Can the DEX/CRH test or markers of oxidative stress distinguish work-related stress from major depressive disorder and normal controls?

Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity measured by the combined dexamethasone-CRH test (DEX-CRH test) has been found in patients with major depressive disorder (MDD), whereas hypoactivity has been found in patients with work-related stress. We aimed to investigate the DEX-CRH test as a biomarker to distinguish between MDD and work-related stress (exhaustion disorder - ED). We hypothesized that there would be lower cortisol and ACTH response in participants with ED compared to MDD and healthy controls (HC). Also, we explored if the cortisol response of those patients interacted with robust markers of oxidative stress. Thirty inpatients with MDD and 23 outpatients with ED were recruited. Plasma cortisol and ACTH were sampled during a DEX-CRH test. The main outcome measure, area under the curve (AUC) for cortisol and ACTH, was compa-red between MDD vs. ED participants and a historical HC group. Secondary markers of oxidative stress urinary 8-oxodG and 8-oxoGuo; quality of sleep and psychometrics were obtained. Cortisol concentrations were higher in MDD and ED participants compared to HC, and no differences in AUC cortisol and ACTH were found between ED vs. MDD. Compared to ED, MDD participants had higher stress symptom severity and a lower sense of well-being. No differences in oxidative stress markers or quality of sleep between the groups were found. The result indicates that the patients with ED, like patients with MDD, are non-suppressors in DEX-CRH test and not hypocortisolemic as suggested.

Schema therapy versus treatment as usual for outpatients with difficult-to-treat depression: study protocol for a parallel group randomized clinical trial (DEPRE-ST).

BACKGROUND: About one third of patients with depression are in a condition that can be termed as "difficult-to-treat". Some evidence suggests that difficult-to-treat depression is associated with a higher frequency of childhood trauma and comorbid personality disorders or accentuated features. However, the condition is understudied, and the effects of psychotherapy for difficult-to-treat depression are currently uncertain. The aim of this trial is to investigate the beneficial and harmful effects of 30 sessions of individual schema therapy versus treatment as usual for difficult-to-treat depression in the Danish secondary, public mental health sector. METHODS: In this randomized, multi-centre, parallel-group, superiority clinical trial, 129 outpatients with difficult-to-treat depression will be randomized (1:1) to 30 sessions of individual schema therapy or treatment as usual; in this context mainly group-based, short-term cognitive behaviour or psychodynamic therapy. The primary outcome is the change from baseline in depressive symptoms 12 months after randomization, measured on the observer-rated 6-item Hamilton Rating Scale for Depression. The secondary outcomes are health-related quality of life assessed with the European Quality of Life 5 Dimensions 5 Level Version, functional impairment assessed with the Work and Social Adjustment Scale, psychological wellbeing assessed with the WHO-5 Well-being Index, and negative effects of treatment assessed with the Negative Effects Questionnaire. Exploratory outcomes are improvement on patient self-defined outcomes, personal recovery, anxiety symptoms, anger reactions, metacognitive beliefs about anger, and perseverative negative thinking. Outcomes will be assessed at 6, 12, and 24 months after randomization; the 12-month time-point being the primary time-point of interest. Outcome assessors performing the depression-rating, data managers, statisticians, the data safety and monitoring committee, and conclusion makers for the outcome article will be blinded to treatment allocation and results. To assess cost-effectiveness of the intervention, a health economic analysis will be performed. DISCUSSION: This trial will provide evidence on the beneficial and harmful effects, as well as the cost-effectiveness of schema therapy versus treatment as usual for outpatients with difficult-to-treat depression. The results can potentially improve treatment for a large and understudied patient group. TRIAL REGISTRATION: ClinicalTrials.gov NCT05833087. Registered on 15th April 2023 (approved without prompts for revision on 27th April 2023).

Effects of erythropoietin on cognitive impairment and prefrontal cortex activity across affective disorders: A randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Persistent cognitive impairment is frequent across bipolar disorder (BD) and major depressive disorder (MDD), highlighting an urgent need for pro-cognitive treatments. AIM: This study investigated effects of erythropoietin (EPO) on cognitive impairment and dorsal prefrontal cortex (dPFC) activity in affective disorders. METHODS: In this randomized, double-blinded, placebo-controlled trial, cognitively impaired patients with remitted BD or MDD received 1 weekly recombinant human EPO (40,000 IU/mL) or saline infusion for a 12-week period. Assessments were conducted at baseline, after 2 weeks of treatment (week 3), immediately after treatment (week 13) and at 6-months follow-up. Participants underwent functional MRI during performance on a n-back working memory (WM) task at baseline and week 3, and for a subgroup 6 weeks post-treatment (week 18). The primary outcome was a cognitive composite score at week 13, whereas secondary outcomes comprised sustained attention and functioning. WM-related dPFC activity was a tertiary outcome. RESULTS: Data were analysed for 101 of the 103 included patients (EPO, n = 58; saline, n = 43). There were no effects of EPO over saline on any cognitive or functional outcomes or on WM-related dPFC activity. CONCLUSIONS: The absence of treatment-related changes in cognition and neural activity was unexpected and contrasts with multiple previous preclinical and clinical studies. It is possible that the lack of effects resulted from a recent change in the manufacturing process for EPO. Nevertheless, the findings support the validity of dPFC target engagement as a biomarker model for pro-cognitive effects, according to which treatments that do not improve cognition should not modulate dPFC activity. TRIAL REGISTRATIONS: EudraCT no.: 2016-004023-24; ClinicalTrials.gov identifier: NCT03315897.

Oxidative Stress-Induced Damage to RNA and DNA and Mortality in Individuals with Psychiatric Illness.

Importance: All-cause mortality and the risk for age-related medical disease is increased in individuals with psychiatric illness, but the underlying biological mechanisms are not known. Oxidative stress on nucleic acids (DNA and RNA; NA-OXS) is a molecular driver of aging and a potential pathophysiological mechanism in a range of age-related disorders. Objective: To study the levels of markers of NA-OXS in a large cohort of community-dwelling individuals with and without psychiatric illness and to evaluate their association with prospective all-cause mortality. Design, Setting, and Participants: This cohort study used a combined cohort of participants from 2 population-based health studies: the Danish General Suburban Population Study (January 2010 to October 2013) and nondiabetic control participants from the Vejle Diabetes Biobank study (March 2007 to May 2010). Individual history of psychiatric illness was characterized using register data on psychiatric diagnoses and use of psychotropic drugs before baseline examination. Urinary markers of systemic RNA (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) and DNA (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG]) damage from oxidation were measured by ultraperformance liquid chromatography-tandem mass spectrometry. Cox proportional hazard regression models were applied for survival analyses, using register-based all-cause mortality updated to May 2023. The follow-up time was up to 16.0 years. Exposures: History of psychiatric illness. Main Outcomes and Measures: Mortality risk according to psychiatric illness status and 8-oxoGuo or 8-oxodG excretion level. Results: A total of 7728 individuals were included (3983 [51.5%] female; mean [SD] age, 58.6 [11.9] years), 3095 of whom (40.0%) had a history of psychiatric illness. Mean (SD) baseline 8-oxoGuo was statistically significantly higher in individuals with psychiatric illness than in those without (2.4 [1.2] nmol/mmol vs 2.2 [0.9] nmol/mmol; P < .001), whereas 8-oxodG was not. All-cause mortality was higher in the psychiatric illness group vs the no psychiatric illness group (hazard ratio [HR], 1.44; 95% CI, 1.27-1.64; P < .001) and increased sequentially with each increasing tertile of 8-oxoGuo excretion in both groups to an almost doubled risk in the psychiatric illness/high 8-oxoGuo group compared to the no psychiatric illness/low 8-oxoGuo reference group (HR, 1.99; 95% CI, 1.58-2.52; P < .001). These results persisted after adjustment for a range of potential confounders and in a sensitivity analysis stratified for sex. Conclusions and Relevance: This study establishes systemic oxidative stress-induced damage to RNA as a potential mechanism in the accelerated aging observed in psychiatric disorders and urinary 8-oxoGuo as a potentially useful marker of mortality risk in individuals with psychiatric illness.

Sedative drug prescription patterns in Danish adults from 2002 through 2021. A register-based cohort study.

OBJECTIVE: Pharmacological treatment strategies for insomnia seem to vary, and there is lack of knowledge about how sedative drugs are used in a real-world setting. We investigated changes in sedative drug prescription patterns in Danish adults who initiated treatment between 2002 and 2016. METHODS: All adults with a first-time purchase of a sedative drug registered in the Danish National Prescription Register from 2002 through 2016 were followed for five years between 2002 and 2021 for subsequent prescriptions of sedative drugs, death, or emigration. Sedative drugs were classified into anxiolytic benzodiazepines (N05BA), hypnotic benzodiazepines (N05CD), Z-drugs (N05CF), melatonin (N05CH01), promethazine (R06AD), and low-dose quetiapine (N05AH04). Analyses were stratified on time: 2002-2006, 2007-2011, and 2012-2016. RESULTS: A total of 842,880 individuals purchased their first sedative drug between 2002 and 2016. Most of them (40.0%) initiated treatment between 2002 and 2006, whereas 29.2% initiated treatment in 2012-2016. In 2002-2006, anxiolytic benzodiazepines (46.4%), Z-drugs (42.8%), and hypnotic benzodiazepines (5.4%) were the most common first treatment. This pattern changed over time with a gradual increase in the use of melatonin, promethazine, and low-dose quetiapine, which in 2011-2016 accounted for 27% of all first treatments. During the five years from first prescription, around 27% shifted to a different sedative drug. This percentage increased slightly over time, but over time the first shift to another drug class was most often to a Z-drug or anxiolytic benzodiazepine. Few individuals (5.8%) had more than one shift and the third choice seemed randomly distributed across all other drug classes. CONCLUSION: Sedative drug prescriptions are distributed on different drug classes, with Z-drugs and anxiolytic benzodiazepines as the most frequent first treatment, and second choice in case of shift.

Long-Term Use of Benzodiazepines and Benzodiazepine-Related Drugs: A Register-Based Danish Cohort Study on Determinants and Risk of Dose Escalation.

OBJECTIVE: The authors investigated the frequency and determinants of long-term use and risk of dose escalation of benzodiazepines and benzodiazepine-related drugs (benzodiazepine receptor agonists, or BZRAs). METHODS: All adults ages 20-80 years living in Denmark on January 1, 2000 (N=4,297,045) were followed for redeemed prescriptions of BZRAs in the Danish National Prescription Registry from January 1, 2000, to December 31, 2020. For each drug class, we calculated long-term use for more than 1 or 7 years, and dose escalation measured as increase in dose to a level above the recommended level. Associations were examined using logistic regression. RESULTS: The authors identified 950,767 incident BZRA users, of whom 15% and 3% became long-term users for more than 1 or 7 years, respectively. These percentages were highest for individuals who initiated Z-drugs (17.8% and 4%). Among the 5% of BZRA users who had at least 3 years of continuous use, there was no indication of dose escalation, as the median dose remained relatively stable. However, 7% (N=3,545) of BZRA users escalated to doses above the recommended level. Psychiatric comorbidity, especially substance use disorder, was associated with higher risk of long-term use and dose escalation. CONCLUSIONS: A limited portion of the population that received BZRA prescriptions were classified as continuous users, and only a small proportion of this group escalated to doses higher than those recommended in clinical guidelines. Thus, this study does not, under the current regulations, support the belief that BZRA use frequently results in long-term use or dose escalation.

Neural correlates of episodic memory decline following electroconvulsive therapy: An exploratory functional magnetic resonance imaging study.

BACKGROUND: Electroconvulsive therapy (ECT) is an efficient and rapid-acting treatment indicated for severe depressive disorders. While ECT is commonly accompanied by transient memory decline, the brain mechanisms underlying these side effects remain unclear. AIMS: In this exploratory functional magnetic resonance (fMRI) study, we aimed to compare effects of ECT versus pharmacological treatment on neural response during episodic memory encoding in patients with affective disorders. METHODS: This study included 32 ECT-treated patients (major depressive disorder (MDD), n = 23; bipolar depression, n = 9) and 40 partially remitted patients in pharmacological treatment (MDD, n = 24; bipolar disorder, n = 16). Participants underwent neuropsychological assessment, a strategic picture encoding fMRI scan paradigm, and mood rating. The ECT group was assessed before ECT (pre-ECT) and 3 days after their eighth ECT session (post-ECT). RESULTS: Groups were comparable on age, gender, and educational years (ps ⩾ 0.05). Within-group analyses revealed a selective reduction in verbal learning and episodic memory pre- to post-ECT (p = 0.012) but no decline in global cognitive performance (p = 0.3). Functional magnetic resonance imaging analyses adjusted for mood symptoms revealed greater activity in ECT-treated patients than pharmacologically treated No-ECT patients across left precentral gyrus (PCG), right dorsomedial prefrontal cortex (dmPFC), and left middle frontal gyrus (MFG). In ECT-treated patients, greater decline in verbal learning and memory performance from pre- to post-ECT correlated with higher PCG response (r = -0.46, p = 0.008), but not with dmPFC or MFG activity (ps ⩾ 0.1), post-ECT. CONCLUSIONS: Episodic memory decline was related to greater neural activity in the left PCG, but unrelated to increased dmPFC and MFG activity, immediately after ECT.

Use of hypnotic-sedative medication and risk of falls and fractures in adults: A self-controlled case series study.

OBJECTIVE: To evaluate the risk of falls and fractures in users of benzodiazepines, Z-drugs, or melatonin. METHODS: We followed 699,335 adults with a purchase of benzodiazepines, Z-drugs, or melatonin in the Danish National Prescription Registry between 2003 and 2016 for falls and fractures in the Danish National Patient Registry between 2000 and 2018. A self-controlled case-series analysis and conditional Poisson regression were used to derive incidence rate ratios (IRR) of falls and fractures during six predefined periods. RESULTS: In total 62,105 and 36,808 adults, respectively, experienced a fall or fracture. For older adults, the risk of falls was highest during the 3-month pre-treatment period (IRRmen+70 , 4.22 (95% confidence interval, 3.53-5.05), IRRwomen + 70 , 3.03 (2.59-3.55)) compared to the baseline (>1 year before initiation). The risk continued to be higher in the later treatment periods. Contrarily, in men and women aged 40-69 years, the risk was only higher in the 3-month pre-treatment period. The incidence of falls among young men and women was slightly lower after initiation of sedating medication (treatment period, IRRmen15-39 , 0.66 (0.50-0.86), IRRwomen15-39 , 0.65 (0.51-0.83)). Analyses with fractures as outcome yielded similar results. CONCLUSIONS: Although falls and fractures occur more often in persons using sedative-hypnotic medication, the higher risk of falls and fractures in the pre-treatment period relative to the period directly after treatment, suggests that this association is better explained by other factors that elicited the prescription of this medication rather than the adverse effects of the sedative-hypnotic medication.

Sexual health and serotonin 4 receptor brain binding in unmedicated patients with depression-a NeuroPharm study.

Sexual dysfunction is prominent in Major Depressive Disorder (MDD) and affects women with depression more than men. Patients with MDD relative to healthy controls have lower brain levels of the serotonin 4 receptor (5-HT4R), which is expressed with high density in the striatum, i.e. a key hub of the reward system. Reduced sexual desire is putatively related to disturbed reward processing and may index anhedonia in MDD. Here, we aim to illuminate plausible underlying neurobiology of sexual dysfunction in unmedicated patients with MDD. We map associations between 5-HT4R binding, as imaged with [11C]SB207145 PET, in the striatum, and self-reported sexual function. We also evaluate if pre-treatment sexual desire score predicts 8-week treatment outcome in women. From the NeuroPharm study, we include 85 untreated MDD patients (71% women) who underwent eight weeks of antidepressant drug treatment. In the mixed sex group, we find no difference in 5-HT4R binding between patients with sexual dysfunction vs normal sexual function. However, in women we find lower 5-HT4R binding in the sexual dysfunctional group compared to women with normal sexual function (ß = -0.36, 95%CI[-0.62:-0.09], p = 0.009) as well as a positive association between sexual desire and 5-HT4R binding (ß = 0.07, 95%CI [0.02:0.13], p = 0.012). Sexual desire at baseline do not predict treatment outcome (ROC curve AUC = 52%[36%:67%]) in women. Taken together, we find evidence for a positive association between sexual desire and striatal 5-HT4R availability in women with depression. Interestingly, this raises the question if direct 5-HT4R agonism can target reduced sexual desire or anhedonia in MDD.

Association of childhood trauma with cognitive impairment and structural brain alterations in remitted patients with bipolar disorder.

BACKGROUND: Cognitive impairment affects many patients with bipolar disorder (BD). No pro-cognitive treatment with robust efficacy exists partly due to limited insight into underlying neurobiological abnormalities. METHODS: This magnetic resonance imaging (MRI) study investigates structural neuronal correlates of cognitive impairment in BD by comparing brain measures in a large sample of cognitively impaired versus cognitively intact patients with BD or cognitively impaired patients with major depressive disorder (MDD) and healthy controls (HC). Participants underwent neuropsychological assessments and MRI scans. The cognitively impaired and - intact BD and MDD patient groups were compared with each other and HC regarding prefrontal cortex measures, hippocampus shape/volume, and total cerebral white (WM) and grey matter (GM). RESULTS: Cognitively impaired BD patients showed lower total cerebral WM volume than HC, which scaled with poorer global cognitive performance and more childhood trauma. Cognitively impaired BD patients also showed lower adjusted GM volume and thickness in the frontopolar cortex than HC but greater adjusted GM volume in the temporal cortex than cognitively normal BD patients. Cognitively impaired BD patients showed decreased cingulate volume than cognitively impaired MDD patients. Hippocampal measures were similar across all groups. LIMITATIONS: The cross-sectional study design prevented insights into causal relationships. CONCLUSIONS: Lower total cerebral WM and regional frontopolar and temporal GM abnormalities may constitute structural neuronal correlates of cognitive impairment in BD, of which the WM deficits scale with the degree of childhood trauma. The results deepen the understanding of cognitive impairment in BD and provide a neuronal target for pro-cognitive treatment development.

Neural basis of memory impairments and relation to functional disability in fully or partially remitted patients with affective disorders.

Bipolar disorder (BD) and major depressive disorder (MDD) are associated with cognitive and functional impairment. Cognitive impairment is often associated with dorsal prefrontal cortex (dPFC) hypo-activity, but the neuronal correlates of functional disability is largely unknown. In this study, 91 patients with affective disorders in full or partial remission (BD, n = 67; MDD, n = 24) with objectively verified cognitive impairment and substantial functional disability underwent neuropsychological assessment and functional magnetic resonance imaging (fMRI) scan during which they completed a strategic picture-encoding task. For comparison, 36 matched healthy controls underwent an identical test protocol. Patients showed encoding-related hypo-activity in the dPFC compared to controls. In patients, lower right dlPFC activity was associated with poorer overall functioning and more antipsychotic drug use. In conclusion, memory impairments were underpinned by failure to recruit the dPFC during task performance which was associated with impaired functioning in fully or partially remitted patients with affective disorders. This aberrant neurocircuitry activity has implications for the design of future pro-cognitive interventions that aim to improve not only cognition but also real-world functioning.

Deep phenotyping towards precision psychiatry of first-episode depression - the Brain Drugs-Depression cohort.

BACKGROUND: Major Depressive Disorder (MDD) is a heterogenous brain disorder, with potentially multiple psychosocial and biological disease mechanisms. This is also a plausible explanation for why patients do not respond equally well to treatment with first- or second-line antidepressants, i.e., one-third to one-half of patients do not remit in response to first- or second-line treatment. To map MDD heterogeneity and markers of treatment response to enable a precision medicine approach, we will acquire several possible predictive markers across several domains, e.g., psychosocial, biochemical, and neuroimaging. METHODS: All patients are examined before receiving a standardised treatment package for adults aged 18-65 with first-episode depression in six public outpatient clinics in the Capital Region of Denmark. From this population, we will recruit a cohort of 800 patients for whom we will acquire clinical, cognitive, psychometric, and biological data. A subgroup (subcohort I, n = 600) will additionally provide neuroimaging data, i.e., Magnetic Resonance Imaging, and Electroencephalogram, and a subgroup of patients from subcohort I unmedicated at inclusion (subcohort II, n = 60) will also undergo a brain Positron Emission Tomography with the [11C]-UCB-J tracer binding to the presynaptic glycoprotein-SV2A. Subcohort allocation is based on eligibility and willingness to participate. The treatment package typically lasts six months. Depression severity is assessed with the Quick Inventory of Depressive Symptomatology (QIDS) at baseline, and 6, 12 and 18 months after treatment initiation. The primary outcome is remission (QIDS ≤ 5) and clinical improvement (≥ 50% reduction in QIDS) after 6 months. Secondary endpoints include remission at 12 and 18 months and %-change in QIDS, 10-item Symptom Checklist, 5-item WHO Well-Being Index, and modified Disability Scale from baseline through follow-up. We also assess psychotherapy and medication side-effects. We will use machine learning to determine a combination of characteristics that best predict treatment outcomes and statistical models to investigate the association between individual measures and clinical outcomes. We will assess associations between patient characteristics, treatment choices, and clinical outcomes using path analysis, enabling us to estimate the effect of treatment choices and timing on the clinical outcome. DISCUSSION: The BrainDrugs-Depression study is a real-world deep-phenotyping clinical cohort study of first-episode MDD patients. TRIAL REGISTRATION: Registered at clinicaltrials.gov November 15th, 2022 (NCT05616559).

Association of Familial Aggregation of Major Depression With Risk of Major Depression.

Importance: Major depression (MD) aggregates within families, but how family history of MD confers risk of MD over the life course is unclear. Such knowledge is important to identify and prevent possible depressogenic effects of family environment. Objective: To examine the association between family MD history and risk of MD including association with age, sex, type of kinship, and age of the affected family member. Design, Setting, and Participants: This cohort study included all Danish citizens born from 1960 to 2003 with known parental identity followed up from their 15th birthday until time of MD, censoring, or December 31, 2018. Analysis took place between April 2022 and December 2022. Exposures: Family members with first-time MD using International Classification of Diseases, Eighth Revision codes 296.09, 296.29, 298.09, and 300.49 or 10th Revision codes F32.0-F33.9, family members' age at MD onset, and individuals' age at exposure to family MD. Main Outcomes and Measures: Multivariable Poisson regression was applied to estimate the incidence rate ratio (IRR) with 95% CI of first-time MD. Results: Of 2 903 430 individuals (1 486 574 [51.2%] men), 37 970 men (2.6%) and 70 223 women (5.0%) developed MD during follow-up. For men, exposure to maternal, paternal, or full sibling MD were associated with a 2-times higher risk of MD (IRR, 2.10 [95% CI, 2.02-2.19]; IRR, 2.04 [95% CI, 1.94-2.14]; IRR, 2.08 [95% CI, 1.97-2.19]) and the associated risk increased with number of affected family members. This pattern was similar for women. For men, family members' age at MD onset was not associated with MD. For women, maternal MD onset at 69 years or younger was associated with higher IRRs of MD (age <40 years: IRR, 1.64 [95% CI, 1.28-2.10]; age 40-49 years: IRR, 1.62 [95% CI, 1.27-2.07]; age 50-59 years: IRR, 1.56 [95% CI, 1.22-2.00]; and age 60-69 years: IRR, 1.67 [95% CI, 1.28-2.16]) compared with women with maternal MD onset at 70 years or older. For men, exposure to maternal MD younger than 30 years (age <1 year: IRR, 1.95 [95% CI, 1.70-2.25]; age 1 to <12 years: IRR, 2.31 [95% CI, 2.16-2.47]; age 12 to <19 years: IRR, 2.18 [95% CI, 2.03-2.35]; age 19 to <30 years: IRR, 1.42 [95% CI, 1.32-1.53]) was associated with increased IRRs, while exposure to maternal MD at 30 years or older was associated with a lower IRR (0.77 [95% CI, 0.70-0.85]). The findings were similar across type of kinships and for women. Conclusions and Relevance: In this study, risk of MD was associated with increased numbers of affected family members but did not vary by gender or type of kinship. Exposure to family MD during childhood and adolescence was associated with increased risk.

Mapping diagnostic trajectories from the first hospital diagnosis of a psychiatric disorder: a Danish nationwide cohort study using sequence analysis.

BACKGROUND: A key clinical problem in psychiatry is predicting the diagnostic future of patients presenting with psychopathology for the first time. The objective of this study was to establish a comprehensive map of subsequent diagnoses after a first psychiatric hospital diagnosis. METHODS: Through the Danish National Patient Registry, we identified patients aged 18 years or older with an inpatient or outpatient psychiatric hospital contact and who had received one of the 20 most common first-time psychiatric diagnoses (defined at the ICD-10 two-cipher level, F00-F99) between Jan 1, 1995, and Dec 31, 2008. For each first-time diagnosis, the 20 most frequent subsequent psychiatric diagnoses (F00-F99), and death, occurring during 10 years of follow-up were identified as outcomes. To assess diagnostic stability, we used social sequence analyses, assigning a subsequent diagnosis to each state with a length of 6 months following each first-time diagnosis. The subsequent diagnosis was defined as the last diagnosis given within each 6-month period. We calculated the normalised entropy of each sequence to show the uncertainty of predicting the states in a given sequence. Cox proportional hazards models were used to assess the risk of receiving a subsequent diagnosis (at the one-cipher level, F0-F9) after each first-time diagnosis. FINDINGS: The cohort consisted of 184 949 adult patients (77 129 [41·7%] men and 107 820 [58·3%] women, mean age 42·5 years [SD 18·5; range 18 to >100). Ethnicity data were not recorded. Over 10 years of follow-up, 86 804 (46·9%) patients had at least one subsequent diagnosis that differed from their first-time diagnosis. Measured by mean normalised entropy values, persistent delusional disorders (ICD-10 code F22), mental and behavioural disorders due to multiple drug use and use of other psychoactive substances (F19), and acute and transient psychotic disorders (F23) had the highest diagnostic variability, whereas eating disorders (F50) and non-organic sexual dysfunction (F52) had the lowest. The risk of receiving a subsequent diagnosis with a psychiatric disorder from an ICD-10 group different from that of the first-time diagnosis varied substantially among first-time diagnoses. INTERPRETATION: These data provide detailed information on possible diagnostic outcomes after a first-time presentation in a psychiatric hospital. This information could help clinicians to plan relevant follow-up and inform patients and families on the degree of diagnostic uncertainty associated with receiving a first psychiatric hospital diagnosis, as well as likely and unlikely trajectories of diagnostic progression. FUNDING: Mental Health Services, Capital region of Denmark. TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

Electroconvulsive Therapy and Risk of Road Traffic Accidents: A Danish Register-Based Cohort Study.

OBJECTIVE: The aim of the study is to examine whether electroconvulsive therapy (ECT) was associated with the subsequent risk of being involved in a road traffic accident. METHODS: A cohort of all 375,435 patients older than 18 years with their first psychiatric hospital contact between 2003 and 2017 in the Danish National Patient Registry was followed for road traffic accidents until December 2018. Associations between ECT and road traffic accidents were examined using Cox regression analyses with multiple adjustments and using propensity score matching on sociodemographic and clinical variables. RESULTS: A total of 8486 patients (0.2%) were treated with ECT. During the median follow-up of 5.9 years, 778 of these patients (12.5%) were involved in a road traffic accident and the unadjusted incidence of road traffic accidents was lower among these patients (incidence rate, 15.5 per 1000 patient-years; 95% confidence interval [CI], 14.5-16.7) compared with patients not treated with ECT (incidence rate, 20.0 per 1000 patient-years; 95% CI, 20.0-20.3). Electroconvulsive therapy was not associated with road traffic accidents in the Cox regression models after adjustment for all covariables (hazard ratio, 1.00; 95% CI, 0.92-1.08) or in the propensity score-matched sample (hazard ratio, 0.91; 95% CI, 0.83-1.08). The HRs did not vary materially with follow-up time or when analyses were stratified on sex, age, or type of hospital contact. CONCLUSIONS: The analysis of Danish National registry data indicates that ECT is not associated with the risk of being involved in major road traffic accidents.

Evaluating cognitive disturbances as treatment target and predictor of antidepressant action in major depressive disorder: A NeuroPharm study.

Cognitive disturbances in major depressive disorder (MDD) constitute a critical treatment target and hold promise as an early predictor of antidepressant treatment response; yet their clinical relevance is not fully established. Therefore, we here investigate if (1) cognitive performance improves over the course of antidepressant treatment and (2) cognitive performance at baseline is predictive of antidepressant treatment response. In the NeuroPharm study (clinical trial id: NCT02869035), 92 antidepressant-free patients with a moderate to severe depressive episode were assessed with a comprehensive cognitive test battery including both cold (emotion-independent) and hot (emotion-dependent) tasks. Patients were tested before and after 12 weeks of standard antidepressant treatment with escitalopram in flexible doses of 10-20 mg. Performance improved across most cognitive domains over the course of antidepressant treatment. Notably, these improvements were independent of improvement in mood symptoms, emphasizing that cognitive disturbances are a distinct symptom and therefore treatment target in MDD. Results did not suggest that performance on any single cognitive measure at baseline was associated with later clinical response to antidepressant treatment. However, a small cluster of patients (N = 28) with globally disturbed cognition at baseline exhibited poorer clinical response after 8 but not 12 weeks of antidepressant treatment, suggesting that severe cognitive disturbances may delay treatment response. Thus, while pretreatment cognitive performance on individual tests may not be useful as clinical markers of treatment response, profiles capturing performance across different cognitive domains may be useful for stratification of patients with MDD and could be helpful in future intervention trials.

Association of Oxidative Stress-Induced Nucleic Acid Damage With Psychiatric Disorders in Adults: A Systematic Review and Meta-analysis.

Importance: Nucleic acid damage from oxidative stress (NA-OXS) may be a molecular mechanism driving the severely increased morbidity and mortality from somatic causes in adults with psychiatric disorders. Objective: To systematically retrieve and analyze data on NA-OXS across the psychiatric disorder diagnostic spectrum. Data Sources: The PubMed, Embase, and PsycINFO databases were searched from inception to November 16, 2021. A hand search of reference lists of relevant articles was also performed. Study Selection: Key study inclusion criteria in this meta-analysis were as follows: adult human study population, measurement of any marker of DNA or RNA damage from oxidative stress, and either a (1) cross-sectional design comparing patients with psychiatric disorders (any diagnosis) with a control group or (2) prospective intervention. Two authors screened the studies, and 2 senior authors read the relevant articles in full and assessed them for eligibility. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two authors performed data extraction independently, and a senior coauthor was consulted in cases of disagreement. Data were synthesized with random-effects and multilevel meta-analyses. Main Outcomes and Measures: The predefined hypothesis was that individuals with psychiatric disorders have increased NA-OXS levels. The main outcome was the standardized mean differences (SMDs) among patients and controls in nucleic acid oxidation markers compared across diagnostic groups. Analyses were divided into combinations of biological matrices and nucleic acids. Results: Eighty-two studies fulfilled the inclusion criteria, comprising 205 patient vs control group comparisons and a total of 10 151 patient and 10 532 control observations. Overall, the data showed that patients with psychiatric disorders had higher NA-OXS levels vs controls across matrices and molecules. Pooled effect sizes ranged from moderate for urinary DNA markers (SMD = 0.44 [95% CI, 0.20-0.68]; P < .001) to very large for blood cell DNA markers (SMD = 1.12 [95% CI, 0.69-1.55; P < .001). Higher NA-OXS levels were observed among patients with dementias followed by psychotic and bipolar disorders. Sensitivity analyses excluding low-quality studies did not materially alter the results. Intervention studies were few and too heterogenous for meaningful meta-analysis. Conclusions and Relevance: The results of this meta-analysis suggest that there is an association with increased NA-OXS levels in individuals across the psychiatric disorder diagnostic spectrum. NA-OXS may play a role in the somatic morbidity and mortality observed among individuals with psychiatric disorders.

Diabetes, sleep disorders and risk of depression - A Danish register-based cohort study.

AIMS: We examined the influence of comorbid sleep disorder on the association between type 2 diabetes (T2D) and risk of incident depression. METHODS: The study population (N = 232,489) was based on all individuals registered aged ≥40 years with a T2D diagnosis between January 1, 2000 to December 31, 2012 in the Danish National Diabetes Register and a matched reference population. The risk of incident depression (diagnosis or anti-depressant medication) following T2D and possible effect modification of comorbid sleep disorder was estimated using adjusted Cox proportional hazards regression. Sleep disorder was defined as a diagnosis of insomnia, hypersomnia or sleep-wake schedule disorders or use of sleep medication (z-drugs or melatonin) in the Danish National Patient Registry or the Danish National Prescription Registry. RESULTS: At study entry, 15.3 % of the participants had a sleep disorder. During follow-up, 2.6 % were diagnosed with depression and 32.1 % received antidepressant medication. The unadjusted hazard ratio (HR) for depression was 1.54 (95%CI 1.52-1.56) for patients with diabetes, which attenuated to 1.50 (1.48-1.52) after adjustment for sleep disorders, which further attenuated to 1.27 (1.26-1.29) in the model further adjusted for psychiatric and somatic comorbidities. The analyses of T2D and sleep disorder as independent and combined variables compared with none of the conditions on risk of depression, showed a HR of 1.27 (95 % CI 1.19-1.35) for T2D without sleep disorder, 1.46 (95 % CI 1.33-1.59) for sleep disorders without T2D, and 1.49 (95%CI 1.37-1.63) for both conditions. CONCLUSIONS: T2D and sleep disorders were independently associated with subsequent risk of depression and individuals with both conditions experienced the greatest relative risk. Sleep disorders neither explained nor amplified the relation between diabetes and depression.

Use of GLP-1 receptor agonists and subsequent risk of alcohol-related events. A nationwide register-based cohort and self-controlled case series study.

Animal studies have related glucagon-like peptide 1 receptor agonists (GLP-1) to lower alcohol intake. We examined whether GLP-1 was associated with risk of alcohol-related events in a nationwide cohort study and a self-controlled case series analysis including all new users of GLP1 (n = 38 454) and dipeptidyl peptidase 4 inhibitors (DPP4) (n = 49 222) in Denmark 2009-2017. They were followed for hospital contacts with alcohol use disorder or purchase of drugs for treatment of alcohol dependence in nationwide registers from 2009 to 2018. Associations were examined using Cox proportional hazard and conditional Poisson regression. During follow-up of median 4.1 years, 649 (0.7%) of participants were registered with an alcohol-related event. Initiation of GLP-1 treatment was associated with lower risk of an alcohol-related event (Hazard ratio = 0.46 (95%CI: 0.24-0.86) compared with initiation of DPP4 during the first 3 months of follow-up. Self-controlled analysis showed the highest risk of alcohol-related events in the 3-month pretreatment period (incidence rate ratio [IRR] = 1.25 (1.00-1.58)), whereas the risk was lowest in the first 3-month treatment period (IRR = 0.74 (0.56-0.97). In conclusion, compared with DPP4 users, individuals who start treatment with GLP-1 had lower incidence of alcohol-related events both in cohort and self-controlled analyses. Thus, there might be a transient preventive effect of GLP1 on alcohol-related events the first months after treatment initiation.