Antipsychotic drugs in first-episode psychosis: A target trial emulation in the FEP-CAUSAL Collaboration.

Good adherence to antipsychotic therapy helps prevent relapses in First Episode Psychosis (FEP). We used data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts to emulate a target trial comparing antipsychotics with treatment discontinuation as the primary outcome. Other outcomes included all-cause hospitalization. We benchmarked our results to estimates from EUFEST, a randomized trial conducted in the 2000s. We included 1097 patients with a psychotic disorder and less than 2 years since psychosis onset. Inverse probability weighting was used to control for confounding. The estimated 12-month risks of discontinuation for aripiprazole, first-generation agents, olanzapine, paliperidone, quetiapine, and risperidone (95% CI) were: 61.5% (52.5-70.6), 73.5% (60.5-84.9), 76.8% (67.2-85.3), 58.4% (40.4-77.4), 76.5% (62.1-88.5), and 74.4% (67.0-81.2) respectively. Compared with aripiprazole, the 12-month risk differences (95% CI) were -15.3% (-30.0, 0.0) for olanzapine, -12.8% (-25.7, -1.0) for risperidone, and 3.0% (-21.5, 30.8) for paliperidone. The 12-month risks of hospitalization were similar between agents. Our estimates support use of aripiprazole and paliperidone as first-line therapies for FEP. Benchmarking yielded similar results for discontinuation and absolute risks of hospitalization as in the original trial, suggesting that data from the FEP-CAUSAL Collaboration data sufficed to approximately remove confounding for these clinical questions.

Making causal inferences from transactional data: A narrative review of opportunities and challenges when implementing the target trial framework.

The target trial framework has emerged as a powerful tool for addressing causal questions in clinical practice and in public health. In the healthcare sector, where decision-making is increasingly data-driven, transactional databases, such as electronic health records (EHR) and insurance claims, present an untapped potential for answering complex causal questions. This narrative review explores the potential of the integration of the target trial framework with real-world data to enhance healthcare decision-making processes. We outline essential elements of the target trial framework, and identify pertinent challenges in data quality, privacy concerns, and methodological limitations, proposing solutions to overcome these obstacles and optimize the framework's application.

Melancholic features and treatment outcome to selective serotonin reuptake inhibitors in major depressive disorder: A re-analysis of the STAR*D trial.

BACKGROUND: Melancholia has been positioned as a qualitatively different form of Major Depressive Disorder (MDD). Some studies have suggested that melancholic MDD patients may show lower remission when receiving treatment with Selective Serotonin Reuptake Inhibitors, but this has not yet been explored in large, representative samples of MDD. METHODS: We used data from the STAR*D, a multisite randomized controlled trial (n = 4041). We defined melancholia status through the BA Melancholia Empirical Index, constructed using items from the Inventory of Depressive Symptomatology (IDSC). The main outcome of interest was symptomatic remission defined as a Quick Inventory of Depressive Symptoms (Clinician version) (QIDS-C) below or equal to 5. Inverse probability weighting was used to control for confounding. RESULTS: 3827 patients were eligible for this study. Melancholic patients were more likely to be unemployed, never married, to self-report an African American race, and to have a higher depressive severity. The adjusted 4-month probability of remission was 26.9 % (22.0, 45.5) for melancholic and 53.8 % (53.2, 58.5), for nonmelancholic patients. Compared with nonmelancholic, the difference in 4-month probability of remission was -26.9 % (-37.0, -15.6). Results were consistent across sensitivity analyses. LIMITATIONS: Items from IDSC were used as a surrogate measure of the BA Melancholia Index, and extrapolation of the results to agents other than citalopram and to psychotic MDD patients requires caution. CONCLUSIONS: Melancholic MDD patients showed lower probabilities of remission at 4-months receiving treatment with citalopram. The results of this study show how validly subtyping episodes could contribute to the personalized treatment of depression.

New antipsychotic prescription and recurrent infections among adult sepsis survivors: A population-based cohort study.

PURPOSE: Antipsychotic agents, which may increase the risk of infection through dopaminergic dysregulation, are prescribed to a fraction of patients following critical illness. We compared the rate of recurrent sepsis among patients who filled a prescription for antipsychotics with high- or low-D2 affinity. METHODS: Population-based cohort with active comparator design. We included sepsis survivors older than 65 years with intensive care unit admission and new prescription of antipsychotics in Ontario 2008-2019. The primary outcome were recurrent sepsis episodes within 1 year of follow-up. Patients who filled a prescription within 30 days of hospital discharge for high-D2 affinity antipsychotics (e.g., haloperidol) were compared with patients who filled a prescription within 30 days of hospital discharge for low-D2 affinity antipsychotics (e.g., quetiapine). Multivariable zero-inflated Poisson regression models with robust standard errors adjusting for confounding at baseline were used to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI). RESULTS: Overall, 1879 patients filled a prescription for a high-D2, and 1446 patients filled a prescription for a low-D2 affinity antipsychotic. Patients who filled a prescription for a high-D2 affinity antipsychotic did not present a higher rate of recurrent sepsis during 1 year of follow-up, compared with patients who filled a prescription for a low-D2 affinity antipsychotic (IRR: 1.12; 95% CI: 0.94, 1.35). CONCLUSIONS: We did not find conclusive evidence of a higher rate of recurrent sepsis associated with the prescription of high-D2 affinity antipsychotics (compared with low-D2 affinity antipsychotics) by 1 year of follow-up in adult sepsis survivors with intensive care unit admission.

Clinical characteristics and outcomes of people with severe mental disorders hospitalized due to COVID-19: A nationwide population-based study.

OBJETIVE: Hospitalized COVID-19 patients with severe mental illness (SMI) have worse outcomes than counterparts without SMI. Barriers in access to acute care medical procedures among SMI patients may partially explain this phenomenon. Here, we examined differences in critical care admission and in-hospital mortality between hospitalized COVID-19 patients with and without SMI. METHODS: This population-based study used Spain's nationwide electronic health records. Based on International Classification Diseases, Tenth Revision, ICD-10-CM codes, we identified all patients aged ≥15 years hospitalized due to COVID-19 between July 1st-December 31st, 2020, and compared patients with and without SMI in terms of (i) critical care admission and (ii) in-hospital mortality - overall and stratified by age. We used logistic regression models including sex, age, and comorbidity burden as measured by Charlson Comorbidity Index Score as covariates. RESULTS: Of 118,691 hospital admissions due to COVID-19 of people aged ≥15 years, 1512 (1.3%) included a diagnosis of SMI. Compared to non-SMI patients, SMI patients had higher in-hospital mortality (OR,95%CI: 1.63,1.42-1.88) and were less frequently admitted to critical care (OR,95%CI: 0.70,0.58-0.85). Admission to critical care in SMI patients was lower than for non-SMI counterparts only among individuals aged ≥60 years. The magnitude of the difference in in-hospital mortality between SMI and non-SMI patients decreased as age increased. CONCLUSIONS: Individuals with SMI had reduced critical care admission and increased in-hospital mortality compared non-SMI counterparts, suggesting that differences in delivery of acute care medical procedures may partially explain higher risk of negative outcomes among COVID-19 patients with SMI.

Suicide Following the COVID-19 Pandemic Outbreak: Variation Across Place, Over Time, and Across Sociodemographic Groups. A Systematic Integrative Review.

PURPOSE OF REVIEW: To systematically examine changes in suicide trends following the initial COVID-19 outbreak, focusing on geographical and temporal heterogeneity and on differences across sociodemographic subgroups. RECENT FINDINGS: Of 46 studies, 26 had low risk of bias. In general, suicides remained stable or decreased following the initial outbreak - however, suicide increases were detected during spring 2020 in Mexico, Nepal, India, Spain, and Hungary; and after summer 2020 in Japan. Trends were heterogeneous across sociodemographic groups (i.e., there were increases among racially minoritized individuals in the US, young adults and females across ages in Japan, older males in Brazil and Germany, and older adults across sex in China and Taiwan). Variations may be explained by differences in risk of COVID-19 contagion and death and in socioeconomic vulnerability. Monitoring geographical, temporal, and sociodemographic differences in suicide trends during the COVID-19 pandemic is critical to guide suicide prevention efforts.

Estimating the per-protocol effect of lithium on suicidality in a randomized trial of individuals with depression or bipolar disorder.

BACKGROUND: The CSP590 randomized trial was designed to estimate the effect of lithium on suicidality. After a third of the intended number of participants were enrolled, the hazard ratio of suicidality was 1.10 (95% CI: 0.77, 1.55). Based on this, the trial was stopped for futility. However, only 17% of patients adhered to the specified protocol. AIMS: The objective was to estimate the per-protocol effect of lithium on suicidality, that is, the effect of adhering to the treatment strategies as specified in the protocol. METHODS: We stopped individuals' follow-up if/when they showed evidence of nonadherence. We then conducted the analysis in the restricted sample, adjusting for prognostic factors that predict adherence via inverse probability weighting. The primary outcome was the 12-month risk of suicidality (including death from suicide, suicide attempt, interrupted attempt, hospitalization specifically to prevent suicide). RESULTS: The estimated 12-month risk of suicidality was 18.8% for lithium, and 24.3% for placebo. The risk ratio was 0.78 (95% CI: 0.43, 1.37) and the risk difference -5.5 percentage points (95% CI: -17.5, 5.5). Results were consistent across sensitivity analyses. CONCLUSIONS: With one-third of the targeted sample size, lithium effects (compared with placebo) ranging between a 17.5% reduction and a 5.5% increase in the risk of suicidality were highly compatible with the data. Thus, a protective effect of lithium on suicidality among patients with bipolar disorder or major depressive disorder cannot be ruled out. Trials should incorporate adequate per-protocol analyses into the decision-making processes for stopping trials for futility.

Emulating a Target Trial of Dynamic Treatment Strategies for Major Depressive Disorder Using Data From the STAR∗D Randomized Trial.

BACKGROUND: Clinical guidelines recommend adding a second drug for patients with major depressive disorder who have a partial response and switching antidepressants for those who show no response or intolerance. This guidelines-based strategy was compared with other strategies for the management of unresponsive depression. METHODS: A total of 1436 individuals experiencing treatment failure with citalopram and still requiring antidepressant therapy were identified in the STAR∗D (Sequenced Treatment Alternatives to Relieve Depression) trial. A (hypothetical) target trial was then designed and emulated. The following strategies for decision making were compared: sequential monotherapy, sequential dual non-selective serotonin reuptake inhibitor therapy (SD), and a guidelines-based strategy. The primary outcome was symptomatic remission defined as a Hamilton Depression Rating Scale score ≤7 or 2 consecutive scores ≤5 on the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated. Secondary outcomes were serious events (hospitalizations, suicide, and mortality). Inverse probability weighting was used to control for possible confounding. RESULTS: A total of 971 patients were eligible for our emulation. Patients initiating SD had the lowest levels of depression at baseline. The estimated 9-month probability of remission was 43.5% for the sequential monotherapy group, 47.6% for the SD group, and 53.2% for the guidelines-based strategy group. Compared with the sequential monotherapy group, the difference in 9-month probability of remission was -4.2% (95% CI, -15.6 to 4.6) for the SD group and -9.7% (-19.3 to 1.9) for the guidelines-based strategy group. The 9-month relative risks of remission were 1.09 (0.90 to 1.38) and 1.22 (0.96 to 1.46), respectively. Results were consistent across sensitivity analyses. The 9-month relative risks of serious events were 0.77 (0.38 to 1.40) and 0.62 (0.33 to 1.00), respectively. CONCLUSIONS: Using the guidelines-based strategy was associated with an increased probability of remission and a lower risk of serious adverse events. The potential implications are substantial given the large number of patients experiencing treatment failure to antidepressants.

Are all antidepressants the same? The consumer has a point.

BACKGROUND: Although a large variety of antidepressants agents (AD) with different mechanisms of action are available, no significant differences in efficacy and safety have been shown. However, there have been few attempts to incorporate data on subjective experiences under different AD. METHOD: We conducted a qualitative and quantitative analysis of the posts from the website www.askapatient.com from different AD. We reviewed a random sample of 1000 posts. RESULT: After applying the inclusion and exclusion criteria, we included a final sample of 450 posts, 50 on each of the most used AD: sertraline, citalopram, paroxetine, escitalopram, fluoxetine, venlafaxine, duloxetine, mirtazapine, and bupropion. Bupropion, citalopram, and venlafaxine had the higher overall satisfaction ratings. Sertraline, paroxetine, and fluoxetine had high reports of emotional blunting, while bupropion very few. Overall satisfaction with AD treatment was inversely associated with the presence of the following side-effects: suicidality, irritability, emotional blunting, cognitive disturbances, and withdrawal symptoms. After adjusting for confounders, only emotional blunting was shown to be more frequently reported by users of serotonergic agents, as compared to non-serotoninergic agents. CONCLUSION: This research points out that the subjective experience of patients under treatment should be taken into consideration when selecting an AD as differences between agents were evident. In contrast to the more frequent treatment decisions, users might prefer receiving a non-serotoninergic agent over a serotonergic one due to their lower propensity to produce emotional blunting.

"Real-world" first-episode psychosis care in Massachusetts: Lessons learned from a pilot implementation of harmonized data collection.

AIM: Increasing evidence points to the value of coordinated specialty care (CSC) for early intervention in psychotic disorders. This report characterizes clinical and socio-demographic features of patients at CSC programs in Massachusetts (MA), assessed by a standardized battery incorporated into "real-world" clinical care. METHODS: The MA psychosis network for early treatment developed a pilot battery to coordinate assessments across six CSC clinics. Programs reported baseline, 6-month, and 12-month data from a sample of 287 patients with intake dates ranging from April 2015 to December 2020. RESULTS: Patients showed improvements in functioning, emergency service use and several symptom domains at 6 and 12 months. Missing data proved to be a limitation. CONCLUSIONS: Patients improved on several meaningful domains within the first year of CSC treatment. Future implementation efforts in cross-program data collection should consider strategies to circumvent limitations related to heterogeneity between clinics, patient discharge and clinics' capacity for data collection.

Impact of the COVID-19 Pandemic on the Employment and Educational Outcomes of Individuals in a First-Episode Psychosis Clinic.

OBJECTIVE: A central objective of early psychosis therapy is to restore social functioning (e.g., through employment and education). Employment and educational outcomes during the COVID-19 pandemic were examined in a well-defined cohort of patients receiving care in an early psychosis clinic. METHODS: Data were extracted from the electronic health records of 128 patients receiving care at McLean Hospital's first-episode psychosis (FEP) clinic between January 1 and September 21 in 2019 and 2020. Using a generalized linear model with a Gaussian distribution and robust standard errors, the authors compared the average changes in the weekly employment and education proportions before and after COVID-19 lockdowns with the same changes in 2019. RESULTS: Employment losses among patients with FEP were greater than among the general population and persisted through the end of follow-up. In 2020, average employment after a stay-at-home order was instituted was 33% lower than before the order compared with the change in employment during the same period in 2019. The effect was stronger among men and those who identified as non-White, were age <21 years, or did not have a college education. Although educational engagement recovered in the fall of 2020, it still remained below the 2019 levels. CONCLUSIONS: Employment disruptions were major and persistent among the FEP population, which might affect short- and long-term outcomes. Innovative approaches are needed to help patients transition to remote employment, file unemployment claims, and use online hiring platforms to ameliorate the indirect effects of the COVID-19 pandemic.

Risk of Overdose Associated With Co-prescription of Antipsychotics and Opioids: A Population-Based Cohort Study.

The US FDA issued a black-box warning against co-prescription of antipsychotic (AP) agents and opioids due to the risk of respiratory depression, but evidence on the comparative safety of sedating vs nonsedating APs is lacking. We classified APs as sedating (eg, quetiapine, olanzapine, and chlorpromazine) and nonsedating (eg, aripiprazole, haloperidol, and risperidone) based on their affinity to the histamine-1 neuroreceptor (Ki < or ≥20, respectively) and sought to compare the rate of overdose between patients using sedating vs nonsedating APs plus opioids. We constructed a population-based cohort nested in the IBM MarketScan database (2004-2017). Patients with concomitant use of sedating APs and prescription opioids ("exposed") were 1:1 matched to patients with concomitant use of nonsedating APs and prescription opioids ("referent") based on the propensity score (PS). The primary outcome was any hospitalization or emergency department visit due to an overdose within 30 days. The final cohort comprised 62 604 exposed and an equal number of PS-matched reference patients. Characteristics of matched exposed and reference patients were similar. There were 178 overdose events among the exposed (35.3 events per 1000 person-years [PY]) vs 133 among the reference group (26.4 events per 1000 PY), for an adjusted hazard ratio of 1.34 (95% CI: 1.07-1.68). This finding was consistent across sensitivity and subgroup analyses. Among patients receiving prescription opioids, concomitant use of sedating APs was associated with an increased risk of overdose compared with nonsedating APs. Caution is required when co-prescribing opioids and APs. If co-prescription is needed, choosing a nonsedating agent should be preferred whenever possible given the clinical context.

Antipsychotic Use and Bloodstream Infections Among Adult Patients With Chronic Obstructive Pulmonary Disease: A Cohort Study.

OBJECTIVE: Mounting evidence suggests that antipsychotics may have immunomodulatory effects, but their impact on disseminated infections remains unknown. This study thus sought to estimate the effect of antipsychotic treatment on the occurrence of bloodstream infection during long-term follow-up in adult patients with chronic obstructive pulmonary disease. METHODS: This retrospective cohort study, with new user and active comparator design, included adult patients seen from January 2008 to June 2018 in a tertiary teaching hospital in Buenos Aires, Argentina. New users of antipsychotic drugs were compared to new users of any benzodiazepine. The primary outcome of interest was incident bloodstream infection at 1 year of follow-up. Propensity score methods and a Cox proportional hazards model were used to adjust for baseline confounding. RESULTS: A total of 923 patients were included in the present analysis. Mean (SD) age was 75.0 (9.8) years, and 51.9% of patients were female. The cumulative incidence of bloodstream infections at 1 year was 6.0% and 2.3% in the antipsychotic and benzodiazepine groups, respectively. Antipsychotic use was associated with a higher risk of bloodstream infections during the first year of follow-up (hazard ratio [HR] = 2.41; 95% CI, 1.13 to 5.14) compared to benzodiazepine use. Antipsychotics with high dopamine receptor affinity presented greater risk than less selective agents (HR = 5.20; 95% CI, 1.53 to 17.67). CONCLUSIONS: Antipsychotic use is associated with bloodstream infections during the first year of follow-up in adult patients with chronic obstructive pulmonary disease. Further studies are warranted to confirm our findings and evaluate this effect in a broader population of patients.

Manic morbidity and executive function impairment as determinants of long-term psychosocial dysfunction in bipolar disorder.

OBJECTIVE: In this study, we aimed to evaluate the role of cognitive performance and measures of clinical course-including both syndromal and subsyndromal symptomatology-as determinants of the functional outcome of patients with Bipolar Disorder (BD) during a mean follow-up period of more than 4 years. METHODS: Seventy patients with euthymic BD completed a neurocognitive battery at study entry. Clinical course was assessed prospectively for a period longer than 48 months by two measures: time spent ill (documented using a modified life charting technique) and density of affective episodes (defined as the number of depressive and hypo/manic episodes per year of follow-up). Psychosocial functioning was assessed during euthymia using the Functioning Assessment Short Test (FAST) total score at the end of follow-up period. RESULTS: Baseline deficits in phonological fluency, a measure of executive functions (ß = -2.49; 95% CI = -3.98, -0.99), and density of hypo/manic episodes during follow-up (ß = 6.54; 95% CI = 0.43, 12.65) were independently associated with FAST total score at the end of study. CONCLUSIONS: Although interrelated, manic morbidity and executive function impairments independently contribute to long-term psychosocial dysfunction in BD and could be potential targets of intervention.

The Risk of Overdose With Concomitant Use of Z-Drugs and Prescription Opioids: A Population-Based Cohort Study.

OBJECTIVE: The Z-drugs (zolpidem, zopiclone, zaleplon) are widely used to treat insomnia in patients receiving prescription opioids, and the risk of overdose resulting from this coprescription has not been explored. The authors compared the rates of overdose among patients using opioids plus Z-drugs and patients using opioids alone. METHODS: All individuals 15 to 85 years of age receiving prescription opioids, regardless of underlying indication and without evidence of cancer, were identified in the IBM MarketScan database (2004-2017). Patients with concomitant exposure to Z-drugs were matched 1:1 to patients with exposure to prescription opioids alone based on opioid prescribed, morphine equivalents, number of days' supply, and hospitalization within the past 30 days. The primary outcome was any hospitalization or emergency department visit due to an overdose within 30 days, using an intention-to-treat approach. Fine stratification on the propensity score was used to control for confounding. RESULTS: A total of 510,529 exposed patients and an equal number of matched reference patients were analyzed. There were 217 overdose events among the exposed patients (52.5 events per 10,000 person-years) and 57 events among the reference patients (14.4 events per 10,000 person-years), corresponding to an unadjusted hazard ratio of 3.67 (95% CI=2.75, 4.90). Using fine stratification on the propensity score (c-statistic: 0.66), the adjusted hazard ratio was 2.29 (95% CI=1.79, 2.91). Results were consistent across sensitivity analyses. CONCLUSIONS: Among patients receiving prescription opioids, after controlling for all confounding factors, concomitant treatment with Z-drugs was associated with a substantial relative increase in the risk of overdose. The potential implications are significant given the large number of opioid-treated patients receiving Z-drugs.

Effects of COVID-19 pandemic on mental health outcomes in a cohort of early psychosis patients.

AIM: To evaluate the impact of the COVID-19 pandemic on clinical outcomes, we used data from Electronic Health Records from 128 patients receiving care at a First Episode Psychosis clinic. METHODS: Rates of admission or emergency room (ER) visits from January 2020 to July 2020 were analysed using difference-in-difference regression. We used the same weeks in 2019 to control for seasonality. RESULTS: We found 17 hospitalizations or ER visits between 1 January 2020 and 13 March 2020 (incidence rate: 71.4 events/1000 person-weeks) and 6 between 14 March 2020 and 20 June 2020 (incidence rate: 18.5 events/1000 person-weeks) for an incidence rate ratio of 0.26. The severity of presentation worsened after transition to telemedicine. No signs of significant interruptions of care were found. CONCLUSIONS: We report that patients have avoided accessing higher levels of care, except in extreme cases. We argue that this is not a sustainable trajectory and that public health actions are required.

Association of depressive symptoms with health care utilization in older adults: Longitudinal evidence from the Survey of Health, Aging, and Retirement in Europe.

OBJECTIVES: Many older adults with depression do not receive adequate treatment. Differences in treatment utilization may reflect the heterogeneous nature of depression, encompassing multiple distinct symptoms. We assessed whether depressive symptoms are differentially associated with subsequent health care utilization with respect to three outcomes as follows: (1) contact with a medical doctor (MD), (2) depression-specific treatment, and (3) inpatient psychiatric admission. METHODS/DESIGN: Longitudinal analyses were based on data from three follow-up cycles conducted between 2004 and 2013 among 53,139 participants from the Survey of Health, Aging, and Retirement in Europe. Depressive symptoms were self-reported at baseline of each follow-up cycle using the 12-item EURO-D scale. Health care utilization was self-reported at the end of each follow-up cycle. RESULTS: After adjustment for sex, age, country of interview, follow-up time, educational attainment, presence of a partner in household, body-mass index, the number of chronic diseases, disability, average/prior frequency of contact with an MD, and all other depressive symptoms, people with more frequent contact with an MD had most often reported sleep problems (IRR = 1.10) and fatigue (IRR = 1.10), followed by sad/depressed mood, tearfulness, concentration problems, guilt, irritability, and changes in appetite. Those treated for depression had most often reported sad/depressed mood (OR = 2.18) and suicidal ideation (OR = 1.72), but also sleep problems, changes in appetite, fatigue, concentration problems, hopelessness, and irritability. Sad/depressed mood (OR = 2.87) was also associated with psychiatric inpatient admission. Similarly to other outcomes, appetite change, fatigue, and sleep problems were associated with inpatient admission. CONCLUSIONS: Specific symptoms of depression may determine utilization of different types of health care among elderly.