveness of lithium versus quetiapine augmentation of antidepressant medication in treatment-resistant depression. Participants were randomised 1 : 1 at baseline to the decision to prescribe either lithium or quetiapine. SETTING: Six National Health Service trusts in England. PARTICIPANTS: Eligible participants were aged ≥ 18 years, met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for major depressive disorder, scored ≥ 14 on the 17-item Hamilton Depression Rating Scale and whose depression had had an inadequate response to at least two therapeutic antidepressant treatment trials in the current episode, with a current antidepressant treatment at or above the therapeutic dose for ≥ 6 weeks. Patients with a history of psychosis or bipolar disorder were excluded. Patients were judged suitable for either treatment. INTERVENTIONS: After randomisation, pre-prescribing safety checks were undertaken as per standard care and trial clinicians decided whether to proceed with prescribing the allocated medication. Trial clinicians received recommendations for titration and dosing in line with current clinical guidelines; however, dosing regimens could be altered according to tolerability and response. Participants were followed up using weekly self-report questionnaires and 8-, 26- and 52-week research visits. MAIN OUTCOME MEASURES: The co-primary outcome measures were depressive symptom severity over 52 weeks, measured weekly using the self-rated Quick Inventory of Depressive Symptomatology, and time to all-cause treatment discontinuation of the trial medication. Economic analyses compared costs between the two treatment arms over 52 weeks, from a National Health Service and Personal Social Services perspective, and a societal perspective. RESULTS: Two hundred and twelve participants were randomised, 107 to quetiapine and 105 to lithium. The quetiapine arm showed a significantly greater reduction in depressive symptoms than the lithium arm over 52 weeks (quetiapine vs. lithium area under the differences curve = -68.36, 95% confidence interval: -129.95 to -6.76, p = 0.0296). Median days to discontinuation did not significantly differ between the two arms (quetiapine = 365.0, interquartile range = 57.0-365.0, lithium = 212.0, interquartile range = 21.0-365.0), p = 0.1196. Quetiapine was more cost effective than lithium. Thirty-two serious adverse events were recorded, only one of which was deemed possibly related to the intervention (lithium). LIMITATIONS: The trial was unblinded, therefore expectancies regarding the trial medications may have influenced the results. Further, there was substantial missing data for some of the secondary outcome measures. CONCLUSIONS: As well as being more cost-effective, quetiapine may be a more clinically effective augmentation option for treatment-resistant depression. FUTURE WORK: Examining predictors of treatment response, including clinical, sociodemographic and biological factors, will help establish whether there are additional factors to consider when choosing an augmentation treatment for treatment-resistant depression. TRIAL REGISTRATION: This trial is registered as ISRCTN16387615. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/222/02) and is published in full in Health Technology Assessment; Vol. 29, No. 12. See the NIHR Funding and Awards website for further award information.
Incidence and Nature of Antidepressant Discontinuation Symptoms: A Systematic Review and Meta-Analysis.
IMPORTANCE: The incidence and nature of discontinuation symptoms following antidepressant cessation remain unclear. OBJECTIVE: To examine the presence of discontinuation symptoms using standardized scales (eg, Discontinuation-Emergent Signs and Symptoms [DESS]) and the incidence of individual discontinuation symptoms in individuals who stop taking antidepressants. DATA SOURCES: The databases Embase, PsycINFO, Ovid MEDLINE, and Cochrane Library were systematically searched from inception until November 7, 2023. STUDY SELECTION: Randomized clinical trials (RCTs) reporting discontinuation symptoms using a standardized scale or individual symptoms (eg, adverse events) following antidepressant cessation were included. DATA EXTRACTION AND SYNTHESIS: Data extracted were cross-checked by 2 reviewers. Additional unpublished data from 11 RCTs were included. A random-effects meta-analysis was conducted to calculate standardized mean difference between individuals who discontinued an antidepressant vs those who continued an antidepressant or discontinued placebo. A proportion and odds ratio (OR) meta-analysis was performed to assess incidence of individual discontinuation symptoms compared to placebo. Subgroup analyses were conducted to compare different antidepressants. Data analysis was conducted between September 2024 and December 2024. MAIN OUTCOMES AND MEASURES: The primary outcomes were incidence and nature of antidepressant discontinuation symptoms measured using standardized or unstandardized scales. RESULTS: A total of 50 studies were included, 49 of which were included in meta-analyses. The 50 studies included 17 828 participants in total, with 66.9% female participants and mean participant age of 44 years. Follow-up was between 1 day and 52 weeks. The DESS meta-analysis indicated increased discontinuation symptoms at 1 week in participants stopping antidepressants (standardized mean difference, 0.31; 95% CI, 0.23-0.39; number of studies [k] = 11; n = 3915 participants) compared to those taking placebo or continuing antidepressants. The effect size was equivalent to 1 more symptom on the DESS. Discontinuation of antidepressants was associated with increased odds of dizziness (OR, 5.52; 95% CI, 3.81-8.01), nausea (OR, 3.16; 95% CI, 2.01-4.96), vertigo (OR, 6.40; 95% CI, 1.20-34.19), and nervousness (OR, 3.15; 95% CI, 1.29-7.64) compared to placebo discontinuation. Dizziness was the most prevalent discontinuation symptom (risk difference, 6.24%). Discontinuation was not associated with depression symptoms, despite being measured in people with major depressive disorder (k = 5). CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis indicated that the mean number of discontinuation symptoms at week 1 after stopping antidepressants was below the threshold for clinically significant discontinuation syndrome. Mood worsening was not associated with discontinuation; therefore, later presentation of depression after discontinuation is indicative of depression relapse.
Yawning as Therapy? The Potential of the Conditioned Yawn Reflex as a Novel Treatment for Insomnia Disorder.
In 1986, Provine, the pioneer of yawning research wrote that 'Yawning may have the dubious distinction of being the least understood, common human behaviour' (p. 120); and so yawning remains some 40 years later, as something of a biological and social curiosity. However, this article examines contemporary scientific understanding of this age-old conundrum, proposing not only that yawning is a universal component of sleep's normal stimulus control paradigm, but that the conditioned yawn reflex might be harnessed to treat insomnia disorder. The core features of yawning as a ubiquitous, involuntary, periodic and conditionable behaviour; its associated actions on arousal, biofeedback and selective attention, as well as thermoregulation and airway patency; and its potential to signal and promote sleep engagement, lead to the proposition that the conditioned yawn reflex as therapy (CYRaT) is a feasible and potentially effective novel therapeutic for sleep-onset and sleep-maintenance insomnia disorder. Much research is required to test this hypothesis, but the article describes preliminary protocols for the administration and testing of CYRaT that might be utilised for this purpose.
Negative bias in encoding and recall memory in depressed patients with inadequate response to antidepressant medication.
RATIONALE: Cognitive theories propose that negative biases in emotional processing contribute to the maintenance of depressive states. Previous studies reported that acute antidepressant treatment in depressed patients reversed negative emotional biases. However, studies addressing the differences in emotional processing between healthy volunteers and clinically depressed patients with inadequate response to standard antidepressant treatments are limited. OBJECTIVES: To investigate the differences in emotional processing domains between depressed patients with inadequate response to current antidepressant treatment and healthy controls. METHODS: Fifty-four medicated patients with major depression and 45 age- and sex-equated healthy volunteers were tested using the Oxford Emotional Testing Battery. RESULTS: There was no difference between the two groups in the accuracy of recognising emotional facial expressions. However, there was a significant difference in the pattern of response times in an emotional categorisation task (F1,97 = 6.44, p = 0.013, partial η2 = 0.017) where healthy controls had faster responses towards positive than negative self-referent words (95%CI: -0.291 - -0.054, p = 0.005). In contrast, patients had no significant differences in reaction time for categorizing positive and negative self-referent descriptors. There was also a significant group interaction in an emotional memory task (F1,91 = 7.90, p = 0.006, partial η2 = 0.080) where healthy volunteers recalled significantly more positively valenced words than depressed patients (95%CI: -2.104 - -0.168, p = 0.022). CONCLUSIONS: Depressed patients with inadequate responses toward antidepressants had negative biases in emotional categorisation and emotional memory. These psychological abnormalities may represent targets for treatment in patients with difficult-to-treat depression.
Cost-effectiveness of pramipexole in addition to mood stabilisers for patients with treatment-resistant bipolar depression: Economic evaluation of the PAX-BD randomised controlled trial.
BACKGROUND: People with bipolar disorders (BD) frequently experience depressive symptoms that do not respond to available treatment options. The resulting burden for people with BD and society is substantial. This study sought to explore the cost-effectiveness of pramipexole in combination with mood stabilisers for people with treatment-resistant bipolar disorder (TRBD). METHODS: We calculated mean incremental cost ratios (ICER) of pramipexole compared to placebo over 12 and 48 weeks from health and social care (NHS + PSS) and societal perspectives for 36 participants with TRBD. Quality-adjusted life years (QALY) were captured with the EQ-5D-5L as the primary outcome measure. We used capability well-being measures (ICECAP-A, OxCAP-MH) to assess the robustness of the results and multiple imputation and bootstrapping to address missing data and small sample size. RESULTS: We found that pramipexole is more effective and cost-saving from the NHS + PSS perspective. The probability of being cost-effective at £30,000/QALY gained was 70 % (12 weeks) and 90 % (48 weeks). From the societal perspective, pramipexole was more effective but also more expensive with lower probability of cost-effectiveness (33 % at 12 weeks and 47 % at 48 weeks). Uncertainty around the mean ICERs was substantial due to the small sample size. LIMITATIONS: The PAX-BD trial was conducted during the COVID-19 pandemic and terminated early, resulting in a limited generalizability of resource use outside the pandemic context and a small sample size. CONCLUSIONS: Pramipexole is a cost-effective treatment option for TRBD from the NHS + PSS perspective, with statistically significant increases in health-related quality of life and capability well-being over extended periods.
Sleep disruption and its psychological treatment in young people at risk of psychosis: A peer methods qualitative evaluation.
OBJECTIVES: A recent randomized controlled feasibility trial showed that sleep problems in young people at risk of psychosis can be successfully treated with psychological therapy and that this may bring additional benefits such as reducing depression, anxiety and paranoia. Here we report participants' qualitative experience of sleep problems and therapy. DESIGN: A peer-methods qualitative study employing reflexive thematic analysis. METHODS: Semi-structured interviews, co-facilitated by peer researchers, were conducted with 16 young patients at risk of psychosis and having sleep problems who participated in the SleepWell Trial (ISRCTN85601537). Ten interviewees had received the 12-week sleep therapy. RESULTS: Four themes were generated: (1) the challenge to access mental health treatment ('bouncing between services'), (2) sleep problems and mental health difficulties are intertwined ('an obvious link'), (3) flexibility in therapy provision matters ('tailored to me as a person') and (4) improving sleep leads to wider benefits ('fixing the sleep helped everything else'). Participants described a frustrating journey to access mental health treatment, marked by rejection and invalidation, which resulted in hopelessness and often resignation. The interaction between sleep disruption and other mental health difficulties was seen as obvious. Treatment for sleep problems was highly valued. The clear focus, therapeutic style and flexible delivery of the treatment was seen to create patient ownership, active engagement and hope. Participants described transformative changes: better sleep, fewer voices and fears and improved mood and confidence. Improving sleep made a difference to everyday life. CONCLUSIONS: Treating sleep problems in people at risk of psychosis is highly valued and often brings rapid and widespread improvements across a range of domains.