Interaction between mental disorders and social disconnectedness on mortality: a population-based cohort study.

BACKGROUND: Despite the recognised importance of mental disorders and social disconnectedness for mortality, few studies have examined their co-occurrence. AIMS: To examine the interaction between mental disorders and three distinct aspects of social disconnectedness on mortality, while taking into account sex, age and characteristics of the mental disorder. METHOD: This cohort study included participants from the Danish National Health Survey in 2013 and 2017 who were followed until 2021. Survey data on social disconnectedness (loneliness, social isolation and low social support) were linked with register data on hospital-diagnosed mental disorders and mortality. Poisson regression was applied to estimate independent and joint associations with mortality, interaction contrasts and attributable proportions. RESULTS: A total of 162 497 individuals were followed for 886 614 person-years, and 9047 individuals (5.6%) died during follow-up. Among men, interaction between mental disorders and loneliness, social isolation and low social support, respectively, accounted for 47% (95% CI: 21-74%), 24% (95% CI: -15 to 63%) and 61% (95% CI: 35-86%) of the excess mortality after adjustment for demographics, country of birth, somatic morbidity, educational level, income and wealth. In contrast, among women, no excess mortality could be attributed to interaction. No clear trends were identified according to age or characteristics of the mental disorder. CONCLUSIONS: Mortality among men, but not women, with a co-occurring mental disorder and social disconnectedness was substantially elevated compared with what was expected. Awareness of elevated mortality rates among socially disconnected men with mental disorders could be of importance to qualify and guide prevention efforts in psychiatric services.

Prior psychiatric morbidity and differential psychopharmacological treatment patterns: Exploring the heterogeneity of bipolar disorder in a nationwide study of 9594 patients.

OBJECTIVES: Individuals with bipolar disorders (BD) have heterogenic pre-onset illness courses and responses to treatment. The pattern of illness preceding the diagnosis of BD may be a marker of future treatment response. Here, we examined associations between psychiatric morbidity preceding the diagnosis of BD and pharmacological treatment patterns in the 2 years following diagnosis. METHODS: In this register-based study, we included all patients with a diagnosis of BD attending Danish Psychiatric Services between January 1, 2012 and December 31, 2016. We examined the association between a diagnosis of substance use disorder, psychosis (other than schizophrenia or schizoaffective disorder), unipolar depression, anxiety/OCD, PTSD, personality disorder, or ADHD preceding BD and pharmacological treatment patterns following the diagnosis of BD (lithium, valproate, lamotrigine, antidepressants, olanzapine, risperidone, and quetiapine) via multivariable Cox proportional hazards regression adjusted for age, sex, and year of BD diagnosis. RESULTS: We included 9594 patients with a median age of 39 years, 58% of whom were female. Antidepressants, quetiapine, and lamotrigine were the most commonly used medications in BD and were all linked to prior depressive illness and female sex. Lithium was used among patients with less diagnostic heterogeneity preceding BD, while valproate was more likely to be used for patients with prior substance use disorder or ADHD. CONCLUSION: The pharmacological treatment of BD is linked to psychiatric morbidity preceding its diagnosis. Assuming that these associations reflect well-informed clinical decisions, this knowledge may inform future clinical trials by taking participants' prior morbidity into account in treatment allocation.

Development and validation of a machine learning model for prediction of type 2 diabetes in patients with mental illness.

BACKGROUND: Type 2 diabetes (T2D) is approximately twice as common among individuals with mental illness compared with the background population, but may be prevented by early intervention on lifestyle, diet, or pharmacologically. Such prevention relies on identification of those at elevated risk (prediction). The aim of this study was to develop and validate a machine learning model for prediction of T2D among patients with mental illness. METHODS: The study was based on routine clinical data from electronic health records from the psychiatric services of the Central Denmark Region. A total of 74,880 patients with 1.59 million psychiatric service contacts were included in the analyses. We created 1343 potential predictors from 51 source variables, covering patient-level information on demographics, diagnoses, pharmacological treatment, and laboratory results. T2D was operationalised as HbA1c ≥48 mmol/mol, fasting plasma glucose ≥7.0 mmol/mol, oral glucose tolerance test ≥11.1 mmol/mol or random plasma glucose ≥11.1 mmol/mol. Two machine learning models (XGBoost and regularised logistic regression) were trained to predict T2D based on 85% of the included contacts. The predictive performance of the best performing model was tested on the remaining 15% of the contacts. RESULTS: The XGBoost model detected patients at high risk 2.7 years before T2D, achieving an area under the receiver operating characteristic curve of 0.84. Of the 996 patients developing T2D in the test set, the model issued at least one positive prediction for 305 (31%). CONCLUSION: A machine learning model can accurately predict development of T2D among patients with mental illness based on routine clinical data from electronic health records. A decision support system based on such a model may inform measures to prevent development of T2D in this high-risk population.

Clinical validation of the self-reported 6-item Hamilton Depression Rating Scale (HAM-D6-SR) among inpatients.

BACKGROUND: Brief and valid patient-rated symptom scales represent a valuable addition to clinician-rated scales for assessing depression. Studies on the psychometric properties of the self-rated 6-item Hamilton Depression Rating Scale (HAM-D6-SR) have shown promising results for outpatients with depression. The aim of the present study was to evaluate the psychometric properties of the HAM-D6-SR among inpatients using the clinician-rated 17-item Hamilton Rating Scale for Depression (HAMD17) as the gold standard. METHODS: Inpatients with unipolar or bipolar depression completed the HAM-D6-SR and were subsequently rated on the HAM-D17 by trained raters, who were blind to the HAM-D6-SR ratings. The pairs of HAM-D6-SR and HAM-D17 ratings were completed twice during admission to evaluate responsiveness over time. Agreement between the HAM-D6-SR and the clinician-rated HAM-D17-derived HAM-D6 was evaluated using the intraclass correlation coefficient (ICC). Responsiveness was evaluated by means of the Spearman's rank correlation coefficient (rho). RESULTS: A total of 102 participants completed the HAM-D6-SR at least once (median age: 41 years; 66 % females). The ICC for the HAM-D6-SR and the HAM-D17-derived HAM-D6 was 0.60 (95%CI = 0.30-0.76), with the ICC at the item level ranging from 0.13 (Psychomotor retardation) to 0.75 (Depressed mood). The correlation between the changes in the baseline-endpoint total scores on the HAM-D6-SR and HAM-D17-derived HAM-D6 was rho = 0.59 (p < 0.001). LIMITATIONS: Test-retest reliability and structural validity were not evaluated. CONCLUSIONS: The HAM-D6-SR holds promise as a valid self-report of core depressive symptoms among inpatients and may aid treatment decisions. However, the validity of self-reported psychomotor retardation was poor.

Is Attention-Deficit/Hyperactivity Disorder (ADHD) a Dimension or a Category? What Does the Relationship Between ADHD Traits and Psychosocial Quality of Life Tell Us?

OBJECTIVE: The question of whether attention-deficit/hyperactivity disorder (ADHD) is a discrete category or a continuous dimension remains clinically relevant. We report the first examination of this question from the viewpoint of the relationship between ADHD traits and psychosocial quality of life (QoL), and whether the level of QoL declines markedly around a certain high ADHD trait range suggestive of a categorical boundary. METHODS: Parents/caregivers of 1,967 schoolchildren aged 6 to 11 from the general population completed the Pediatric Quality of Life Inventory and the ADHD-Rating Scale IV. Piecewise linear and non-linear regression analyses were performed. RESULTS: No evidence for a non-linear association or an abrupt change in the rate of decrease in QoL was observed in the high end of the ADHD traits continuum. Instead, the relationship was consistent with linearity. CONCLUSION: Psychosocial QoL gradually declines in a linear manner as ADHD trait levels increase providing further support for a dimensional model.

Does risk-taking or alcohol misuse mediate the association between anger and suicidal ideation in male depression?

Anger is among the core symptoms in male-specific inventories of depression and has consistently been linked with suicidal ideation. In this study, we assessed whether this link may be mediated via other prominent symptoms of depression in men, namely risk-taking and alcohol misuse. We used self-reported data from 322 men responding to a 3-wave survey over 6 months. Regression with mediation analysis was employed to test whether anger at baseline predicted suicidal ideation six months later through the mediating effects of risk-taking or alcohol misuse at 3 months. We found a statistically significant indirect effect (indicating a mediation effect) of anger at baseline on suicidality at 6-months follow-up through risk taking at 3-months follow-up (effect = 0.007, SE = 0.003, 99% Confidence interval = 0.0002 to 0.0161). Anger at baseline was not significantly associated with alcohol misuse at 3-months follow-up (ß = .062, t = 0.919, p = .358), thus nullifying alcohol misuse as a possible mediator between anger and suicidal ideation. In conclusion, the results of this study suggest that risk-taking, but not alcohol misuse, may be a mediator between anger and suicidal ideation in the context of male depression. If these results are replicated, assessing anger and risk-taking may inform monitoring of suicidality. Also, anger and risk-taking may be promising targets for treatment aimed at reducing the risk of suicide.

Clinical and Legal Differences in the Use of Involuntary Electroconvulsive Therapy for Life-Threatening Illness Across European Countries.

OBJECTIVES: Electroconvulsive therapy (ECT) can be life-saving in situations where patients are at risk of dying from severe manifestations of psychiatric illness. In some of these cases, patients are unwilling/unable to consent to ECT, and involuntary ECT is required. Such use of involuntary ECT varies substantially across European countries for unclear reasons. The aim of this study was to examine clinical and legal differences in this use of involuntary ECT across European countries. METHODS: A questionnaire based on a case vignette (a 55-year-old female inpatient with psychotic depression at imminent risk of dying from metabolic derangement because of refusal to eat and drink) was sent to an ECT practitioner in each of 31 European countries. RESULTS: We received responses from ECT practitioners in 18 countries. In 7 of these countries, involuntary ECT could be carried out without approval from others and/or involvement of the court system in the case described in the vignette. Practitioners in the remaining 11 countries responded that they either could not carry out involuntary ECT or would have to meet certain requirements before initiating involuntary ECT (e.g., approval from medical/ethics committee and second opinion from an independent psychiatrist). Notably, the rules regarding involuntary ECT differed for adults and minors (more restrictive for the latter) in 6 of the 18 countries. CONCLUSIONS: In many European countries, legislation precludes or delays the use of involuntary ECT. Harmonization of the legislation on involuntary ECT across European countries to allow for better access to this potentially life-saving treatment seems warranted.

Structural validity of the 5-item World Health Organization Well-being Index (WHO-5) in patients with schizophrenia spectrum disorders.

BACKGROUND: When monitoring the severity and impact of schizophrenia spectrum disorders, a measure of subjective well-being should ideally accompany measures of symptom severity and medication side effects. The self-reported 5-item World Health Organization Well-being Index (WHO-5) is a brief, generic, and widely used measure of subjective well-being. However, the structural validity of the WHO-5, namely, whether the individual item scores can be combined to produce a meaningful total score, has not been examined among patients with schizophrenia spectrum disorders. METHOD: Utilizing data from 399 Danish patients with schizophrenia spectrum disorders attending the Psychiatric Services of the Central Denmark Region, we employed Rasch analysis to examine the structural validity (i.e., unidimensionality, overall fit to the Rasch model, and differential item functioning) of the WHO-5. RESULTS: The WHO-5 was found to be unidimensional with no differential item functioning for age, sex, or inpatient/outpatient status. However, in the initial analysis, some misfit to the Rasch model, partially caused by the disordering of response categories, was evident. In adjusted analyses in which the item response categories 2 (Less than half of the time) and 3 (More than half of the time) were merged, overall fit to the model was improved. CONCLUSIONS: When two item response categories were merged, the Danish version of the WHO-5 was found to be structurally valid for patients with schizophrenia spectrum disorders. This suggests that the WHO-5 holds promise as a measure of subjective well-being in this patient population.

Association between lithium treatment and renal, thyroid and parathyroid function: A cohort study of 6659 patients with bipolar disorder.

OBJECTIVES: Although potential adverse effects of lithium treatment on renal and endocrine systems have been extensively investigated, most prior studies are limited by selected populations and short follow-up. METHODS: Within the Psychiatric Services of the Central Denmark Region, we identified all patients with bipolar disorder and ≥1 serum-lithium (se-Li) measurements between January 1, 2013, and July 20, 2022, and reference patients with bipolar disorder matched on age, sex, and baseline creatinine. Outcomes were diagnoses of renal, thyroid and parathyroid disease, and blood tests measuring creatinine, estimated glomerular filtration rate (eGFR), thyroid-stimulating hormone (TSH), parathyroid hormone (PTH) and calcium. Analyses included unadjusted multilevel regression to describe changes in biochemical markers, and adjusted Cox regression to compare rates of disease/biochemical outcomes between lithium users and reference patients. RESULTS: Among 1646 lithium users (median age 36 years, 63% women) and 5013 reference patients, lithium users had decreasing TSH and eGFR, stable PTH, and increasing calcium levels over time. Lithium use was associated with increased rates of renal, thyroid and parathyroid disease, and levels of biochemical markers outside normal ranges (hazard rate ratios: 1.07-11.22), but the absolute number of severe outcomes was low (e.g., chronic kidney disease: N = 10, 0.6%). Notably, the rate of blood testing was substantially higher among lithium users than among reference patients (e.g., mean number of creatinine tests during the second year of follow-up: lithium users = 2.5, reference patients = 1.4). CONCLUSIONS: Severely adverse renal and endocrine outcomes are rare during lithium treatment. Observational studies of long-term lithium treatment are prone to detection bias.

PDZome-wide and structural characterization of the PDZ-binding motif of VANGL2.

VANGL2 is a core component of the non-canonical Wnt/Planar Cell Polarity signaling pathway that uses its highly conserved carboxy-terminal type 1 PDZ-binding motif (PBM) to bind a variety of PDZ proteins. In this study, we characterize and quantitatively assess the largest VANGL2 PDZome-binding profile documented so far, using orthogonal methods. The results of our holdup approach support VANGL2 interactions with a large panel of both long-recognized and unprecedented PDZ domains. Truncation and point mutation analyses of the VANGL2 PBM establish that, beyond the strict requirement of the P-0 / V521 and P-2 / T519 amino acids, upstream residues, including E518, Q516 and R514 at, respectively, P-3, P-5 and P-7 further contribute to the robustness of VANGL2 interactions with two distinct PDZ domains, SNX27 and SCRIBBLE-PDZ3. In agreement with these data, incremental amino-terminal deletions of the VANGL2 PBM causes its overall affinity to progressively decline. Moreover, the holdup data establish that the PDZome binding repertoire of VANGL2 starts to diverge significantly with the truncation of E518. A structural analysis of the SYNJ2BP-PDZ/VANGL2 interaction with truncated PBMs identifies a major conformational change in the binding direction of the PBM peptide after the P-2 position. Finally, we report that the PDZome binding profile of VANGL2 is dramatically rearranged upon phosphorylation of S517, T519 and S520. Our crystallographic approach illustrates how SYNJ2BP accommodates a S520-phosphorylated PBM peptide through the ideal positioning of two basic residues, K48 and R86. Altogether our data provides a comprehensive view of the VANGL2 PDZ network and how this network specifically responds to the post-translation modification of distinct PBM residues. These findings should prove useful in guiding future functional and molecular studies of the key PCP component VANGL2.

Treatment of schizophrenia evaluated via the pharmacopsychometric triangle-An integrative approach with emphasis on well-being and functioning.

Quantification of treatment response is crucial to optimize outcomes for patients with schizophrenia. In this study, we evaluated the relationship between quantitative measures of clinician-rated symptom severity and self-rated side effects, well-being, and functioning among inpatients with schizophrenia using the six-item version of the Positive and Negative Syndrome Scale (PANSS-6), the Glasgow Antipsychotic Side-effect Scale (GASS), the WHO-Five Well-being Index (WHO-5), and the Sheehan Disability Scale (SDS). All measurements were conducted as close to admission and discharge as possible. Well-being and functioning were found to be most strongly associated with the additive effect of symptoms and side effects, while changes in side effects, well-being, and functioning appeared to be relatively independent from changes in symptom severity. The use of both symptom and side effect measures should inform clinical decision-making in the treatment of schizophrenia, as it has the potential to optimize functioning and well-being.

Lexical stability of psychiatric clinical notes from electronic health records over a decade.

OBJECTIVE: Natural language processing (NLP) methods hold promise for improving clinical prediction by utilising information otherwise hidden in the clinical notes of electronic health records. However, clinical practice - as well as the systems and databases in which clinical notes are recorded and stored - change over time. As a consequence, the content of clinical notes may also change over time, which could degrade the performance of prediction models. Despite its importance, the stability of clinical notes over time has rarely been tested. METHODS: The lexical stability of clinical notes from the Psychiatric Services of the Central Denmark Region in the period from January 1, 2011, to November 22, 2021 (a total of 14,811,551 clinical notes describing 129,570 patients) was assessed by quantifying sentence length, readability, syntactic complexity and clinical content. Changepoint detection models were used to estimate potential changes in these metrics. RESULTS: We find lexical stability of the clinical notes over time, with minor deviations during the COVID-19 pandemic. Out of 2988 data points, 17 possible changepoints (corresponding to 0.6%) were detected. The majority of these were related to the discontinuation of a specific note type. CONCLUSION: We find lexical and syntactic stability of clinical notes from psychiatric services over time, which bodes well for the use of NLP for predictive modelling in clinical psychiatry.

Are informants required to obtain valid ratings on the Positive and Negative Syndrome Scale (PANSS)?

Ratings on the Positive and Negative Syndrome Scale (PANSS) are ideally based on both a patient interview and an informant questionnaire. In research and clinical settings, however, the informant questionnaire is often omitted. This study investigated the consequences of omitting informant information by comparing PANSS ratings of patients with schizophrenia (n = 49 patients, 77 ratings) conducted with and without informant information, respectively. Additionally, changes in symptom severity over time based on ratings with and without informant information were also compared for the full PANSS and the six-item version of the PANSS (PANSS-6). PANSS ratings including informant information were higher than those without, both at the total score and individual item level. Additionally, the full PANSS appeared less "responsive" to baseline-to-endpoint changes for ratings without informant information compared to ratings including informant information, while no differences were found for the PANSS-6.

Initial severity of the Positive and Negative Syndrome Scale (PANSS)-30, its main subscales plus the PANSS-6, and the relationship to subsequent improvement and trial dropout: a pooled participant-level analysis of 18 placebo-controlled risperidone and paliperidone trials.

Greater initial severity on the 30-item Positive and Negative Syndrome Scale (PANSS-30) correlates positively with antipsychotic-placebo separation and trial dropout, but it is unknown whether these associations are present also on PANSS-derived subscales. We assessed the relationship between initial severity and antipsychotic-placebo separation as measured by PANSS-30 and four PANSS symptom subscales: the positive (PANSS-POS), negative (PANSS-NEG), general (PANSS-GEN) and 6-item (PANSS-6) subscales, using patient-level data from 18 placebo-controlled risperidone and paliperidone trials. Analysis of covariance in the intention-to-treat population (last-observation-carried-forward) was used to assess antipsychotic-placebo separation and trial dropout. Across 6685 participants (90% schizophrenia, 10% schizoaffective disorder), the initial severity-by-treatment interaction was statistically significant for PANSS-30 (beta: -0.155; p < 0.001) and all PANSS subscales (beta range: -0.097 to -0.135; p-value range: < 0.001 to 0.002). In all cases, antipsychotic-placebo differences increased with initial severity. Judging by the distribution of relative outcomes (percent remaining symptoms), the interaction was partly explained by an increased chance of responding, but also by larger numerical responses in those who did respond, as initial severity increased. Except for PANSS-NEG, high initial severity on all PANSS scales predicted increased trial dropout, although not statistically significantly so for PANSS-6. In summary, we thus replicate previous findings showing greater initial severity to predict larger antipsychotic-placebo separation and extend these results to four PANSS subscales. For PANSS-POS and PANSS-GEN, but not for PANSS-NEG and PANSS-6, we also replicate the association between initial severity and trial dropout. Patients with low initial negative symptom severity were identified as a group of particular interest for further study since their results diverged most from the average both with regard to antipsychotic-placebo separation (low separation measured by PANSS-NEG) and trial dropout (high level).