Patient trust in the use of machine learning-based clinical decision support systems in psychiatric services: A randomized survey experiment.

BACKGROUND: Clinical decision support systems (CDSS) based on machine-learning (ML) models are emerging within psychiatry. If patients do not trust this technology, its implementation may disrupt the patient-clinician relationship. Therefore, the aim was to examine whether receiving basic information about ML-based CDSS increased trust in them. METHODS: We conducted an online randomized survey experiment in the Psychiatric Services of the Central Denmark Region. The participating patients were randomized into one of three arms: Intervention = information on clinical decision-making supported by an ML model; Active control = information on a standard clinical decision process, and Blank control = no information. The participants were unaware of the experiment. Subsequently, participants were asked about different aspects of trust and distrust regarding ML-based CDSS. The effect of the intervention was assessed by comparing scores of trust and distrust between the allocation arms. RESULTS: Out of 5800 invitees, 992 completed the survey experiment. The intervention increased trust in ML-based CDSS when compared to the active control (mean increase in trust: 5% [95% CI: 1%; 9%], p = 0.0096) and the blank control arm (mean increase in trust: 4% [1%; 8%], p = 0.015). Similarly, the intervention reduced distrust in ML-based CDSS when compared to the active control (mean decrease in distrust: -3%[-1%; -5%], p = 0.021) and the blank control arm (mean decrease in distrust: -4% [-1%; -8%], p = 0.022). No statistically significant differences were observed between the active and the blank control arms. CONCLUSIONS: Receiving basic information on ML-based CDSS in hospital psychiatry may increase patient trust in such systems.

Associations between physical diseases and subsequent mental disorders: a longitudinal study in a population-based cohort.

People with physical diseases are reported to be at elevated risk of subsequent mental disorders. However, previous studies have considered only a few pairs of conditions, or have reported only relative risks. This study aimed to systematically explore the associations between physical diseases and subsequent mental disorders. It examined a population-based cohort of 7,673,978 people living in Denmark between 2000 and 2021, and followed them for a total of 119.3 million person-years. The study assessed nine broad categories of physical diseases (cardiovascular, endocrine, respiratory, gastrointestinal, urogenital, musculoskeletal, hematological and neurological diseases, and cancers), encompassing 31 specific diseases, and the subsequent risk of mental disorder diagnoses, encompassing the ten ICD-10 groupings (organic, including symptomatic, mental disorders; mental disorders due to psychoactive substance use; schizophrenia and related disorders; mood disorders; neurotic, stress-related and somatoform disorders; eating disorders; personality disorders; intellectual disabilities; pervasive developmental disorders; and behavioral and emotional disorders with onset usually occurring in childhood and adolescence). Using Poisson regression, the overall and time-dependent incidence rate ratios (IRRs) for pairs of physical diseases and mental disorders were calculated, adjusting for age, sex and calendar time. Absolute risks were estimated with the Aalen-Johansen estimator. In total, 646,171 people (8.4%) were identified as having any mental disorder during follow-up. All physical diseases except cancers were associated with an elevated risk of any mental disorder. For the nine broad pairs of physical diseases and mental disorders, the median point estimate of IRR was 1.51 (range: 0.99-1.84; interquartile range: 1.29-1.59). The IRRs ranged from 0.99 (95% CI: 0.98-1.01) after cancers to 1.84 (95% CI: 1.83-1.85) after musculoskeletal diseases. Risks varied over time after the diagnosis of physical diseases. The cumulative mental disorder incidence within 15 years after diagnosis of a physical disease varied from 3.73% (95% CI: 3.67-3.80) for cancers to 10.19% (95% CI: 10.13-10.25) for respiratory diseases. These data document that most physical diseases are associated with an elevated risk of subsequent mental disorders. Clinicians treating physical diseases should constantly be alert to the possible development of secondary mental disorders.

Risk of Suicide Across Medical Conditions and the Role of Prior Mental Disorder.

Importance: According to the World Health Organization, more than 700 000 individuals worldwide die by suicide each year. Medical conditions likely increase the risk of suicide. Objective: To (1) provide age- and sex-specific pairwise estimates of the risk of suicide across a comprehensive range of medical conditions, (2) investigate whether there is a dose-response-like relationship at play (ie, the higher the disability burden due to medical morbidity, the higher the risk of suicide), and (3) determine if the risk of suicide with medical conditions is particularly pronounced among those who had mental disorder preceding the medical conditions. Design, Setting, and Participants: This cohort study was an observational study of population-based data for all individuals living in Denmark at some point between 2000 and 2020. The data analysis took place from September 2023 to May 2024. Exposures: Thirty-one specific medical conditions as well as prior mental disorder. Main Outcomes and Measures: The main outcome was suicide. Associations between the 31 specific medical conditions, nested within 9 categories, and suicide were examined via Poisson regression, yielding incidence rate ratios (IRRs). Subsequent analyses included an interaction term to assess whether a previous hospital-treated mental disorder modified the associations. Finally, the association between the disability burden of medical conditions and suicide was examined for those with and without prior mental disorder, respectively. Results: A total of 6 635 857 individuals (3 337 613 females and 3 298 244 males) were included in the analyses of the associations between medical conditions and suicide. Except for endocrine disorders, all categories of medical conditions were associated with a statistically significant increased risk of suicide (which was most pronounced for gastrointestinal conditions [IRR, 1.7; 95% CI,1.5-1.8], cancer [IRR, 1.5; 95% CI, 1.4-1.6], and hematological conditions [IRR, 1.5; 95% CI, 1.3-1.6]). Interaction between mental disorder and individual medical conditions did not seem to play a major role for suicide risk. For those without but not for those with mental disorder, there was a dose-response-like relationship between the disability burden of medical conditions and suicide. Conclusions and Relevance: Medical conditions are generally associated with increased risk of suicide in a dose-response-like manner. Individuals with hospital-treated mental disorder appear to be at such elevated risk of suicide that additional disability associated with medical conditions has little impact in this regard.

Brief report: ADHD Rating Scale-IV (parent/caregiver-report) norms for young Danish schoolchildren.

OBJECTIVE: The Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) assesses ADHD symptoms in children and adolescents. The original United States norms comprise percentiles. Yet, no Nordic percentile norms exist, and only T-scores, which (often falsely) assume normally distributed data, are currently available. Here, we for the first time provide Danish percentile norms for children aged 6-9 based on parent/caregiver-reports, and illustrate the potential consequences of T-scores when derived based on the expected skewed distribution of an ADHD scale in the population. MATERIALS AND METHODS: The sample comprised 1895 Danish schoolchildren (879 girls and 1016 boys) in 1st, 2nd, or 3rd grade from the general population. Their parents/caregivers completed the ADHD-RS-IV. Sex and age differences were investigated, percentiles were derived based on the observed score distributions, and for comparison, T-scores > 70 were estimated, which are expected to identify the top 2.3% under the assumption of normality. RESULTS: Boys were rated to have higher ADHD-RS-IV scores than girls except on the impulsivity score. No age effects were found on the majority of scores. Sex-stratified and unisex percentiles (80, 90, 93, 98) were reported. The distribution of ADHD-RS-IV scores were highly skewed. T-score cutoffs identified a significantly higher proportion of and about twice as many children as having elevated ADHD symptoms than expected (4.3-5.2% vs. 2.3%). CONCLUSIONS: ADHD-RS-IV (parent/caregiver-report) percentile norms for young Danish schoolchildren are now available for future reference. The use of percentiles is considered appropriate given the skewed score distribution and since T-scores appear to over-identify children as having clinically elevated ADHD symptoms.

Clinical and sociodemographic characteristics associated with relapse following electroconvulsive therapy for bipolar disorder.

OBJECTIVES: Electroconvulsive therapy (ECT) is an effective treatment for bipolar disorder, but relapse following a successful ECT series is common. We aimed to identify clinical and sociodemographic characteristics associated with the risk of relapse following ECT in bipolar disorder. METHODS: Using data from nationwide Danish registers, we identified all patients receiving their first ECT series with an indication diagnosis of bipolar disorder between 2006 and 2018. We then followed these patients for relapse, defined as either psychiatric admission or a new ECT series, for 6 months following ECT. Associations between clinical and sociodemographic characteristics and relapse were examined via multivariable Cox proportional-hazards regression, yielding adjusted hazard rate ratios (aHRR). RESULTS: Of the 1473 patients receiving ECT for bipolar disorder (62% females, mean age = 53 years), 34% met the relapse criterion. The following characteristics were associated with an elevated risk of relapse; age <40 (aHRR = 1.54, 95% CI = 1.05-2.26); being a pensioner (aHRR = 1.73, 95% CI = 1.29-2.32), indication diagnosis for ECT being psychotic mania (aHRR = 1.63, 95% CI = 1.16-2.28), psychotic bipolar depression (aHRR = 1.37, 95% CI = 1.06-1.80), mixed episode (aHRR = 1.51, 95% CI = 1.13-2.02), or other bipolar episodes (aHRR = 1.68, 95% CI = 1.28-2.21); and treatment with antipsychotics prior to the course of ECT (aHRR = 1.32, 95% CI = 1.04-1.67). CONCLUSION: Patients with bipolar disorder face a particularly high risk of relapse following ECT if they present with the following characteristics when initiating ECT: age <40, being a pensioner, having received treatment with an antipsychotic before initiating ECT, or having psychotic bipolar depression, psychotic mania, mixed episodes, or other bipolar episodes as the indication for ECT. These findings may guide relapse monitoring following ECT in bipolar disorder.

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.

A target trial emulation comparing the antidepressant effectiveness of selective serotonin reuptake inhibitors (SSRIs) highlighting the importance of patent-related confounding by indication.

BACKGROUND: The comparative effectiveness of selective serotonin reuptake inhibitors (SSRIs) has been subjected to relatively little research. However, a recent study based on target trial emulation suggested that sertraline may be more effective than escitalopram. AIMS: To investigate whether sertraline, citalopram, and escitalopram differ in their effectiveness-assessed via the risk of psychiatric hospital admission and suicide following treatment initiation. The choice to focus on sertraline, citalopram, and escitalopram was made to limit confounding by indication, as the Danish depression treatment guideline from 2007 specifically listed these three SSRIs as first choice. METHOD: We conducted a target trial emulation based on data from Danish registers. We identified all individuals that initiated treatment for depression with sertraline, citalopram, or escitalopram in the period from January 1, 2007, to March 1, 2019. These individuals were followed until psychiatric hospital admission or suicide (separate analyses), death, 1 year after treatment initiation or end of data. Cox proportional hazards regression adjusted for relevant baseline covariates was performed to emulate randomized treatment allocation, comparing the rate of psychiatric hospital admission and suicide for individuals treated with sertraline (used as reference), citalopram or escitalopram, respectively. For escitalopram, we conducted a sensitivity analysis excluding data from the period during which the drug was sold under patent, as the price of the drug during that time likely entailed a different prescription pattern, increasing the risk of ("patent-related") confounding by indication. RESULTS: We identified 56,865, 118,145, and 31,083 individuals initiating treatment with sertraline, citalopram, and escitalopram, respectively. Using sertraline as reference, the adjusted hazard rate ratio (aHRR) for psychiatric admission was 0.98 (95% CI = 0.91-1.05) for citalopram and 1.21 (95% CI = 1.10-1.32) for escitalopram. Notably, in the sensitivity analysis only including patients initiating treatment after the escitalopram patent had expired, the increased risk of psychiatric hospital admission associated with escitalopram treatment was no longer present (aHRR = 0.98, 95% CI = 0.82-1.18). The results of the analyses of suicide were inconclusive, due to few outcome events. CONCLUSIONS: Sertraline, citalopram, and escitalopram do not seem to have differential effectiveness in the treatment of depression. Taking potential patent-related, time varying, confounding by indication (via severity) into account is critical for pharmacoepidemiological studies, including those employing target trial emulation.

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.

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.

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.

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).