A Nationwide Target Trial Emulation Assessing the Risk of Antidepressant-Induced Mania Among Patients With Bipolar Depression.

OBJECTIVE: Antidepressants are commonly used to treat bipolar depression but may increase the risk of mania. The evidence from randomized controlled trials, however, is limited by short treatment durations, providing little evidence for the long-term risk of antidepressant-induced mania. The authors performed a target trial emulation to compare the risk of mania among individuals with bipolar depression treated or not treated with antidepressants over a 1-year period. METHODS: The authors emulated a target trial using observational data from nationwide Danish health registers. The study included 979 individuals with bipolar depression recently discharged from a psychiatric ward. Of these, 358 individuals received antidepressant treatment, and 621 did not. The occurrence of mania and bipolar depression over the following year was ascertained, and the intention-to-treat effect of antidepressants was analyzed by using Cox proportional hazards regression with adjustment for baseline covariates to emulate randomized open-label treatment allocation. RESULTS: The fully adjusted analyses revealed no statistically significant associations between treatment with an antidepressant and the risk of mania in the full sample (hazard rate ratio=1.08, 95% CI=0.72-1.61), in the subsample concomitantly treated with a mood-stabilizing agent (hazard rate ratio=1.16, 95% CI=0.63-2.13), and in the subsample not treated with a mood-stabilizing agent (hazard rate ratio=1.16, 95% CI=0.65-2.07). Secondary analyses revealed no statistically significant association between treatment with an antidepressant and bipolar depression recurrence. CONCLUSIONS: These findings suggest that the risk of antidepressant-induced mania is negligible and call for further studies to optimize treatment strategies for individuals with bipolar depression.

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.

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.

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.

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.

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.

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.

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).

Revisiting the association between treatment with antidepressants and mania: A nationwide within-individual study of 3554 patients with bipolar disorder.

INTRODUCTION: Antidepressants are commonly used "off-label" for bipolar depression, despite concerns over the risk of potential treatment-emergent mania (or "manic switch"). Treatment-emergent mania is difficult to study with adequate power in clinical trials as it requires a large group of participants and long follow-up. Therefore, naturalistic register-based studies have been applied to assess this phenomenon. Here, we aimed to replicate previous findings and address key methodological limitations that were not previously taken into account. METHODS: We utilized data from nationwide Danish health registries to identify patients with bipolar disorder treated with an antidepressant, either with or without concomitant treatment with a mood stabilizer (drug treatment proxied via redeemed prescriptions). We plotted the incidence of manic and depressive episodes relative to the initiation of antidepressant treatment and compared the incidence of mania in the period prior to and following initiation of antidepressant treatment (within-individual design). RESULTS: In 3554 patients with bipolar disorder initiating treatment with an antidepressant, the number of manic episodes peaked approximately 3 months prior to initiation of antidepressant treatment, and the number of depressive episodes peaked around the initiation of antidepressant prescription. This temporal pattern suggests that antidepressants were used to treat post-manic depression. CONCLUSION: Within-individual designs do not control sufficiently for confounding by indication, when the treatment indication is time-varying. Thus, results from prior within-individual studies of antidepressant treatment in the context of bipolar disorder may be invalid due to time-varying confounding by indication.

Psychometric validation of the full Yale food addiction scale for children 2.0 among adolescents from the general population and adolescents with a history of mental disorder.

OBJECTIVE: Food addiction is a phenotype characterised by an addiction-like attraction to highly processed foods. Adolescence is a sensitive period for developing addictive disorders. Therefore, a valid measure to assess food addiction in adolescents is needed. Accordingly, the aim of the study was to establish a categorical scoring option for the full version of the Yale Food Addiction Scale for Children 2.0 (YFAS-C 2.0), and to psychometrically validate the full YFAS-C 2.0. METHOD: The data stem from the Food Addiction Denmark (FADK) Project. Random samples of 3750 adolescents from the general population aged 13-17 years, and 3529 adolescents with a history mental disorder of the same age were invited to participate in a survey including the full version of the YFAS-C 2.0. A confirmatory factor analysis was carried out and the weighted prevalence of food addiction was estimated. RESULTS: The confirmatory factor analysis of the YFAS-C 2.0 supported a one-factor model in both samples. The weighted prevalence of food addiction was 5.0% in the general population, and 11.2% in the population with a history of mental disorder. CONCLUSIONS: The full version of the YFAS-C 2.0 is a psychometrically valid measure for assessing clinically significant food addiction in adolescents.

Food addiction is strongly associated with type 2 diabetes.

BACKGROUND & AIMS: Individuals can develop an addiction-like attraction towards highly processed foods, which has led to the conceptualization of food addiction, a phenotype linked to obesity. In this study, we investigated whether food addiction is associated with type 2 diabetes (T2D). METHODS: 1699 adults from the general population and 1394 adults from a population with clinically verified mental disorder completed a cross-sectional survey including the Yale Food Addiction Scale 2.0. Logistic regression was employed to examine the association between food addiction and T2D, the latter operationalized via Danish registers. RESULTS: Food addiction was strongly associated with T2D in the general population (adjusted odds ratio (AOR) = 6.7) and among individuals with mental disorder (AOR = 2.4) in a dose-response-like manner. CONCLUSION: This is the first study to demonstrate a positive association between food addiction and T2D in a general population sample. Food addiction may be a promising target for prevention of T2D.

Risk factors for suicide among patients having received treatment with electroconvulsive therapy: A nationwide study of 11,780 patients.

OBJECTIVES: Despite the putative anti-suicidal effect of electroconvulsive therapy (ECT), patients receiving ECT remain at high risk of dying from suicide due to the severity of their underlying mental illness. We aimed to quantify this risk and to identify risk factors for suicide among patients receiving ECT. METHODS: Using nationwide Danish registers, we identified all patients that initiated ECT between 2006 and 2016. These patients were matched on sex and age to 10 reference individuals from the general Danish population. Firstly, we compared 2-year suicide risk between patients initiating ECT and the matched reference individuals. Secondly, we investigated if any patient characteristics were associated with suicide following ECT via Cox proportional hazards regression. RESULTS: A total of 11,780 patients receiving ECT and 117,800 reference individuals were included in the analyses. Among the patients receiving ECT, 161 (1.4%) died from suicide within two years. Compared to the reference individuals, patients having received ECT had a substantially elevated suicide rate (Hazard rate ratio (HRR) = 44.48, 95%CI = 31.12-63.59). Among those having received ECT, the following characteristics were associated with suicide: Male sex (adjusted HRR (AHRR) = 2.32, 95%CI = 1.63-3.30), medium-term higher education (AHRR = 2.64, 95%CI = 1.57-4.44); long-term higher education (AHRR = 3.16, 95%CI = 1.68-5.94), history of substance use disorder (AHRR = 1.51, 95%CI = 1.01-2.26) and history of intentional self-harm/suicide attempt (AHRR = 4.18, 95%CI = 2.76-6.32). CONCLUSIONS: Those who are male, have obtained medium-/long-term higher education, or have a history of substance use disorder or intentional self-harm/suicide attempt, are at particularly elevated risk of suicide following ECT. These findings may guide clinical initiatives to reduce suicides.