Effects of PDE-3 inhibition in persistent post-traumatic headache: evidence of cAMP-dependent signaling.

BACKGROUND: Phosphodiesterase 3 (PDE-3) inhibition have been implicated in the neurobiologic underpinnings of migraine. Considering the clinical similarities between migraine and persistent post-traumatic headache (PPTH), we aimed to ascertain whether PDE-3 inhibition can elicit migraine-like headache in persons with PPTH. METHODS: We tested cilostazol, which inhibits PDE-3, in a randomized, double-blind, placebo-controlled, two-way crossover study involving persons with PPTH attributed to mild traumatic brain injury. The randomized participants were allocated to receive oral administration of either 200-mg cilostazol or placebo (calcium tablet) on two separate experiment days. The primary end point was the incidence of migraine-like headache during a 12-hour observation window post-ingestion. The secondary endpoint was the area under the curve (AUC) for reported headache intensity scores during the same observation window. RESULTS: Twenty-one persons underwent randomization and completed both experiment days. The mean participants' age was 41.4 years, and most (n = 17) were females. During the 12-hour observation window, 14 (67%) of 21 participants developed migraine-like headache post-cilostazol, in contrast to three (14%) participants after placebo (P =.003). The headache intensity scores were higher post-cilostazol than after placebo (P <.001). CONCLUSIONS: Our results provide novel evidence showing that PDE-3 inhibition can elicit migraine-like headache in persons with PPTH. Given that PDE-3 inhibition increases intracellular cAMP levels, our findings allude to the potential therapeutic value of targeting cAMP-dependent signaling pathways in the management of PPTH. Further investigations are imperative to substantiate these insights and delineate the importance of cAMP-dependent signaling pathways in the neurobiologic mechanisms underlying PPTH. GOV IDENTIFIER: NCT05595993.

Differences in Cortical Morphology in People With and Without Migraine: A Registry for Migraine (REFORM) MRI Study.

BACKGROUND AND OBJECTIVES: Structural imaging can offer insights into the cortical morphometry of migraine, which might reflect adaptations to recurring nociceptive messaging. This study compares cortical morphometry between a large sample of people with migraine and healthy controls, as well as across migraine subtypes. METHODS: Adult participants with migraine and age-matched and sex-matched healthy controls attended a single MRI session with magnetization-prepared rapid acquisition gradient echo and fluid-attenuated inversion recovery sequences at 3T. Cortical surface area, thickness, and volume were compared between participants with migraine (including subgroups) and healthy controls across the whole cortex within FreeSurfer and reported according to the Desikan-Killiany atlas. The analysis used cluster-determining thresholds of p < 0.0001 and cluster-wise thresholds of p < 0.05, adjusted for age, sex, and total intracranial volume. RESULTS: A total of 296 participants with migraine (mean age 41.6 years ± 12.4 SD, 261 women) and 155 healthy controls (mean age 41.1 years ± 11.7 SD, 133 women) were included. Among the participants with migraine, 180 (63.5%) had chronic migraine, 103 (34.8%) had migraine with aura, and 88 (29.7%) experienced a migraine headache during the scan. The total cohort of participants with migraine had reduced cortical surface area in the left insula, compared with controls (p < 0.0001). Furthermore, participants with chronic migraine (n = 180) exhibited reduced surface area in the left insula (p < 0.0001) and increased surface area in the right caudal anterior cingulate cortex (p < 0.0001), compared with controls. We found no differences specific to participants with aura or ongoing migraine headache. Post hoc tests revealed a positive correlation between monthly headache days and surface area within the identified anterior cingulate cluster (p = 0.014). DISCUSSION: The identified cortical changes in migraine were limited to specific pain processing regions, including the insula and caudal anterior cingulate gyrus, and were most notable in participants with chronic migraine. These findings suggest persistent cortical changes associated with migraine. TRIAL REGISTRATION INFORMATION: The REFORM study (clinicaltrials.gov identifier: NCT04674020).

Premonitory symptoms in migraine: A REFORM Study.

BACKGROUND: Estimates of proportions of people with migraine who report premonitory symptoms vary greatly among previous studies. Our aims were to establish the proportion of patients reporting premonitory symptoms and its dependency on the enquiry method. Additionally, we investigated the impact of premonitory symptoms on disease burden using Headache Impact Test (HIT-6), Migraine Disability Assessment (MIDAS) and World Health Organization Disability Assessment 2.0 (WHODAS 2.0), whilst investigating how various clinical factors influenced the likelihood of reporting premonitory symptoms. METHODS: In a cross-sectional study, premonitory symptoms were assessed among 632 patients with migraine. Unprompted enquiry was used first, followed by a list of 17 items (prompted). Additionally, we obtained clinical characteristics through a semi-structured interview. RESULTS: Prompted enquiry resulted in a greater proportion reporting premonitory symptoms than unprompted (69.9% vs. 43.0%; p < 0.001) and with higher symptom counts (medians 2, interquartile range = 0-6 vs. 1, interquartile range = 0-1; p < 0.001). The number of symptoms correlated weakly with HIT-6 (ρ = 0.14; p < 0.001) and WHODAS scores (ρ = 0.09; p = 0.041). Reporting postdromal symptoms or triggers increased the probability of reporting premonitory symptoms, whereas monthly migraine days decreased it. CONCLUSIONS: The use of a standardized and optimized method for assessing premonitory symptoms is necessary to estimate their prevalence and to understand whether and how they contribute to disease burden.

Epidemiology and clinical features of paroxysmal hemicrania: A systematic review and meta-analysis.

OBJECTIVE: To assess the prevalence or relative frequency of paroxysmal hemicrania and its clinical features in the adult general population and among adult patients evaluated for headache in tertiary care. BACKGROUND: Paroxysmal hemicrania is a rare trigeminal autonomic cephalalgia with characteristic attacks of headache, associated cranial autonomic symptoms and signs, and an absolute response to indomethacin. Its epidemiological burden remains unknown in both the adult general population and among adult patients evaluated for headache in a tertiary care setting. Moreover, the frequencies of the clinical features associated with paroxysmal hemicrania have not been well established. METHODS: A literature search of PubMed and Embase was conducted from January 1, 1988, to January 20, 2023. Eligible for inclusion were observational studies reporting the point prevalence or relative frequency of paroxysmal hemicrania or its clinical features in the adult general population or among adult patients evaluated for headache in tertiary care. Two independent investigators (M.J.H. and J.G.L.) performed the title, abstract, and full-text article screening. Each included study's risk of bias was critically appraised using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data. Estimates of prevalence or relative frequency were calculated using a random-effects meta-analysis. The between-study heterogeneity was assessed using the I2 statistic and further explored with meta-regression. This study was pre-registered on PROSPERO (identifier: CRD42023391127). RESULTS: A total of 17 clinic-based studies and one population-based study met the eligibility criteria. Importantly, an overall high risk of bias was observed across the eligible studies. The relative frequency of paroxysmal hemicrania was estimated to be 0.3% (95% CI, 0.2%-0.5%) among adult patients evaluated for headache in tertiary care with considerable heterogeneity (I2 = 76.4%). No cases with paroxysmal hemicrania were identified among 1,838 participants in a population-based sample. Moreover, the most prevalent cranial autonomic symptoms were lacrimation (77.3% [95% Cl, 62.7%-87.3%]), conjunctival injection (75.0% [95% Cl, 60.3%-85.6%]), and nasal congestion (47.7% [95% Cl, 33.6%-62.3%]). CONCLUSIONS: Our findings suggest that paroxysmal hemicrania is a rare disorder among adults evaluated for headache in tertiary care, while its prevalence in the general population remains unknown. Further studies focusing on the clinical features of paroxysmal hemicrania are warranted.

Immune Cell Alterations in Psychotic Disorders: A Comprehensive Systematic Review and Meta-Analysis.

BACKGROUND: A comprehensive meta-analysis on the composition of circulating immune cells from both the myeloid and the lymphoid lines including specialized subsets in blood and cerebrospinal fluid (CSF) of patients with psychotic disorders compared with healthy control participants has been lacking. METHODS: Multiple databases (PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, and PsycINFO) were searched for eligible studies up until October 18, 2022. All studies investigating circulating immune cells in the blood and CSF from patients with psychotic disorders (ICD-10: F20 and F22-29) compared with healthy control participants were included. RESULTS: A total of 86 studies were included in the meta-analysis. In the blood, the following categories of immune cells were elevated: leukocyte count (31 studies, standardized mean difference [SMD] = 0.35; 95% CI, 0.24 to 0.46), granulocyte count (4 studies, SMD = 0.57; 95% CI, 0.12 to 1.01), neutrophil granulocyte count (21 studies, SMD = 0.32; 95% CI, 0.11 to 0.54), monocyte count (23 studies, SMD = 0.40; 95% CI, 0.23 to 0.56), and B lymphocyte count (10 studies, SMD = 0.26; 95% CI, 0.04 to 0.48). Additionally, the neutrophil/lymphocyte ratio (23 studies, SMD = 0.40; 95% CI, 0.19 to 0.60), the monocyte/lymphocyte ratio (9 studies, SMD = 0.31; 95% CI, 0.04 to 0.57), and the platelet/lymphocyte ratio (10 studies, SMD = 0.23; 95% CI, 0.03 to 0.43) were elevated. The CSF cell count showed a similar tendency but was not significantly elevated (3 studies, SMD = 0.14; 95% CI, -0.04 to 0.32). CONCLUSIONS: The results indicate a broad activation of the immune system in psychotic disorders, with cells from both the myeloid and the lymphoid line being elevated. However, CSF analyses were lacking in most of the studies, and many studies were hampered by insufficient adjustment for confounding factors such as body mass index and smoking.

Hypersensitivity to PACAP-38 in post-traumatic headache: a randomized clinical trial.

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), known for its role in migraine pathogenesis, has been identified as a novel drug target. Given the clinical parallels between post-traumatic headache (PTH) and migraine, we explored the possible role of PACAP-38 in the pathogenesis of PTH. To this end, we conducted a randomized, double-blind, placebo-controlled, two-way crossover trial involving adult participants diagnosed with persistent PTH resulting from mild traumatic brain injury. Participants were randomly assigned to receive a 20-min continuous intravenous infusion of either PACAP-38 (10 pmol/kg/min) or placebo (isotonic saline) on two separate experimental days, with a 1-week washout period in between. The primary outcome was the difference in incidence of migraine-like headache between PACAP-38 and placebo during a 12-h observational period post-infusion. The secondary outcome was the difference in the area under the curve (AUC) for baseline-corrected median headache intensity scores during the same 12-h observational period. Of 49 individuals assessed for eligibility, 21 were enrolled and completed the trial. The participants had a mean age of 35.2 years, and 16 (76%) were female. Most [19 of 21 (90%)] had a migraine-like phenotype. During the 12-h observational period, 20 of 21 (95%) participants developed migraine-like headache after intravenous infusion of PACAP-38, compared with two (10%) participants after placebo (P < 0.001). Furthermore, the baseline-corrected AUC values for median headache intensity scores during the 12-h observational period was higher after PACAP-38 than placebo (P < 0.001). These compelling results demonstrate that PACAP-38 is potent inducer of migraine-like headache in people with persistent PTH. Thus, targeting PACAP-38 signalling might be a promising avenue for the treatment of PTH.

Prediction models of suicide and non-fatal suicide attempt after discharge from a psychiatric inpatient stay: A machine learning approach on nationwide Danish registers.

INTRODUCTION: To develop machine learning models capable of predicting suicide and non-fatal suicide attempt as separate outcomes in the first 30 days after discharge from a psychiatric inpatient stay. METHODS: Prospective cohort study using nationwide Danish registry data. We included individuals who were 18 years or older, and all discharges from psychiatric hospitalizations in Denmark from 1995 to 2018. We trained predictive models using 10-fold cross validation on 80% of the data and did testing on the remaining 20%. RESULTS: The best model for predicting non-fatal suicide attempt was an ensemble of predictions from gradient boosting (XGBoost) and categorical boosting (catBoost). The ROC-AUC for predicting suicide attempt was 0.85 (95% CI: 0.84-0.85). At a risk threshold of 4.36%, positive predictive value (PPV) was 11.0% and sensitivity was 47.2%. The best model for predicting suicide was an ensemble of predictions from random forest, XGBoost and catBoost. For suicide, the ROC-AUC was 0.71 (95% CI: 0.70-0.73). At a risk threshold of 0.15%, PPV was 0.34% and sensitivity was 56.0%. The most contributing predictors differed when predicting suicide and suicide attempt, indicating that separate models are needed. The ensemble model was fair across sex and age, and more so than the penalized logistic regression model. CONCLUSIONS: We achieved good performance for predicting suicide attempts and demonstrated a clinical application of ensemble models. Our results indicate a difference in predictive performance for models predicting suicide and suicide attempt, respectively. Thus, we recommend that suicide and suicide attempt are treated as two separate endpoints, in particular for clinical application. We demonstrated that the ensemble model is fairer across sex and age compared with a penalized logistic regression, and therefore we recommend the use of well-tested ensembles despite a more complex explainability.

Hypersensitivity to opening of ATP-sensitive potassium channels in post-traumatic headache.

OBJECTIVE: To investigate whether levcromakalim (a KATP channel opener) induces migraine-like headache in people with persistent post-traumatic headache who had no known history of migraine. METHODS: In a randomized, double-blind, placebo-controlled, 2-way crossover trial, participants were randomly assigned to receive a 20-minute continuous intravenous infusion of levcromakalim (50 µg/mL) or placebo (isotonic saline) on two separate experimental days with a 1-week wash-out period in between. The primary endpoint was the difference in incidence of migraine-like headache between levcromakalim and placebo during a 12-hour observational period after infusion start. The secondary endpoint was the difference in area under the curve for baseline-corrected median headache intensity scores between levcromakalim and placebo during the 12-hour observational period. RESULTS: A total of 21 participants with persistent post-traumatic headache were randomized and completed the trial. During the 12-hour observational period, 12 (57%) of 21 participants reported experiencing migraine-like headache following the levcromakalim infusion, compared with three after placebo (P = 0.013). Moreover, the baseline-corrected median headache intensity scores were higher following the levcromakalim infusion than after placebo (P = 0.003). CONCLUSION: Our findings suggest that KATP channels play an important role in the pathogenesis of migraine-like headache in people with persistent post-traumatic headache. This implies that KATP channel blockers might represent a promising avenue for drug development. Further research is warranted to explore the potential therapeutic benefits of KATP channel blockers in managing post-traumatic headache.Trial Registration: ClinicalTrials.gov Identifier: NCT05243953.

Long-term neurological outcome after COVID-19 using all SARS-CoV-2 test results and hospitalisations in Denmark with 22-month follow-up.

Hospitalisation with COVID-19 is associated with an increased risk of neurological sequelae; however, representative nationwide studies comparing to other infections with similar severity and also including milder SARS-CoV-2 infections have been lacking. Using the nationwide Danish registers including all SARS-CoV-2 PCR test results and hospitalisations between March 1, 2020, and December 31, 2021, we estimate the risk of any first neurological disorder diagnosed in inpatient, outpatient, or emergency room settings. We show that positive tests increase the rate of neurological disorders by a hazard ratio of 1.96 (95% confidence interval: 1.88-2.05) compared to individuals not tested and by a hazard ratio of 1.11 (95% confidence interval: 1.07-1.16) compared to individuals with negative tests only. However, there is no evidence that the risk of neurological disorders is higher for individuals who test positive compared to non-COVID-19 infections treated with anti-infective medication. The risk of neurological disorders is increased after COVID-19-hospitalisation compared to no COVID-19 hospital admission; however, these risks are comparable to hospitalisation with other respiratory infections (P value 0.328). In conclusion, COVID-19 is associated with an increased risk of neurological disorders, but no more than that observed after other infections of similar severity.

COVID-19 and Risk for Mental Disorders Among Adults in Denmark.

Importance: Psychiatric outcomes after COVID-19 have been of high concern during the pandemic; however, studies on a nationwide level are lacking. Objective: To estimate the risk of mental disorders and use of psychotropic medication among individuals with COVID-19 compared with individuals not tested, individuals with SARS-CoV-2-negative test results, and those hospitalized for non-COVID-19 infections. Design, Setting, and Participants: This nationwide cohort study used Danish registries to identify all individuals who were alive, 18 years or older, and residing in Denmark between January 1 and March 1, 2020 (N = 4 152 792), excluding individuals with a mental disorder history (n = 616 546), with follow-up until December 31, 2021. Exposures: Results of SARS-CoV-2 polymerase chain reaction (PCR) testing (negative, positive, and never tested) and COVID-19 hospitalization. Main Outcomes and Measures: Risk of new-onset mental disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes F00-F99) and redeemed psychotropic medication (Anatomical Therapeutic Chemical classification codes N05-N06) was estimated through survival analysis using a Cox proportional hazards model, with a hierarchical time-varying exposure, reporting hazard rate ratios (HRR) with 95% CIs. All outcomes were adjusted for age, sex, parental history of mental illness, Charlson Comorbidity Index, educational level, income, and job status. Results: A total of 526 749 individuals had positive test results for SARS-CoV-2 (50.2% men; mean [SD] age, 41.18 [17.06] years), while 3 124 933 had negative test results (50.6% women; mean [SD] age, 49.36 [19.00] years), and 501 110 had no tests performed (54.6% men; mean [SD] age, 60.71 [19.78] years). Follow-up time was 1.83 years for 93.4% of the population. The risk of mental disorders was increased in individuals with positive (HRR, 1.24 [95% CI, 1.17-1.31]) and negative (HRR, 1.42 [95% CI, 1.38-1.46]) test results for SARS-CoV-2 compared with those never tested. Compared with individuals with negative test results, the risk of new-onset mental disorders in SARS-CoV-2-positive individuals was lower in the group aged 18 to 29 years (HRR, 0.75 [95% CI, 0.69-0.81]), whereas individuals 70 years or older had an increased risk (HRR, 1.25 [95% CI, 1.05-1.50]). A similar pattern was seen regarding psychotropic medication use, with a decreased risk in the group aged 18 to 29 years (HRR, 0.81 [95% CI, 0.76-0.85]) and elevated risk in those 70 years or older (HRR, 1.57 [95% CI, 1.45-1.70]). The risk for new-onset mental disorders was substantially elevated in hospitalized patients with COVID-19 compared with the general population (HRR, 2.54 [95% CI, 2.06-3.14]); however, no significant difference in risk was seen when compared with hospitalization for non-COVID-19 respiratory tract infections (HRR, 1.03 [95% CI, 0.82-1.29]). Conclusion and Relevance: In this Danish nationwide cohort study, overall risk of new-onset mental disorders in SARS-CoV-2-positive individuals did not exceed the risk among individuals with negative test results (except for those aged ≥70 years). However, when hospitalized, patients with COVID-19 had markedly increased risk compared with the general population, but comparable to risk among patients hospitalized for non-COVID-19 infections. Future studies should include even longer follow-up time and preferentially include immunological biomarkers to further investigate the impact of infection severity on postinfectious mental disorder sequelae.

White matter hyperintensities and cerebral microbleeds in persistent post-traumatic headache attributed to mild traumatic brain injury: a magnetic resonance imaging study.

OBJECTIVE: To examine whether white matter hyperintensities (WMHs) and cerebral microbleeds (CMBs) are more prevalent in people with persistent post-traumatic headache attributed to mild traumatic brain injury (TBI), compared with healthy controls. METHODS: A magnetic resonance imaging (MRI) study of adults with persistent post-traumatic headache attributed to mild TBI and age- and gender-matched healthy controls. A semi-structured interview and validated self-report instruments were used to record data on demographics, clinical characteristics, and comorbidities. Imaging data were obtained on a 3T MRI Scanner using a 32-channel head coil. Participants and controls underwent a single MRI session, in which fluid-attenuated inversion recovery was used to visualize WMHs, and susceptibility-weighted imaging was used to detect CMBs. The primary outcomes were (I) the difference in the mean number of WMHs between participants with persistent post-traumatic headache and healthy controls and (II) the difference in the mean number of CMBs between participants with persistent post-traumatic headache and healthy controls. All images were examined by a certified neuroradiologist who was blinded to the group status of the participants and controls. RESULTS: A total of 97 participants with persistent post-traumatic headache and 96 age- and gender-matched healthy controls provided imaging data eligible for analyses. Among 97 participants with persistent post-traumatic headache, 43 (44.3%) participants presented with ≥ 1 WMH, and 3 (3.1%) participants presented with ≥ 1 CMB. Compared with controls, no differences were found in the mean number of WMHs (2.7 vs. 2.1, P = 0.58) and the mean number of CMBs (0.03 vs. 0.04, P = 0.98). CONCLUSIONS: WMHs and CMBs were not more prevalent in people with persistent post-traumatic headache than observed in healthy controls. Future studies should focus on other MRI techniques to identify radiologic biomarkers of post-traumatic headache.

Psychopharmacological treatment patterns prior to a schizophrenia diagnosis: A Danish nationwide study.

BACKGROUND: Many patients with schizophrenia experience psychiatric symptoms long before being diagnosed. We investigated patterns of pre-diagnostic psychopharmacological treatment in individuals diagnosed with first-episode schizophrenia during the last two decades. DESIGN: Using Danish nationwide healthcare registers, we identified all individuals aged ≥10 years registered with their first ICD-10 schizophrenia diagnosis between January 1999 and March 2019. For each calendar year from 1999 to 2019, we calculated the proportion of patients - among those having received their first schizophrenia diagnosis in the respective calendar year - who redeemed prescriptions for various psychotropics in the two years preceding the schizophrenia diagnosis. We calculated proportions of all pre-diagnostic prescriptions since 1995 for a sub-population diagnosed 2011-2019 and for an age- and sex-matched reference group without schizophrenia. RESULTS: Among 33,361 individuals with schizophrenia (58 % males), the schizophrenia incidence rate was stable during the study period but the mean age at diagnosis decreased by >10 years. In the two pre-diagnostic years, 69 % received psychopharmacological treatment (52 % antipsychotics, 40 % antidepressants). This was stable between 1999 and 2019. Among 14,425 individuals diagnosed 2011-2019, psychotropic drug use was observed among 14-20 % between 24 and 10 years before the diagnosis, being four times higher than the reference group. Particularly antipsychotic and antidepressant drug use increased steadily during the ten pre-diagnostic years. CONCLUSIONS: Pre-diagnostic psychotropic drug use in schizophrenia was frequent but stable between 1999 and 2019 despite an earlier identification of schizophrenia patients. Our findings emphasize the continued importance of thorough diagnostic interviews, particularly among patients in need of antipsychotic treatment.

Neuropsychiatric and Cognitive Outcomes in Patients 6 Months After COVID-19 Requiring Hospitalization Compared With Matched Control Patients Hospitalized for Non-COVID-19 Illness.

Importance: Prolonged neuropsychiatric and cognitive symptoms are increasingly reported in patients after COVID-19, but studies with well-matched controls are lacking. Objective: To investigate cognitive impairment, neuropsychiatric diagnoses, and symptoms in survivors of COVID-19 compared with patients hospitalized for non-COVID-19 illness. Design, Setting, and Participants: This prospective case-control study from a tertiary referral hospital in Copenhagen, Denmark, conducted between July 2020 and July 2021, followed up hospitalized COVID-19 survivors and control patients hospitalized for non-COVID-19 illness, matched for age, sex, and intensive care unit (ICU) status 6 months after symptom onset. Exposures: Hospitalization for COVID-19. Main Outcomes and Measures: Participants were investigated with the Mini-International Neuropsychiatric Interview, the Montreal Cognitive Assessment (MoCA), neurologic examination, and a semi-structured interview for subjective symptoms. Primary outcomes were total MoCA score and new onset of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) psychiatric diagnoses. Secondary outcomes included specific psychiatric diagnoses, subjective symptoms, and neurologic examination results. All outcomes were adjusted for age, sex, ICU admission, admission length, and days of follow-up. Secondary outcomes were adjusted for multiple testing. Results: A total of 85 COVID-19 survivors (36 [42%] women; mean [SD] age 56.8 [14] years) after hospitalization and 61 matched control patients with non-COVID-19 illness (27 [44%] women, mean age 59.4 years [SD, 13]) were enrolled. Cognitive status measured by total geometric mean MoCA scores at 6-month follow-up was lower (P = .01) among COVID-19 survivors (26.7; 95% CI, 26.2-27.1) than control patients (27.5; 95% CI, 27.0-27.9). The cognitive status improved substantially (P = .004), from 19.2 (95% CI, 15.2-23.2) at discharge to 26.1 (95% CI, 23.1-29.1) for 15 patients with COVID-19 with MoCA evaluations from hospital discharge. A total of 16 of 85 patients with COVID-19 (19%) and 12 of 61 control patients (20%) had a new-onset psychiatric diagnosis at 6-month follow-up, which was not significantly different (odds ratio, 0.93; 95% CI, 0.39-2.27; P = .87). In fully adjusted models, secondary outcomes were not significantly different, except anosmia, which was more common after COVID-19 (odds ratio, 4.56; 95% CI, 1.52-17.42; P = .006); but no longer when adjusting for multiple testing. Conclusions and Relevance: In this prospective case-control study, cognitive status at 6 months was worse among survivors of COVID-19, but the overall burden of neuropsychiatric and neurologic signs and symptoms among survivors of COVID-19 requiring hospitalization was comparable with the burden observed among matched survivors hospitalized for non-COVID-19 causes.

Vagotomy and the risk of mental disorders: A nationwide population-based study.

OBJECTIVE: To investigate vagotomy, the severance of the vagus nerve, and its association with mental disorders, as gut-brain communication partly mediated by the vagus nerve have been suggested as a risk factor. METHODS: Nationwide population-based Danish register study of all individuals alive and living in Denmark during the study period 1977-2016 and who had a hospital contact for ulcer with or without vagotomy. Follow-up was until any diagnosis of mental disorders requiring hospital contact, emigration, death, or end of follow-up on December 31, 2016, whichever came first. Data were analyzed using survival analysis and adjusted for sex, age, calendar year, ulcer type, and Charlson comorbidity index score. RESULTS: During the study period, 113,086 individuals had a hospital contact for ulcer. Of these, 5,408 were exposed to vagotomy where 375 (6.9%) subsequently developed a mental disorder. Vagotomy overall was not associated with mental disorders (HR: 1.10; 95%CI: 0.99-1.23), compared to individuals with ulcer not exposed to vagotomy. However, truncal vagotomy was associated with an increased HR of 1.22 (95%CI: 1.06-1.41) for mental disorders, whereas highly selective vagotomy was not associated with mental disorders (HR: 0.98; 95%CI: 0.84-1.15). Truncal vagotomy was also associated with higher risk of mental disorders when compared to highly selective vagotomy (p = 0.034). CONCLUSIONS: Overall, vagotomy did not increase the risk of mental disorders; however, truncal vagotomy specifically was associated with a small risk increase in mental disorders, whereas no association was found for highly selective vagotomy. Thus, the vagus nerve does not seem to have a major impact on the development of mental disorders.

Pre-diagnostic and post-diagnostic psychopharmacological treatment of 16 288 patients with bipolar disorder.

OBJECTIVES: The aim was to describe the pre-diagnostic and post-diagnostic psychopharmacological treatment of bipolar disorder over the past two decades. METHODS: We identified all 16 288 individuals aged ≥ 18 years, who received their first diagnosis of bipolar disorder at a psychiatric hospital in Denmark between 1997 and 2014. For each calendar year, we calculated the proportion of patients (with index date in the respective calendar years) who were prescribed psychopharmacological treatment in the 2 years preceding and the 2 years following the date of the first diagnosis of bipolar disorder. For patients diagnosed with bipolar disorder from 2007 to 2010 (n = 3949), we described the psychopharmacological treatment from 1995 to 2016, that is, from up to 16 years prior to and up to 10 years after the diagnosis. RESULTS: Concomitant use of ≥ 2 antidepressants in the 2 years preceding the bipolar disorder diagnosis increased over the study period. In the 2 years following the diagnosis, the use of lithium decreased, while use of atypical antipsychotics (particularly quetiapine), valproate, and lamotrigine increased over the study period. During the 10 years following the diagnosis, 53%-90% of the patients received any psychotropic drug while 12%-26% received treatment with an antidepressant without overlapping treatment with a mood-stabilizing drug. CONCLUSION: The increased use of two or more antidepressants suggests more focus on bipolar disorder as a differential diagnosis to treatment-resistant unipolar depression. The decreased use of lithium (consistent with international trends) and the prevalent use of antidepressants without overlapping treatment with a drug with mood-stabilizing properties are concerning.

The Duffy-null genotype and risk of infection.

Many medical treatments, from oncology to psychiatry, can lower white blood cell counts and thus access to these treatments can be restricted to individuals with normal levels of white blood cells, principally in order to minimize risk of serious infection. This adversely affects individuals of African or Middle Eastern ancestries who have on average a reduced number of circulating white blood cells, because of the Duffy-null (CC) genotype at rs2814778 in the ACKR1 gene. Here, we investigate whether the Duffy-null genotype is associated with the risk of infection using the UK Biobank sample and the iPSYCH Danish case-cohort study, two population-based samples from different countries and age ranges. We found that a high proportion of those with the Duffy-null genotype (21%) had a neutrophil count below the threshold often used as a cut-off for access to relevant treatments, compared with 1% of those with the TC/TT genotype. In addition we found that despite its strong association with lower average neutrophil counts, the Duffy-null genotype was not associated with an increased risk of infection, viral or bacterial. These results have widespread implications for the clinical treatment of individuals of African ancestry and indicate that neutrophil thresholds to access treatments could be lowered in individuals with the Duffy-null genotype without an increased risk of infection.

Efficacy and safety of anti-inflammatory agents in treatment of psychotic disorders - A comprehensive systematic review and meta-analysis.

OBJECTIVE: Antipsychotic effects of immunomodulating drugs have been suggested; however, a thorough, comprehensive meta-analysis on the effect and safety of anti-inflammatory add-on treatment on psychotic disorders is lacking. METHOD: Multiple databases were searched up until February 2020. Only double-blinded, randomized, placebo-controlled clinical trials (RCTs) were included. Primary outcomes were change in total psychopathology and adverse events. Secondary outcomes included, amongst others, positive and negative symptoms, general psychopathology and cognitive domains. We performed random-effects meta-analyses estimating mean differences (MD) and standardized mean differences (SMD) for effect sizes. RESULTS: Seventy RCTs (N = 4104) were included, investigating either primarily anti-inflammatory drugs, i.e. drugs developed for immunomodulation, such as NSAIDs, minocycline and monoclonal antibodies (k = 15), or drugs with potential anti-inflammatory properties (k = 55), e.g. neurosteroids, N-acetyl cysteine, estrogens, fatty acids, statins, and glitazones. Antipsychotics plus anti-inflammatory treatment, compared to antipsychotics plus placebo, was associated with a PANSS scale MD improvement of -4.57 (95%CI = -5.93 to -3.20) points, corresponding to a SMD effect size of -0.29 (95%CI = -0.40 to -0.19). Trials on schizophrenia (MD = -6.80; 95%CI, -9.08 to -4.52) showed greater improvement (p < 0.01) than trials also including other psychotic disorders. However, primarily anti-inflammatory drugs (MD = 4.00; 95%CI = -7.19 to -0.80) were not superior (p = 0.69) to potential anti-inflammatory drugs (MD = 4.71; 95%CI = -6.26 to -3.17). Furthermore, meta-regression found that smaller studies showed significantly larger effect sizes than the larger studies (p = 0.0085), and only 2 studies had low risk of bias on all domains. Small but significant effects were found on negative symptoms (MD = -1.29), positive symptoms (MD = -0.53), general psychopathology (MD = -1.50) and working memory (SMD = 0.21). No differences were found regarding adverse events, but only 26 studies reported hereon. CONCLUSIONS: Anti-inflammatory add-on treatment to antipsychotics showed improvement of psychotic disorders; however, no superiority was found in primarily anti-inflammatory drugs, raising the question of the mechanism behind the effect, and treatment effect might be overestimated due to the large number of small studies.

Infections of the central nervous system as a risk factor for mental disorders and cognitive impairment: A nationwide register-based study.

BACKGROUND: CNS infections have been suggested as risk factors for cognitive decline and mental disorders; however, large-scale studies have been lacking regarding types and agents of CNS infections. METHODS: We utilized the unique personal registration number to create a cohort of 1,709,867 individuals born 1977-2010. CNS infection was exposure and data were analysed with 1) cox regression analyses estimating hazard ratios (HR) for developing mental disorders and 2) binomial regression estimating relative risk (RR) for completion of 9th grade including average grade score in a sub-cohort born 1988-1998. RESULTS: CNS infection increased the risk for developing mental disorders with a HR of 1.34 (95% CI 1.27-1.42). The highest risk observed was within the first 6 months after the CNS infection with a HR of 26.98 (95% CI 21.19-34.35). Viral CNS infections (HR 1.47, 95% CI 1.35-1.61) conferred a higher risk (p < 0.001) than bacterial (HR 1.24, 95% CI 1.15-1.35). Encephalitis (HR 1.64, 95% CI 1.41-1.90) conferred a higher risk (p < 0.001) than meningitis (HR 1.26, 95% CI 1.18-1.35). The risk was highest for organic mental disorders (HR 6.50, 95% CI 5.11-8.28) and disorders of intellectual development (HR 3.56, 95% CI 2.94-4.31), with a HR of 19.19 (95% CI 7.46-49.35) for profound disorder of intellectual development (IQ < 20). Furthermore, CNS infection decreased the RR of completing 9th grade of mandatory schooling (RR 0.89, 95% CI 0.88-0.91) and lowered average grade score for completers (p < 0.001). CONCLUSIONS: CNS infections increased the risk for mental disorders and decreased the likelihood of completing 9th grade, indicating long-term consequences of CNS infections.

Development and validation of multivariable prediction models of remission, recovery, and quality of life outcomes in people with first episode psychosis: a machine learning approach.

BACKGROUND: Outcomes for people with first-episode psychosis are highly heterogeneous. Few reliable validated methods are available to predict the outcome for individual patients in the first clinical contact. In this study, we aimed to build multivariable prediction models of 1-year remission and recovery outcomes using baseline clinical variables in people with first-episode psychosis. METHODS: In this machine learning approach, we applied supervised machine learning, using regularised regression and nested leave-one-site-out cross-validation, to baseline clinical data from the English Evaluating the Development and Impact of Early Intervention Services (EDEN) study (n=1027), to develop and internally validate prediction models at 1-year follow-up. We assessed four binary outcomes that were recorded at 1 year: symptom remission, social recovery, vocational recovery, and quality of life (QoL). We externally validated the prediction models by selecting from the top predictor variables identified in the internal validation models the variables shared with the external validation datasets comprised of two Scottish longitudinal cohort studies (n=162) and the OPUS trial, a randomised controlled trial of specialised assertive intervention versus standard treatment (n=578). FINDINGS: The performance of prediction models was robust for the four 1-year outcomes of symptom remission (area under the receiver operating characteristic curve [AUC] 0·703, 95% CI 0·664-0·742), social recovery (0·731, 0·697-0·765), vocational recovery (0·736, 0·702-0·771), and QoL (0·704, 0·667-0·742; p<0·0001 for all outcomes), on internal validation. We externally validated the outcomes of symptom remission (AUC 0·680, 95% CI 0·587-0·773), vocational recovery (0·867, 0·805-0·930), and QoL (0·679, 0·522-0·836) in the Scottish datasets, and symptom remission (0·616, 0·553-0·679), social recovery (0·573, 0·504-0·643), vocational recovery (0·660, 0·610-0·710), and QoL (0·556, 0·481-0·631) in the OPUS dataset. INTERPRETATION: In our machine learning analysis, we showed that prediction models can reliably and prospectively identify poor remission and recovery outcomes at 1 year for patients with first-episode psychosis using baseline clinical variables at first clinical contact. FUNDING: Lundbeck Foundation.