Effect of minocycline on changes in affective behaviors, cognitive function, and inflammation in breast cancer survivors undergoing chemotherapy: a pilot randomized controlled trial.

PURPOSE: Minocycline suppresses chemotherapy-induced neuroinflammation in preclinical models, but its effects in cancer survivors are unknown. This study evaluated the longitudinal effects of minocycline on affective behaviors, cognitive functions, and inflammation in women with breast cancer (BC) undergoing chemotherapy. METHODS: This is a pilot, double-blind, randomized controlled trial of oral minocycline (100 mg BID) versus placebo for chemotherapy-induced affective disorders in women initiating chemotherapy for stage I-III BC. Participants received minocycline or placebo up to one week before chemotherapy, continuing through cycle 4 (C4). Epidemiologic Studies Depression Scale (CES-D) and State-Trait Anxiety Inventory (STAI) were assessed at baseline, each cycle of chemotherapy (C1-C4), 2-3-week post-chemotherapy (end of chemotherapy), and 6-month post-chemotherapy (6 M) as the primary outcomes. Sub-group analysis of CES-D and STAI based on the severity of symptoms was also performed. Changes in self-reported cognition and serum inflammatory markers were also evaluated. RESULTS: Fifty-seven women enrolled and 55 completed the study. Except for Interleukin-8 (p ≤ 0.03), changes in inflammatory markers, cognitive function, CES-D, and STAI were not significantly different between groups from baseline to any cycle or post-chemotherapy time point (all p > 0.05), adjusting for baseline scores. Increases in serum Interleukin-8 from baseline to C4 and 6 M were ameliorated by minocycline (p < 0.05). The sub-group symptomatic for depression (CES-D > = 16 at baseline) treated with minocycline had a greater reduction in CES-D score compared to placebo from baseline to 6 M (p = 0.01). CONCLUSION: Despite attenuation of IL-8, minocycline did not alter self-reported affective symptoms or cognition in this cohort of BC survivors undergoing chemotherapy. The effect of minocycline on BC survivors symptomatic for depression before chemotherapy warrants further investigation.

From human herpes virus-6 reactivation to autoimmune reactivity against tight junctions and neuronal antigens, to inflammation, depression, and chronic fatigue syndrome due to Long COVID.

Inflammation and autoimmune responses contribute to the pathophysiology of Long COVID, and its affective and chronic fatigue syndrome symptoms, labeled "the physio-affective phenome." To investigate whether Long COVID and its physio-affective phenome are linked to autoimmunity to the tight junction proteins, zonulin and occludin (ZOOC), and immune reactivity to lipopolysaccharides (LPS), and whether the latter are associated with signs of human herpes virus-6 (HHV-6) reactivation, autoimmunity directed against oligodendrocyte and neuronal proteins, including myelin basic protein. IgA/IgM/IgG responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), HHV-6, ZOOC, and neuronal proteins, C-reactive protein (CRP), and advanced oxidation protein products (AOPPs), were measured in 90 Long COVID patients and 90 healthy controls. The physio-affective phenome was conceptualized as a factor extracted from physical and affective symptom domains. Neural network identified IgA directed to LPS (IgA-LPS), IgG-ZOOC, IgG-LPS, and IgA-ZOOC as important variables associated with Long COVID diagnosis with an area under the ROC curve of 0.755. Partial Least Squares analysis showed that 40.9% of the variance in the physio-affective phenome was explained by CRP, IgA-myelin basic protein (MBP), and IgG-MBP. A large part of the variances in both autoimmune responses to MBP (36.3%-39.7%) was explained by autoimmunity (IgA and IgG) directed to ZOOC. The latter was strongly associated with indicants of HHV-6 reactivation, which in turn was associated with increased IgM-SARS-CoV-2. Autoimmunity against components of the tight junctions and increased bacterial translocation may be involved in the pathophysiology of Long COVID's physio-affective phenome.

Dissecting the impact of complement component 4A in bipolar disorder.

The genetic overlap between schizophrenia (SZ) and bipolar disorder (BD) is substantial. Polygenic risk scores have been shown to dissect different symptom dimensions within and across these two disorders. Here, we focused on the most strongly associated SZ risk locus located in the extended MHC region, which is largely explained by copy numbers of the gene coding for complement component 4A (C4A). First, we utilized existing brain tissue collections (N = 1,202 samples) and observed no altered C4A expression in BD samples. The generated C4A seeded co-expression networks displayed no genetic enrichment for BD. To study if genetically predicted C4A expression discriminates between subphenotypes of BD, we applied C4A expression scores to symptom dimensions in a total of 4,739 BD cases with deep phenotypic data. We identified a significant association between C4A expression and psychotic mood episodes in BD type 1 (BDI). No significant association was observed between C4A expression and the occurrence of non-affective psychotic episodes in BDI, the psychosis dimensions in the total BD sample, or any other subphenotype of BD. Overall, these results points to a distinct role of C4A in BD that is restricted to vulnerability for developing psychotic symptoms during mood episodes in BDI.

Family dysfunction, stressful life events, and mental health problems across development in the offspring of parents with an affective disorder.

BACKGROUND: Offspring of parents with affective disorders (OAD) are at risk of developing a wide range of mental disorders. Deficits in the rearing environment and high levels of stress are well-known risk factors for negative outcomes in OAD. Building on prior research, we aim to examine the longitudinal relationships between family dysfunction, stressful life events, and mental health in OAD and control offspring of parents with no affective disorder. In the present study, we hypothesized that high levels of family dysfunction would be associated with more internalizing and externalizing problems across time in OAD than in controls, and that family dysfunction would mediate the relationship between stressful life events in adolescence and poor mental health in adulthood, particularly in OAD. METHODS: As part of the TRacking Adolescents' Lives Survey (TRAILS), 2230 participants (51% female, Mage = 11.1 years, SD = 0.6, at baseline) and their parents completed measures across six time points, spanning 15 years. Mental health, family dysfunction, and stressful life events were assessed with the Youth and Adult Self-Report, Family Assessment Device, and an in-house measure, respectively. RESULTS: Multi-group structured equation modeling revealed that family dysfunction was linked to internalizing and externalizing problems in OAD, but not controls, across time. Risk status did not moderate family dysfunction's mediation of the relationship between stressful life events and negative outcomes in adulthood. CONCLUSIONS: OAD show high sensitivity to dysfunction in the rearing environment across childhood and adolescence, which supports the use of family based interventions to prevent the development of mental disorders in high-risk youth.

The development of type 2 diabetes management in people with severe mental illness in the Capital Region of Denmark from 2001 to 2015.

BACKGROUND: Type 2 diabetes (T2D) treatment has changed markedly within the last decades. We aimed to explore whether people with severe mental illness (SMI) have followed the same changes in T2D treatment as those without SMI, as multiple studies suggest that people with SMI receive suboptimal care for somatic disorders. METHODS: In this registry-based annual cohort study, we explored the T2D treatment from 2001 to 2015 provided in general practices of the Greater Copenhagen area. We stratified the T2D cohorts by their pre-existing SMI status. T2D was defined based on elevated glycated hemoglobin (≥48 mmol/mol) or glucose (≥11 mmol/L) using data from the Copenhagen Primary Care Laboratory Database. Individuals with schizophrenia spectrum disorders (ICD-10 F20-29) or affective disorders (bipolar disorder or unipolar depression, ICD-10 F30-33) were identified based on hospital-acquired diagnoses made within 5 years before January 1 each year for people with prevalent T2D or 5 years before meeting our T2D definition for incident patients. For comparison, we defined a non-SMI group, including people who did not have a hospital-acquired diagnosis of schizophrenia spectrum disorders, affective disorders, or personality disorders. For each calendar year, we assembled cohorts of people with T2D with or without SMI. We used Poisson regression to calculate the rates per 100 person-years of having at least one biochemical test (glycated hemoglobin, low-density lipoprotein cholesterol, estimated glomerular filtration rate, and urine albumin-creatinine ratio), having poor control of these biochemical results, taking glucose-lowering or cardiovascular medications, or experiencing a clinical outcome, including all-cause mortality and cardiovascular mortality. Three outcomes (cardiovascular events, cardiovascular mortality, and all-cause mortality) were additionally examined and adjusted for age and sex in a post hoc analysis. RESULTS: From 2001 to 2015, 66,914 individuals were identified as having T2D. In 2015, 1.5% of the study population had schizophrenia spectrum disorder and 1.4% had an affective disorder. The number of people who used biochemical tests or had poor biochemical risk factor control was essentially unrelated to SMI status. One exception was that fewer LDL cholesterol tests were done on people with affective disorders and schizophrenia spectrum disorders at the beginning of the study period compared to people in the non-SMI group. This difference gradually diminished and was almost nonexistent by 2011. There was also a slightly slower rise in UACR test rates in the SMI groups compared to other people with T2D during the period. Throughout the study period, all groups changed their use of medications in similar ways: more metformin, less sulfonylurea, more lipid-lowering drugs, and more ACEi/ARBs. However, people with schizophrenia disorder consistently used fewer cardiovascular medications. Cardiovascular events were more common in the affective disorder group compared to the non-SMI group from 2009 to 2015 (rate ratio 2015 : 1.36 [95% CI 1.18-1.57]). After adjustment for age and sex, all-cause mortality was significantly higher among people with a schizophrenia spectrum disorder each year from 2003 to 2015 compared to the non-SMI group (rate ratio 2015 : 1.99 [95% CI 1.26-3.12]). CONCLUSION: Persons with schizophrenia or affective disorders demonstrated the same treatment changes for T2D as those without SMI in general practice. The lower use of most types of cardiovascular medications among people with schizophrenia disorders indicates potential undertreatment of hypertension and dyslipidemia and remains throughout the study period. Cardiovascular events were most common among people with affective disorders, but this was not reflected in a higher proportion using cardiovascular preventive medications. This knowledge should be considered in the management of this vulnerable patient group.

How do we make progress in phenotyping patients with LUT such as OAB and underactive detrusor, including using urine markers and microbiome data, in order to personalize therapy? ICI-RS 2023: Part 1.

INTRODUCTION: Overactive bladder (OAB) and Underactive bladder (UAB) could be associated with metabolic syndrome, affective disorders, sex hormone deficiency, changes in urinary microbiota, functional gastrointestinal disorders, or autonomic nervous system dysfunction. OBJECTIVES: The aim of this Think Tank was to provide a guide on how to investigate OAB and/or detrusor underactivity (DU) patients to better clarify the underlying pathophysiology and possibly personalize the treatment. METHODS: A compendium of discussion based on the current evidence related to phenotyping patients with OAB or DU investigating metabolic, neurogical, psychological and gastrointestinal aspects with the aim to personalize the treatment. RESULTS AND CONCLUSIONS: The article emphasizes the critical significance of adopting a comprehensive yet tailored approach to phenotyping patients with lower urinary tract symptoms, such as OAB and UAB. The intricate interplay between the lower urinary tract and various factors, metabolic, neurological, psychological, and gastrointestinal can define unique LUT profiles, enabling personalized therapies to replace the one-size-fits-all approach.

Factors associated with low fruit and vegetable consumption among people with severe mental ill health.

Severe mental ill health (SMI) is associated with excess mortality, and poor diet is one associated modifiable risk factor. This study investigated factors associated with low consumption of fruit and vegetables among people with SMI (N = 9914). A total of 8.4% of participants ate no portions per day, while only 15% ate 5 + portions. Individuals who never consumed fruit and vegetables or ate < 5 portions per day were more likely to be male, younger than 65, unemployed, experience poorer general health, or perceive health as unimportant. Poor diet is common among people with SMI and tailored dietary improvement interventions are required.

Network analysis of neuropsychiatric, cognitive, and functional complications of stroke: implications for novel treatment targets.

AIM: Recovery from stroke is adversely affected by neuropsychiatric complications, cognitive impairment, and functional disability. Better knowledge of their mutual relationships is required to inform effective interventions. Network theory enables the conceptualization of symptoms and impairments as dynamic and mutually interacting systems. We aimed to identify interactions of poststroke complications using network analysis in diverse stroke samples. METHODS: Data from 2185 patients were sourced from member studies of STROKOG (Stroke and Cognition Consortium), an international collaboration of stroke studies. Networks were generated for each cohort, whereby nodes represented neuropsychiatric symptoms, cognitive deficits, and disabilities on activities of daily living. Edges characterized associations between them. Centrality measures were used to identify hub items. RESULTS: Across cohorts, a single network of interrelated poststroke complications emerged. Networks exhibited dissociable depression, apathy, fatigue, cognitive impairment, and functional disability modules. Worry was the most central symptom across cohorts, irrespective of the depression scale used. Items relating to activities of daily living were also highly central nodes. Follow-up analysis in two studies revealed that individuals who worried had more densely connected networks than those free of worry (CASPER [Cognition and Affect after Stroke: Prospective Evaluation of Risks] study: S = 9.72, P = 0.038; SSS [Sydney Stroke Study]: S = 13.56, P = 0.069). CONCLUSION: Neuropsychiatric symptoms are highly interconnected with cognitive deficits and functional disabilities resulting from stroke. Given their central position and high level of connectedness, worry and activities of daily living have the potential to drive multimorbidity and mutual reinforcement between domains of poststroke complications. Targeting these factors early after stroke may have benefits that extend to other complications, leading to better stroke outcomes.

Habenular volume changes after venlafaxine treatment in patients with major depression.

BACKGROUND: Habenula, a hub brain region controlling monoaminergic brain center, has been implicated in major depressive disorder (MDD) and as a possible target of antidepressant response. Nevertheless, the effect of antidepressant drug treatment on habenular volumes remains unknown. The objective of the present research was to study habenular volume change after antidepressant treatment in patients with MDD, and assess whether it is associated with clinical improvement. METHODS: Fifty patients with a current major depressive episode (MDE) in the context of MDD, and antidepressant-free for at least 1 month, were assessed for habenula volume (3T MRI with manual segmentation) before and after a 3 months sequence of venlafaxine antidepressant treatment. RESULTS: A 2.3% significant increase in total habenular volume (absolute volume: P = 0.0013; relative volume: P = 0.0055) and a 3.3% significant increase in left habenular volume (absolute volume: P = 0.00080; relative volume: P = 0.0028) were observed. A significant greater variation was observed in male patients (4.8%) compared to female patients. No association was observed between habenular volume changes and response and remission. Some habenula volume changes were associated with improvement of olfactory pleasantness. CONCLUSION: Habenular volumes increased after 3 months of venlafaxine treatment in depressed patients. Further studies should assess whether cell proliferation and density or dendritic structure variations are implied in these volume changes.

Reactivation of herpesvirus type 6 and IgA/IgM-mediated responses to activin-A underpin long COVID, including affective symptoms and chronic fatigue syndrome.

BACKGROUND: Persistent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reactivation of dormant viruses, and immune-oxidative responses are involved in long COVID. OBJECTIVES: To investigate whether long COVID and depressive, anxiety, and chronic fatigue syndrome (CFS) symptoms are associated with IgA/IgM/IgG to SARS-CoV-2, human herpesvirus type 6 (HHV-6), Epstein-Barr Virus (EBV), and immune-oxidative biomarkers. METHODS: We examined 90 long COVID patients and ninety healthy controls. We measured serum IgA/IgM/IgG against HHV-6 and EBV and their deoxyuridine 5'-triphosphate nucleotidohydrolase (duTPase), SARS-CoV-2, and activin-A, C-reactive protein (CRP), advanced oxidation protein products (AOPP), and insulin resistance (HOMA2-IR). RESULTS: Long COVID patients showed significant elevations in IgG/IgM-SARS-CoV-2, IgG/IgM-HHV-6, and HHV-6-duTPase, IgA/IgM-activin-A, CRP, AOPP, and HOMA2-IR. Neural network analysis yielded a highly significant predictive accuracy of 80.6% for the long COVID diagnosis (sensitivity: 78.9%, specificity: 81.8%, area under the ROC curve = 0.876); the topmost predictors were as follows: IGA-activin-A, IgG-HHV-6, IgM-HHV-6-duTPase, IgG-SARS-CoV-2, and IgM-HHV-6 (all positively) and a factor extracted from all IgA levels to all viral antigens (inversely). The top 5 predictors of affective symptoms due to long COVID were IgM-HHV-6-duTPase, IgG-HHV-6, CRP, education, IgA-activin-A (predictive accuracy of r = 0.636). The top 5 predictors of CFS due to long COVID were in descending order: CRP, IgG-HHV-6-duTPase, IgM-activin-A, IgM-SARS-CoV-2, and IgA-activin-A (predictive accuracy: r = 0.709). CONCLUSION: Reactivation of HHV-6, SARS-CoV-2 persistence, and autoimmune reactions to activin-A combined with activated immune-oxidative pathways play a major role in the pathophysiology of long COVID as well as the severity of its affective symptoms and CFS.

Tinnitus-on the interplay between emotion and cognition.

Subjective tinnitus (hereafter tinnitus) is often considered and studied as a perceptual phenomenon. Accordingly, various abnormalities in the area of cognitive processing have been reported in patients with tinnitus. At the same time, the disorder is characterized by considerable emotional distress, which is associated with a high comorbidity of affective disorders. Here, we aim to outline the close link between cognition and emotion, and how current research from the field of cognitive neuroscience examines the processing and acquisition of emotional stimuli. The emotional valence of stimuli can be acquired after brief exposure to learning, leading from neutral to appetitive or aversive evaluation. In contrast to neutral stimuli, emotional stimuli attract attention very early (about 100 ms) during processing, leading to deeper processing and corresponding memory effects. The involved subcortical and cortical network encompasses limbic and sensory areas. In particular, prefrontal regions are involved in the acquisition and evaluation of emotional stimuli as also shown in studies of patients with affect disorders. The interplay of cognitive and emotional processes seems to be central to the development, maintenance, and treatment of tinnitus.

Epigenetic and Coping Mechanisms of Stress in Affective Disorders: A Scoping Review.

This review aims to explore the intricate relationship among epigenetic mechanisms, stress, and affective disorders, focusing on how early life experiences and coping mechanisms contribute to susceptibility to mood disorders. Epigenetic factors play a crucial role in regulating gene expression without altering the DNA (deoxyribonucleic acid) sequence, and recent research has revealed associations between epigenetic changes and maladaptive responses to stress or psychiatric disorders. A scoping review of 33 studies employing the PRISMA-S (Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Statement) guidelines investigates the role of stress-induced epigenetic mechanisms and coping strategies in affective disorder occurrence, development, and progression. The analysis encompasses various stress factors, including childhood trauma, work-related stress, and dietary deficiencies, alongside epigenetic changes, such as DNA methylation and altered gene expression. Findings indicate that specific stress-related genes frequently exhibit epigenetic changes associated with affective disorders. Moreover, the review examines coping mechanisms in patients with bipolar disorder and major depressive disorder, revealing mixed associations between coping strategies and symptom severity. While active coping is correlated with better outcomes, emotion-focused coping may exacerbate depressive or manic episodes. Overall, this review underscores the complex interplay among genetic predisposition, environmental stressors, coping mechanisms, and affective disorders. Understanding these interactions is essential for developing targeted interventions and personalized treatment strategies for individuals with mood disorders. However, further research is needed to elucidate specific genomic loci involved in affective disorders and the clinical implications of coping strategies in therapeutic settings.

Treating neuropathic pain and comorbid affective disorders: Preclinical and clinical evidence.

INTRODUCTION: Neuropathic pain (NP) significantly impacts quality of life and often coexists with affective disorders such as anxiety and depression. Addressing both NP and its psychiatric manifestations requires a comprehensive understanding of therapeutic options. This study aimed to review the main pharmacological and non-pharmacological treatments for NP and comorbid affective disorders to describe their mechanisms of action and how they are commonly used in clinical practice. METHODS: A review was conducted across five electronic databases, focusing on pharmacological and non-pharmacological treatments for NP and its associated affective disorders. The following combination of MeSH and title/abstract keywords were used: "neuropathic pain," "affective disorders," "depression," "anxiety," "treatment," and "therapy." Both animal and human studies were included to discuss the underlying therapeutic mechanisms of these interventions. RESULTS: Pharmacological interventions, including antidepressants, anticonvulsants, and opioids, modulate neural synaptic transmission to alleviate NP. Topical agents, such as capsaicin, lidocaine patches, and botulinum toxin A, offer localized relief by desensitizing pain pathways. Some of these drugs, especially antidepressants, also treat comorbid affective disorders. Non-pharmacological techniques, including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and photobiomodulation therapy, modulate cortical activity and have shown promise for NP and mood disorders. CONCLUSIONS: The interconnection between NP and comorbid affective disorders necessitates holistic therapeutic strategies. Some pharmacological treatments can be used for both conditions, and non-pharmacological interventions have emerged as promising complementary approaches. Future research should explore novel molecular pathways to enhance treatment options for these interrelated conditions.

Engaging the AQ10 to Predict Professional Burnout or Poor Work-Related Psychological Wellbeing Among Anglican Clergy in Wales.

The ten-item Autism Spectrum Quotient (AQ10) is a self-report instrument originally designed to identify referrals for professional diagnosis for Autism Spectrum Disorders (ASD). Recent studies suggest that this instrument may also be tapping more generalised affective disorders. Working with this interpretation, this study examines the predictive power of the AQ10 to account for additional variance, after personal and personality factors have been taken into account, on the two scales of the Francis Burnout Inventory. Data provided by 220 Anglican clergy serving in Wales demonstrated that 8.6% of the participants recorded six or more red flags on the AQ10 (and so qualified for referral for specialist diagnostic assessment) and that higher scores on the AQ10 are associated with significantly lower levels of satisfaction in ministry and with significantly higher levels of emotional exhaustion in ministry. These data suggest that screening with the AQ10 may be helpful in identifying clergy vulnerable to professional burnout and to poor work-related psychological wellbeing, in addition to its primary purpose of screening for ASD.

Real-world effectiveness of pharmacological treatments for bipolar disorder: register-based national cohort study.

BACKGROUND: Pharmacological treatment patterns for bipolar disorder have changed during recent years, but for better or worse? AIMS: To investigate the comparative real-world effectiveness of antipsychotics and mood stabilisers in bipolar disorder. METHOD: Register-based cohort study including all Finnish residents aged 16-65 with a diagnosis of bipolar disorder from in-patient care, specialised out-patient care, sickness absence and disability pensions registers between 1996 and 2018, with a mean follow-up of 9.3 years (s.d. = 6.4). Antipsychotic and mood stabiliser use was modelled using the PRE2DUP method and risk for hospital admission for psychiatric and non-psychiatric reasons when using versus not using medications was estimated using within-individual Cox models. RESULTS: Among 60 045 individuals (56.4% female; mean age 41.7 years, s.d. = 15.8), the five medications associated with lowest risk of psychiatric admissions were olanzapine long-acting injection (LAI) (aHR = 0.54, 95% CI 0.37-0.80), haloperidol LAI (aHR = 0.62, 0.47-0.81), zuclopenthixol LAI (aHR = 0.66, 95% CI 0.52-0.85), lithium (aHR = 0.74, 95% CI 0.71-0.76) and clozapine (aHR = 0.75, 95% CI 0.64-0.87). Only ziprasidone (aHR = 1.26, 95% CI 1.07-1.49) was associated with a statistically higher risk. For non-psychiatric (somatic) admissions, only lithium (aHR = 0.77, 95% CI 0.74-0.81) and carbamazepine (aHR = 0.91, 95% CI 0.85-0.97) were associated with significantly reduced risk, whereas pregabalin, gabapentin and several oral antipsychotics, including quetiapine, were associated with an increased risk. Results for a subcohort of first-episode patients (26 395 individuals, 54.9% female; mean age 38.2 years, s.d. = 13.0) were in line with those of the total cohort. CONCLUSIONS: Lithium and certain LAI antipsychotics were associated with lowest risks of psychiatric admission. Lithium was the only treatment associated with decreased risk of both psychiatric and somatic admissions.

Modelling mood updating: a proof of principle study.

BACKGROUND: Recent developments in computational psychiatry have led to the hypothesis that mood represents an expectation (prior belief) on the likely interoceptive consequences of action (i.e. emotion). This stems from ideas about how the brain navigates its external world by minimising an upper bound on surprisal (free energy) of sensory information and echoes developments in other perceptual domains. AIMS: In this paper we aim to present a simple partial observable Markov decision process that models mood updating in response to stressful or non-stressful environmental fluctuations while seeking to minimise surprisal in relation to prior beliefs about the likely interoceptive signals experienced with specific actions (attenuating or amplifying stress and pleasure signals). METHOD: We examine how, by altering these prior beliefs we can model mood updating in depression, mania and anxiety. RESULTS: We discuss how these models provide a computational account of mood and its related psychopathology and relate it to previous research in reward processing. CONCLUSIONS: Models such as this can provide hypotheses for experimental work and also open up the potential modelling of predicted disease trajectories in individual patients.

The effectiveness of a primary care-based collaborative care model to improve quality of life in people with severe mental illness: PARTNERS2 cluster randomised controlled trial.

BACKGROUND: Individuals living with severe mental illness can have significant emotional, physical and social challenges. Collaborative care combines clinical and organisational components. AIMS: We tested whether a primary care-based collaborative care model (PARTNERS) would improve quality of life for people with diagnoses of schizophrenia, bipolar disorder or other psychoses, compared with usual care. METHOD: We conducted a general practice-based, cluster randomised controlled superiority trial. Practices were recruited from four English regions and allocated (1:1) to intervention or control. Individuals receiving limited input in secondary care or who were under primary care only were eligible. The 12-month PARTNERS intervention incorporated person-centred coaching support and liaison work. The primary outcome was quality of life as measured by the Manchester Short Assessment of Quality of Life (MANSA). RESULTS: We allocated 39 general practices, with 198 participants, to the PARTNERS intervention (20 practices, 116 participants) or control (19 practices, 82 participants). Primary outcome data were available for 99 (85.3%) intervention and 71 (86.6%) control participants. Mean change in overall MANSA score did not differ between the groups (intervention: 0.25, s.d. 0.73; control: 0.21, s.d. 0.86; estimated fully adjusted between-group difference 0.03, 95% CI -0.25 to 0.31; P = 0.819). Acute mental health episodes (safety outcome) included three crises in the intervention group and four in the control group. CONCLUSIONS: There was no evidence of a difference in quality of life, as measured with the MANSA, between those receiving the PARTNERS intervention and usual care. Shifting care to primary care was not associated with increased adverse outcomes.

Cost-effectiveness analysis of physical activity interventions for people with schizophrenia or bipolar disorder: systematic review.

BACKGROUND: Clinical guidelines recommend providing physical activity interventions (PAIs) to people with schizophrenia or bipolar disorder for weight management. However, the cost-effectiveness of PAIs is unknown. AIMS: To evaluate the availability and methodological quality of economic evaluations of PAIs for people with schizophrenia or bipolar disorder. METHOD: Four databases (MEDLINE, Embase, PsycInfo and Scopus) were searched on 5 July 2022. Based on the retrieved studies, forward and backward citation searches were conducted. Two reviewers independently selected studies for inclusion. Study quality was assessed using the Drummond checklist. Review results were presented using narrative synthesis. RESULTS: Fourteen articles reporting nine studies were included. All included studies assessed PAIs within a multicomponent lifestyle intervention. Mixed findings were reported on the cost-effectiveness of multicomponent lifestyle intervention: three studies reported it as cost-effective; four studies reported it as not cost-effective; and two studies did not conclude whether it was cost-effective or not. Very limited evidence suggests that certain patient subgroups might be more likely to benefit from multicomponent lifestyle interventions with a PAI component: men; individuals with comorbid type 2 diabetes; and individuals who have been psychiatric hospital in-patients for ≥1 year. The quality of included studies ranged from moderate to high. CONCLUSIONS: The current economic evidence suggests that not all modalities of multicomponent lifestyle intervention including a PAI component are cost-effective for people with schizophrenia or bipolar disorder; and not all people with schizophrenia or bipolar disorder would benefit equally from the intervention. Future research is urgently needed to identify the cost-effective modality of PAI for different patient subgroups.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

Reverse cholesterol transport and lipid peroxidation biomarkers in major depression and bipolar disorder: A systematic review and meta-analysis.

BACKGROUND: Major depression (MDD) and bipolar disorder (BD) are linked to immune activation, increased oxidative stress, and lower antioxidant defenses. OBJECTIVES: To systematically review and meta-analyze all data concerning biomarkers of reverse cholesterol transport (RCT), lipid-associated antioxidants, lipid peroxidation products, and autoimmune responses to oxidatively modified lipid epitopes in MDD and BD. METHODS: Databases including PubMed, Google scholar and SciFinder were searched to identify eligible studies from inception to January 10th, 2023. Guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS: The current meta-analysis included 176 studies (60 BD and 116 MDD) and examined 34,051 participants, namely 17,094 with affective disorders and 16,957 healthy controls. Patients with MDD and BD showed a) significantly decreased RCT (mainly lowered high-density lipoprotein cholesterol and paraoxonase 1); b) lowered lipid soluble vitamins (including vitamin A, D, and coenzyme Q10); c) increased lipid peroxidation and aldehyde formation, mainly increased malondialdehyde (MDA), 4-hydroxynonenal, peroxides, and 8-isoprostanes; and d) Immunoglobulin (Ig)G responses to oxidized low-density lipoprotein and IgM responses to MDA. The ratio of all lipid peroxidation biomarkers/all lipid-associated antioxidant defenses was significantly increased in MDD (standardized mean difference or SMD = 0.433; 95% confidence intervals (CI): 0.312; 0.554) and BD (SMD = 0.653; CI: 0.501-0.806). This ratio was significantly greater in BD than MDD (p = 0.027). CONCLUSION: In MDD/BD, lowered RCT, a key antioxidant and anti-inflammatory pathway, may drive increased lipid peroxidation, aldehyde formation, and autoimmune responses to oxidative specific epitopes, which all together cause increased immune-inflammatory responses and neuro-affective toxicity.