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.

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.

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.

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.

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.

Personality Disturbances in Melancholic and Nonmelancholic Unipolar Major Depression: A Systematic Review and Meta-Analysis.

Although melancholic depression has been associated with a more adequate premorbid personality style, the empirical evidence supporting this statement is inconclusive. We conducted a systematic review and meta-analyzed studies comparing the presence of personality disturbances in melancholic and nonmelancholic subtypes of major depressive disorder (MDD). We defined a) a continuous outcome, defining personality traits as a dimensional construct, and b) a dichotomous outcome, defined as the presence/absence of personality disorders (PD). We also evaluated the role of potential moderators. Our results showed significantly higher levels of neuroticism and interpersonal sensitivity, and a higher likelihood of presenting a PD in nonmelancholic depression. No significant differences were found for extraversion. The scarcity of studies and high heterogeneity were among our limitations. In conclusion, personality disturbances seem to be overrepresented in nonmelancholic MDD. The assessment of personality disturbances can be useful in clinical practice and in the study of MDD heterogeneity.

The Effect of Antipsychotic Treatment on Recurrent Venous Thromboembolic Disease: A Cohort Study.

BACKGROUND: Venous thromboembolism (VTE) represents a major cause of morbidity and mortality worldwide. Antipsychotic treatment is associated with an increased risk of thromboembolic disease, an effect that seems to be constant across the spectrum of distinct agents. This study sought to delineate the effect of new antipsychotic use on the risk of recurrent thromboembolic events after a first episode of either deep venous thrombosis or pulmonary embolism. METHODS: This cohort study, conducted between January 2010 and June 2017, was based on a prospectively collected database of adult patients with VTE. The main exposure was the new onset of antipsychotic treatment after having a first episode of venous thromboembolic disease. The primary outcome was defined as recurrent VTE, either deep venous thrombosis or pulmonary embolism, during long-term follow-up. The composite of all-cause mortality and recurrent VTE served as the secondary outcome. An inverse probability weighted multivariable Cox proportional hazards model was fitted to adjust for measured confounding and competing risks. RESULTS: One thousand one hundred three patients were included in the present analysis, of whom 136 were identified as new users of antipsychotic agents. A total of 67% of patients were currently treated with full-dose anticoagulation at baseline. No association was found between the new use of antipsychotic agents and recurrent VTE during follow-up (adjusted hazard ratio (HR) = 1.08; 95% CI, 0.38-3.08). However, the use of these agents was associated with a 63% increased risk of recurrent VTE or all-cause mortality (adjusted HR = 1.63; 95% CI, 1.26-2.10). CONCLUSIONS: The use of antipsychotic agents among patients with a first episode of VTE and full-dose anticoagulation was not associated with an increased risk of recurrent thromboembolic events. However, antipsychotic treatment was associated with a higher risk of both VTE and all-cause mortality. Further studies are warranted to confirm these findings.

Melancholia: An Attempt at Definition Based on a Review of Empirical Data.

We sought to identify clinical features that best discriminate melancholia from nonmelancholic depressive conditions. An extensive review of studies using latent factor models that identified a melancholic depression dimension/factor was undertaken. Clinical variables extracted from these studies were analyzed in terms of their contribution to a diagnosis of melancholia and their consistency across studies. Psychomotor retardation and mood nonreactivity were the most relevant clinical features for the identification of melancholic depressions. Other clinical features commonly described as weighted to melancholia, such as anhedonia, psychomotor agitation, late insomnia, or appetite/weight loss, seemed less useful in distinguishing these subtypes of depression. Study results are considered in relation to the potential limitations of current operational definitions of melancholia, and how symptom sets could be modified.

Social cognition in first episode bipolar disorder patients.

The aim of this study was to describe theory of mind (ToM) and emotional processing (EP) functioning in recently diagnosed bipolar disorder (BD). We evaluated 26 first episode BD (mean age 22.9 ±â€¯7.4) and 26 controls matched on age, gender, education, and premorbid intelligence. A significant poorer performance on the capacity of patients to infer other's intentions (cognitive ToM) that was partially independent from neurocognitive deficits (p < 0.01) as well as a lower recognition of fear was observed among patients. No significant association between any of these deficits and psychosocial functioning emerged in multivariate regression analyses.

A quantitative review on outcome-to-antidepressants in melancholic unipolar depression.

The aim of this study was to explore outcome to antidepressants profile in melancholic unipolar depression. We conducted a systematic review of electronic databases and meta-analysis of randomized and nonrandomized trials comparing: 1) outcome to antidepressants and placebo between melancholic and non-melancholic depression; 2) outcome to different antidepressant classes in melancholic depression. Two outcomes were considered: clinical remission and response. Significant lower odds of remission to antidepressants in melancholic than in non-melancholic depressions were found. Although no significant differences were observed in the response to antidepressants between both subtypes of depression, those with melancholic features had lower odds of response to placebo. Finally, treatment of melancholic depression with serotonin reuptake inhibitors was associated with lower odds of remission compared with tricyclic antidepressants, and similar outcome compared with venlafaxine. Melancholia seems to show a differential pattern of outcome to antidepressants, which could be clinically valuable for a better implementation of personalized medicine of depression. Due to several limitations, further research is needed to support these preliminary findings.

All-cause mortality in older adults with affective disorders and dementia under treatment with antipsychotic drugs: A matched-cohort study.

We aimed to compare the mortality risk between patients with affective disorders and dementia under treatment with antipsychotics. To do this, a matched-cohort study based on an electronic database of a tertiary teaching hospital in Argentina was performed. Antipsychotic exposure was defined as any antipsychotic drug initiated by the patient. Primary outcome was defined as all-cause mortality during the 5-year follow-up period. To estimate the association between baseline diagnosis (affective disorders vs. dementia) and all-cause mortality, we used a multivariate generalized linear model with robust standard errors. Of 1008 eligible patients, 114 age-matched pairs were included in the present study. The primary event occurred in 23 patients (20%) and 17 patients (15%) in the dementia and affective disorder group respectively. In the adjusted model, the risk of all cause mortality for the affective disorders group was 0.92 times the risk for the dementia group (95%CI, 0.54-1.59, p = 0.77). In conclusion, older patients with affective disorders starting antipsychotic treatment presented with a similar risk of all-cause mortality during the 5-year follow-up when compared to older patients with dementia who were also initiating either typical or atypical antipsychotic medications. Closer medical attention to older patients with mental conditions under antipsychotic treatment remains warranted.

Neurocognitive functioning in first-episode Bipolar Disorder: Relationship with functional status.

BACKGROUND: The aim of this study was to assess if an association between neurocognitive deficits and psychosocial functioning exists in first-episode BD patients. METHODS: Twenty-five euthymic first-episode BD patients and thirty-seven healthy controls were recruited. History of suicide attempts, psychiatric comorbidities, pharmacological exposure, and previous depressive episodes were investigated. Performances on neurocognitive domains (verbal memory, attention, processing speed, and executive functions) as well as a measure of psychosocial functioning were used as outcomes. RESULTS: First-episode BD patients showed medium-to-large size deficits on measures of attention, processing speed, and executive functions. A significant association between verbal memory and psychosocial functioning at the moment of BD diagnosis was detected (beta coefficient -3.9, IC 95% -6.7 to -1.2, p < 0.01). CONCLUSIONS: A relationship between cognitive performance at the moment of BD diagnosis and psychosocial functioning was detected. Possible therapeutic implications of this finding are discussed.

Antipsychotic Use Among Adult Outpatients and Venous Thromboembolic Disease: A Retrospective Cohort Study.

BACKGROUND: Treatment with antipsychotic (AP) agents is associated with incident thromboembolic events. However, the underpinnings of this association remain unknown. We sought to evaluate the effect of AP agents-categorized by their metabolic/sedative and hyperprolactinemia adverse effect profile-on the risk of venous thromboembolic disease during long-term follow-up. METHODS: A retrospective cohort study of adult patients initiating AP treatment for the first time was conducted. Primary outcome was defined as the time to venous thromboembolism (VTE) (either deep venous thrombosis or acute pulmonary embolism). Antipsychotic agents were categorized by their risk (high vs low) of either drug-induced (a) sedation/metabolic adverse event or (b) hyperprolactinemia. We used a propensity score-adjusted Cox proportional hazards model to control for confounding. FINDINGS: One thousand eight patients (mean age, 72.4 y) were followed for a median of 36 months. Incident VTE occurred in 6.25% of patients, corresponding to an incidence rate of 184 cases per 10,000 person-years. We found no difference in the hazard of VTE during follow-up between high- and low-risk groups (hazard ratio, 1.23 [95% confidence interval, 0.74-2.04] for drug-induced sedation/metabolic adverse event risk categories, and hazard ratio 0.81 [95% confidence interval, 0.50-1.35] for high versus low hyperprolactinemia risk). CONCLUSIONS: These results suggest that the risk of thromboembolic events in older adults who started AP treatment for the first time does not seem to be related to these drugs' risk of either sedation/metabolic adverse events or hyperprolactinemia. However, VTE remains a common problem in this subgroup of patients.

Long-Term Antipsychotic Use and Major Cardiovascular Events: A Retrospective Cohort Study.

OBJECTIVE: Chronic treatment with antipsychotics may result in both metabolic side effects and cardiovascular disease. Our aim was to evaluate the effect of antipsychotic medications categorized by their metabolic side effect profiles as low, intermediate, or high risk on major cardiovascular events. METHODS: A retrospective cohort study was conducted in adult outpatients aged 30 years or older initiating antipsychotic treatment from 2002 to 2007. Antipsychotic medications were divided into 3 groups (low-, intermediate-, and high-risk) according to the severity of their side-effect profiles in developing metabolic abnormalities associated with cardiovascular disease. The primary outcome measure was the time to the composite of acute myocardial infarction, acute coronary syndrome, ischemic stroke, peripheral artery disease, or a new revascularization procedure. Inverse probability weighting of a marginal structural Cox model was used to adjust for confounding. RESULTS: A total of 1,008 patients were included (mean age = 72.4 years, median follow-up = 36.5 months), and 19.6% of patients experienced the primary outcome. The adjusted hazard ratios of a major cardiovascular event for patients in the high- or intermediate-risk medication groups compared to the low-risk group were 2.82 (95% CI, 1.57-5.05) and 2.57 (95% CI, 1.43-4.63), respectively. CONCLUSIONS: Older adult patients under antipsychotic regimens with high or intermediate risk of metabolic side effects may face a higher incidence of major cardiovascular events than those under a low-risk regimen during long-term follow-up.

Neuropsychological profiles of major depressive disorder and bipolar disorder during euthymia. A systematic literature review of comparative studies.

Bipolar disorder and major depressive disorder have been shown to be associated with neurocognitive abnormalities during periods of clinical remission. However, at present, there is no consensus on whether these disorders have distinctive cognitive profiles. The aim of this study was to provide an updated systematic review of studies comparing neuropsychological functioning between bipolar disorder and major depressive disorder during remission. Main findings included the following: 1) no differences regarding performances in measures of attention and processing speed, executive functions and theory of mind were found between both patient groups and 2) regarding verbal memory, preliminary evidence points towards a more defective performance in patients with bipolar disorder than those with major depressive disorder. However, several variables with negative impact on cognition (medication status, age at onset, premorbid IQ, bipolar subtype, among others) were not adequately controlled in most studies. In conclusion, evidence from studies exploring neuropsychological profiles in bipolar disorder and major depressive disorder could not provide clues to differentiate these mood disorders. Larger studies with adequate control of confounding variables would be necessary to elucidate if the finding of more defective verbal memory performance in bipolar disorder is truly explained by distinct underlying mechanisms.