Comparative Effectiveness of Antipsychotics for Risk of Attempted or Completed Suicide Among Persons With Schizophrenia

ObjectiveThe objective of our study was to investigate the comparative effectiveness of antipsychotics for the risk of attempted or completed suicide among all patients with schizophrenia in Finland and Sweden. MethodsTwo nationwide register-based cohort studies were conducted, including all individuals with schizophrenia in Finland (n = 61 889) and Sweden (n=29 823). The main exposure was 10 most commonly used antipsychotic monotherapies; also, adjunctive pharmacotherapies were investigated. The main outcome measure was attempted or completed suicide, which was analyzed with within-individual models by comparing use and nonuse periods in the same individual to minimize selection bias. Sensitivity analyses included attempted suicide (hospitalization only) as an outcome. ResultsCompared with no use of antipsychotics, clozapine use was the only antipsychotic consistently associated with a decreased risk of suicidal outcomes. Hazard ratios (HRs) and 95% CIs for attempted or completed suicide were 0.64 (0.49–0.84) in the Finnish cohort and 0.66 (0.43–0.99) in the Swedish cohort. No other antipsychotic was associated with a reduced risk of attempted and/or completed suicide. Benzodiazepines and Z-drugs were associated with an increased risk of attempted or completed suicide (HRs: 1.29–1.30 for benzodiazepines and 1.33–1.62 for Z-drugs). ConclusionClozapine was the only antipsychotic associated with decreased risk of attempted or completed suicide among patients with schizophrenia, and it should be considered as first-line treatment for high-risk patients.     

Association of pharmacological treatments and real-world outcomes in borderline personality disorder

Objective

Most patients with borderline personality disorder (BPD) receive psychopharmacological treatment, but clinical guidelines on BPD lack consensus on the role of pharmacotherapy. We investigated the comparative effectiveness of pharmacological treatments for BPD.

Methods

We identified patients with BPD with treatment contact during 2006–2018 using Swedish nationwide register databases. By leveraging within-individual design, in which each individual was used as their own control to eliminate selection bias, we assessed the comparative effectiveness of pharmacotherapies. For each medication, we calculated the hazard ratios (HRs) for the following outcomes: (1) psychiatric hospitalization and (2) hospitalization owing to any cause or death.

Results

We identified 17,532 patients with BPD (2649 men; mean [SD] age = 29.8 [9.9]). Treatment with benzodiazepines (HR = 1.38, 95% CI = 1.32–1.43), antipsychotics (HR = 1.19, 95% CI = 1.14–124), and antidepressants (HR = 1.18, 95% CI = 1.13–1.23) associated with increased risk of psychiatric rehospitalization. Similarly, treatment with benzodiazepines (HR = 1.37, 95% CI = 1.33–1.42), antipsychotics (HR = 1.21, 95% CI = 1.17–1.26), and antidepressants (HR = 1.17, 95% CI = 1.14–1.21) was associated with a higher risk of all-cause hospitalization or death. Treatment with mood stabilizers did not have statistically significant associations with the outcomes. Treatment with ADHD medication was associated with decreased risk of psychiatric hospitalization (HR = 0.88, 95% CI = 0.83–0.94) and decreased risk of all-cause hospitalization or death (HR = 0.86, 95% CI = 0.82–0.91). Of the specific pharmacotherapies, clozapine (HR = 0.54, 95% CI = 0.32–0.91), lisdexamphetamine (HR = 0.79, 95% CI = 0.69–0.91), bupropion (HR = 0.84, 95% CI = 0.74–0.96), and methylphenidate (HR = 0.90, 95% CI = 0.84–0.96) associated with decreased risk of psychiatric rehospitalization.

Conclusions

ADHD medications were associated with a reduced risk of psychiatric rehospitalization or hospitalization owing to any cause or death among individuals with BPD. No such associations were found for benzodiazepines, antidepressants, antipsychotics, or mood stabilizers.     

Psychotic Disorders in Adolescence and Later Long-term Exclusion From Education and Employment

Background and hypothesisPsychotic disorders have been associated with not being in education, employment, and training (NEET). There is a lack of knowledge on the importance of risk markers for NEET among people with psychotic disorders and what rehabilitation they receive.Study designWe based our research on the register-based 1987 Finnish Birth Cohort study, which included all live births in Finland during that year. The study cohort were 288 people who had been diagnosed with psychotic disorders during 2004–2007, when they were 16–20 year old, and 55 883 who had not. We looked at the national register data for those subjects in 2008–2015, when they were 20–28 year old, and compared any associations between sociodemographic factors and NEET status.Study resultsNEET for more than 5 year affected 2.2% of those without psychosis, 35.8% of those with any nonaffective psychotic disorder, and 57.0% of those with schizophrenia or schizoaffective disorders. Family-related risk factors were weaker predictors of long-term NEET in subjects with psychotic disorders than other cohort members. Having a psychotic disorder plus long-term NEET was associated with not applying for upper secondary education, not finishing upper secondary education, parents receiving welfare benefits, being diagnosed with schizophrenia or schizoaffective disorders and being hospitalized for psychosis. Only 24.3% with psychotic disorders had participated in vocational rehabilitation.ConclusionsA diagnosis of psychosis in adolescence is independently associated with serious long term functional disability. Among those with psychotic disorders, educational problems are markers for adverse labor market outcomes. Despite this, vocational rehabilitation is seldom provided.     

Women with Schizophrenia-Spectrum Disorders After Menopause: A Vulnerable Group for Relapse

Background and HypothesisThroughout the life stages of women with schizophrenia-spectrum disorders (SSD), lower estrogen levels are associated with more severe disease course. At perimenopause in the mid-forties, estrogen levels decline to remain persistently low after menopause. This period is hypothesized to increase relapse risk and reduce antipsychotic effectiveness in preventing relapse.Study DesignThe cohort of persons with schizophrenia/schizoaffective disorder was identified from Finnish nationwide registers (N = 61 889) and stratified by sex and age <45 vs. ≥45 years. Hospitalizations for psychosis were defined per 5-year age group during the follow-up 1996–2017. Risk of psychosis hospitalization (Adjusted Hazard Ratio, aHR) was assessed using within-individual design, by comparing antipsychotic monotherapy use to nonuse periods in the same individuals for seven dose categories in defined daily doses (DDDs/day).ResultsStarting at age 45–50, women were consistently more often hospitalized for psychosis than their male peers. Women ≥45 had significantly higher aHRs than women <45 at antipsychotic monotherapy >0.6 DDDs/day, and than men at >1.1 DDDs/day. This female-specific age-dependent decrease in effectiveness was present for clozapine doses >0.6 DDDs/day, olanzapine doses >1.4 DDDs/day, and for specific doses of quetiapine (0.9–1.1 DDDs/day) and risperidone (0.6–0.9 DDDs/day).ConclusionsWhile younger women have a lower risk of relapse and generally need a lower antipsychotic dose to prevent rehospitalization than men, antipsychotic effectiveness declines in women after the age of 45. Starting in mid-forties, older women with SSD should be regarded as a vulnerable group that deserve special attention.     

Risk Factors,Incidence, and Outcomes of Neuroleptic Malignant Syndrome on Long-Acting Injectable vs Oral Antipsychotics in a Nationwide Schizophrenia Cohort

IntroductionLong-acting injectable antipsychotics (LAIs) are associated with multiple positive outcomes in psychosis, but it is unclear whether LAIs are associated with worse outcomes if neuroleptic malignant syndrome (NMS), a potentially lethal adverse effect, occurs.MethodsWe used nationwide and nationally representative databases of healthcare encounters in Finland to study the incidence and outcome predictors of NMS in patients diagnosed with schizophrenia/schizoaffective disorder between January 01, 1972 and December 31, 2017. Using a nested case-control design, we also explored differences by antipsychotic formulation (LAI vs oral antipsychotic [OAP]) and class (first-generation antipsychotic [FGA] vs second-generation antipsychotic [SGA]).ResultsOne hundred seventy-two NMS cases and 1441 sex-, age-, and diagnosis-matched controls were included (age = 58.8 ± 13.1 years, males = 59.9%). Incidence of NMS was 1.99 (1.98–2.00) per 10 000 person-years. The likelihood of developing NMS did not differ by antipsychotic formulation (adjusted odds ratio [aOR]: 0.89, 95% confidence intervals [95% CI]: 0.59–1.33, for LAIs vs OAPs) or class (FGA-OAP vs SGA-OAP [aOR: 1.08, 95% CI: 0.66–1.76], FGA-LAI [aOR: 0.89, 95% CI: 0.52–1.53], SGA-LAI [aOR: 1.35, 95% CI: 0.58–3.12]). NMS risk factors included antipsychotic treatment change: increased number (odds ratios [OR]: 5.00, 95% CI: 2.56–9.73); decreased number/switch (OR: 2.43, 95% CI: 1.19–4.96); higher antipsychotic dose (>2DDDs–OR: 3.15, 95% CI: 1.61–6.18); co-treatment with anticholinergics (OR: 2.26, 95% CI: 1.57–3.24), lithium (OR: 2.16, 95% CI: 1.30–3.58), benzodiazepines (OR: 2.02, 95% CI: 1.44–3.58); and comorbid cardiovascular disease (OR: 1.73, 95% CI: 1.22–2.45). Within 30 days, 4.7% of cases with NMS died (15.1% within 1 year) without differences by antipsychotic formulation. NMS reoccurred in 5 of 119 subjects (4.2%), after a median = 795 (range = 77–839) days after rechallenge with antipsychotics.ConclusionNMS remains a potentially life-threatening risk, yet these results should further contribute to mitigate concerns about LAI safety regarding NMS onset or outcomes, including mortality.     

Hospital Admission With Infection During Childhood and Risk for Psychotic Illness—A Population-based Cohort Study

A growing body of literature suggests that exposure to infections, particularly maternal infections, during pregnancy confers risk for later development of psychotic disorder. Though brain development proceeds throughout childhood and adolescence, the influence of infections during these ages on subsequent psychosis risk is insufficiently examined. The aim of this study was to investigate the potential association between infections during childhood and nonaffective psychoses in a large population-based birth cohort with follow up long enough to include peak incidence of nonaffective psychosis. We included all individuals born in Sweden between 1973 and 1985, (N = 1172879), with follow up on first time inpatient care with nonaffective psychosis from age 14 years until 2006, (N = 4638). Following adjustment for differences in sex, socioeconomic status, family history of psychosis, and hospital admissions involving noninfectious, nonpsychiatric care, we observed a small but statistically significant association between hospital admissions for infections, in general, throughout childhood (0–13 years) and a later diagnosis of nonaffective psychosis, hazard ratio (HR) = 1.10 (95% CI 1.03–1.18), and this association seemed to be driven by bacterial infection, HR = 1.23 (95% CI 1.08–1.40). Bacterial infections and central nervous system infections during preadolescence (10–13 years) conferred the strongest risk, HR 1.57 (95% CI 1.21–2.05) and HR 1.96 (95% CI 1.05–3.62), respectively. Although preadolescence appeared to be a vulnerable age period, and bacterial infection the most severe in relation to psychosis development, the present findings can also indicate an increased susceptibility to hospital admission for infections among children who will later develop nonaffective psychosis due to social or familial/genetic factors.Key words: psychosis, prenatal, schizophrenia, epidemiology, cohort study     

Optimal Doses of Specific Antipsychotics for Relapse Prevention in a Nationwide Cohort of Patients with Schizophrenia

Background and HypothesisOptimal doses of most antipsychotics in the maintenance treatment of schizophrenia are unknown. We aimed to study the risk of severe relapse indicated by rehospitalization for different dose categories of 15 most frequently used antipsychotics in monotherapy in Finland. Study MethodsWe studied the risk of rehospitalization (Adjusted Hazard Ratio, aHR) associated with six antipsychotic monotherapy dose categories (as time-varying dose, measured in defined daily dose, DDDs/day) in a nationwide cohort of persons diagnosed with schizophrenia (n = 61 889), using within-individual analyses to eliminate selection bias. Study ResultsAmong the 15 most widely used antipsychotics, 13 had a U- or J-shaped dose-response curve, showing the lowest risks of relapse for doses of 0.6–<1.1 DDDs/day vs nonuse of antipsychotics. The exceptions were oral perphenazine (aHR = 0.72, 95% CI = 0.68–0.76, <0.6 DDDs/day), and olanzapine-long-acting injectable (LAI), which had the lowest aHR of any antipsychotic (aHR = 0.17, 95% CI = 0.11–0.25, 1.4–<1.6 DDDs/day). Certain risperidone and perphenazine doses <0.9 DDD/day were associated with 21%–45% lower risk of rehospitalization (P < .001) than the standard dose of 0.9–1.1 DDD/day (ie, 5 mg for risperidone and 30 mg for perphenazine). ConclusionsFor most antipsychotics, the risk of severe relapse was the lowest during use of standard dose. Our results suggest that olanzapine LAI is highly effective in dose ranges >0.9 DDD/day, and especially at 1.4–<1.6 DDDs/day (405 mg/4 weeks) associated with substantially lower risk of rehospitalization than any dose of any other antipsychotic. The current WHO standard dose definitions appear to be clearly too high for perphenazine and somewhat too high for risperidone.     

Clozapine Is Better Tolerated in Younger Patients: Risk Factors for Discontinuation from a Nationwide Database in Japan

Objective The effectiveness of clozapine is clearly superior to other antipsychotics in the treatment of refractory schizophrenia. Clozapine leads to various side effects, and therefore many patients are forced to discontinue. In this study, we analyzed the registry database of all cases in Japan to identify risk factors for discontinuation of clozapine. Methods The Clozaril patient monitoring service^® (CPMS) database from July 31, 2009 to January 26, 2020 was acquired. We defined the following exclusion criteria: patients who had ever taken clozapine by a non-CPMS method, such as an individual import or clinical trial, patients who did not receive clozapine after being enrolled in CPMS, and patients with initial doses other than 12.5 mg (outside the current protocol). Therefore, all patients in this study are new users. Multivariate Cox regression analysis was used to investigate independent risk factors associated with time to discontinuation of clozapine. Results We identified 8,263 patients as the study population. Clozapine discontinuation was significantly associated with age 40 and older [hazard ratio (HR)=1.66, p<0.001], intolerance to olanzapine (HR=1.31, p=0.018), previous treatment with clozapine (HR=1.30, p=0.001), and leukocyte counts <6,000/mm³ (HR=1.24, p<0.001). The Kaplan-Meier curves for clozapine discontinuation by age group revealed that older age at the time of clozapine introduction tended to have lower continuation rates. Conclusion Careful administration is important because patients with these factors have a high risk of discontinuation. In addition, the initiation of clozapine during the younger period was more effective and more tolerated.     

Antipsychotics Use Is Associated With Greater Adherence to Cardiometabolic Medications in Patients With Schizophrenia: Results From a Nationwide,Within-subject Design Study

BackgroundPeople with schizophrenia/schizoaffective disorder (schizophrenia) die early, largely due to cardiovascular-related mortality. Antipsychotics are associated with lower mortality. We aimed to explore whether antipsychotic use can reduce discontinuation of medications for cardiovascular risk factors and diseases (“cardiometacolic drugs”), using a within-study design controlling for subject-related factors.MethodsPersons diagnosed with schizophrenia between 1972 and 2014, aged <65 years at cohort entry were identified in Finnish national databases. Four subcohorts were formed based on cardiometabolic drug use during the follow-up period, 1996–2017, namely statin (n = 14,047), antidiabetic (n = 13,070), antihypertensive (n = 17,227), and beta-blocker (n = 21,464) users. To control for subject-related factors, including likelihood of adherence as a trait characteristic, we conducted a within-subject study comparing the risk of discontinuation of each cardiometabolic drug during periods on vs off antipsychotics within each subject. We also accounted for number of psychiatric and nonpsychiatric visits in sensitivity analyses.ResultsIn 52,607 subjects with schizophrenia, any antipsychotic use vs nonuse was associated with decreased discontinuation risk of antidiabetics (adjusted hazard ratio [aHR] = 0.56, 95% confidence interval [CI] = 0.47–0.66), statins (aHR = 0.61, 95%CI = 0.53–0.70), antihypertensives (aHR = 0.63, 95%CI = 0.56–0.71), and beta-blockers (aHR = 0.79, 95%CI = 0.73–0.87). Antipsychotics ranking best for discontinuation of all cardiometabolic drug categories were clozapine (aHR range = 0.34–0.55), followed by olanzapine (aHR = 0.43–0.71). For statins, aHRs ranged from aHR = 0.30 (95%CI = 0.09–0.98) (flupentixol-long-acting injectable (LAI) to aHR = 0.71 (95%CI = 0.52–0.97) (risperidone-LAI), for anti-diabetic medications from aHR = 0.37 (95%CI = 0.28–0.50) (clozapine) to aHR = 0.70 (95%CI = 0.53–0.92) (quetiapine), for antihypertensives from aHR = 0.14 (95%CI = 0.04–0.46) (paliperidone-LAI) to aHR = 0.69 (95%CI = 0.54–0.88) (perphenazine), for beta-blockers from aHR = 0.55 (95%CI = 0.48–0.63) (clozapine) to aHR = 0.76 (95%CI = 0.59–0.99) (perphenazine-LAI). The decreased risk of discontinuation associated with antipsychotic use somewhat varied between age strata. Sensitivity analyses confirmed main findings.DiscussionIn this national database within-subject design study, current antipsychotic use was associated with substantially decreased risk of discontinuation of statins, anti-diabetics, antihypertensives, and beta-blockers, which might explain reduced cardiovascular mortality observed with antipsychotics in people with schizophrenia.     

Comparative Effectiveness of Risperidone Long-Acting Injectable vs First-Generation Antipsychotic Long-Acting Injectables in Schizophrenia: Results From a Nationwide,Retrospective Inception Cohort Study

Objective: To compare in a generalizable sample/setting objective outcomes in patients receiving first-generation antipsychotic long-acting injectables (FGA-LAIs) or risperidone-LAI (RIS-LAI). Methods: Nationwide, retrospective inception cohort study of adults with International Classification of Diseases-10 schizophrenia using Danish registers from 1995 to 2009 comparing outcomes between clinician’s/patient’s choice treatment with FGA-LAIs or RIS-LAI. Primary outcome was time to psychiatric hospitalization using Cox-regression adjusting for relevant covariates. Secondary outcomes included time to all-cause discontinuation and psychiatric hospitalization in patients without LAI possession gap >28 days, and number of bed-days after psychiatric hospitalization. Results: Among 4532 patients followed for 2700 patient-years, 2078 received RIS-LAI and 2454 received FGA-LAIs (zuclopenthixol decanoate = 52.2%, perphenazine decanoate = 37.2%, haloperidol decanoate = 5.0%, flupenthixol decanoate = 4.4%, fluphenazine decanoate = 1.3%). RIS-LAI was similar to FGA-LAIs regarding time to hospitalization (RIS-LAI = 246.2±323.7 days vs FGA-LAIs = 276.6±383.3 days; HR = 0.95, 95% confidence interval (CI) = 0.87–1.03, P = 0.199) and time to all-cause discontinuation (RIS-LAI = 245.8±324.0 days vs FGA-LAIs = 287.0±390.9 days; HR = 0.93, 95% CI = 0.86–1.02, P = 0.116). Similarly, in patients without LAI discontinuation, RIS-LAI and FGA-LAIs did not differ regarding time to hospitalization (RIS-LAI = 175.0±268.1 days vs FGA-LAIs = 210.7±325.3 days; HR = 0.95, 95% CI = 0.86–1.04, P = 0.254). Finally, duration of hospitalization was also similar (incidence rate ratio = 0.97, 95% CI = 0.78–1.19, P = 0.744). Results were unchanged when analyzing only patients treated after introduction of RIS-LAI. Conclusions: In this nationwide cohort study, RIS-LAI was not superior to FGA-LAIs regarding time to psychiatric hospitalization, all-cause discontinuation, and duration of hospitalization. Given the cost of hospitalization and second-generation antipsychotic (SGA)-LAIs, these findings require consideration when making treatment choices, but also need to be balanced with the individual relevance of adverse effects/patient centered outcomes. In future, head-to-head trials and additional nationwide database studies including other SGA-LAIs is needed.Key words: schizophrenia, long-acting injectable, risperidone, first-generation antipsychotics, hospitalization, all-cause discontinuation, cohort study     

Guideline-Concordant Antipsychotic Use and Mortality in Schizophrenia

Objective: To determine if care concordant with 2009 Schizophrenia Patient Outcomes Research Team (PORT) pharmacological recommendations for schizophrenia is associated with decreased mortality. Methods: We conducted a retrospective cohort study of adult Maryland Medicaid beneficiaries with schizophrenia and any antipsychotic use from 1994 to 2004 (N = 2132). We used Medicaid pharmacy data to measure annual and average antipsychotic continuity, to calculate chlorpromazine (CPZ) dosing equivalents, and to examine anti-Parkinson medication use. Cox proportional hazards regression models were used to examine the relationship between antipsychotic continuity, antipsychotic dosing, and anti-Parkinson medication use and mortality. Results: Annual antipsychotic continuity was associated with decreased mortality. Among patients with annual continuity greater than or equal to 90%, the hazard ratio [HR] for mortality was 0.75 (95% confidence interval [CI] 0.57–0.99) compared with patients with annual medication possession ratios (MPRs) of less than 10%. The HRs for mortality associated with continuous annual and average antipsychotic continuity were 0.75 (95% CI 0.58–0.98) and 0.84 (95% CI 0.58–1.21), respectively. Among users of first-generation antipsychotics, doses greater than or equal to 1500 CPZ dosing equivalents were associated with increased risk of mortality (HR 1.88, 95% CI 1.10–3.21), and use of anti-Parkinson medication was associated with decreased risk of mortality (HR 0.72, 95% CI 0.55–0.95). Mental health visits were also associated with decreased mortality (HR 0.96, 95% CI 0.93–0.98). Conclusions: Adherence to PORT pharmacological guidelines is associated with reduced mortality among patients with schizophrenia. Adoption of outcomes monitoring systems and innovative service delivery programs to improve adherence to the PORT guidelines should be considered.Key words: schizophrenia, antipsychotic continuity, mortality     

Risks of all-cause death and completed suicide in patients with schizophrenia/schizoaffective disorder treated with long-acting injectable or oral antipsychotics: A population-based retrospective cohort study in Taiwan

BackgroundLong-acting injectable (LAI) antipsychotics improve medication adherence in patients with schizophrenia and extend the duration of therapeutic drug levels but with administration of an increased dose. Real-world mortality data in patients prescribed LAIs are lacking. We conducted a population-based cohort study to estimate and compare the incidence rates of all-cause death and completed suicide in patients with schizophrenia/schizoaffective disorder exposed to LAIs and oral antipsychotics.MethodsPatients with a diagnosis of schizophrenia/schizoaffective disorder between January 1, 2015 and November 30, 2019 were enrolled from the Taiwan National Health Insurance Research Database and linked to Death Registry records. Eligible patients were new antipsychotic users. Relative risks of death for each antipsychotic compared with oral paliperidone were evaluated using a Cox proportional hazard model adjusted for age, sex, Charlson Comorbidity Index, index year, bipolar or major depressive or other mood disorders, mental disorders due to drug use, and baseline hospitalization frequency.ResultsThere were 228,791.08 person-years of follow-up (mean 2.48 years). The incidence rates of all-cause death in users of LAI paliperidone administered monthly (PP1M) and every 3 months (PP3M) were 7.40/1,000 person-years (95% confidence interval 5.94–9.11) and 9.93 (5.88–15.79), respectively. The incidences of completed suicide were 2.03/1,000 person-years (1.32–2.99) and 3.10 (1.14–6.88), respectively. No significant associations were observed between PP1M and PP3M compared to oral paliperidone in incidences of all-cause death or for completed suicide.DiscussionNo increased risk of all-cause death or completed suicide was observed in users of antipsychotic LAIs, including PP1M and PP3M.     

Elevated gamma‐glutamyl transferase levels are associated with stroke recurrence after acute ischemic stroke or transient ischemic attack

AimsGamma‐glutamyl transferase (GGT) is considered a marker of oxidative stress in vivo. In this study, we aimed to examine the association of serum GGT levels with 3‐month and 1‐year stroke recurrence in patients with acute ischemic stroke or transient ischemic attack (TIA).MethodsWe conducted a large and multicenter cohort study. Participants with ischemic stroke or TIA who had a baseline GGT measurement were enrolled in the China National Stroke Registry‐3 study from August 2015 to March 2018. They were divided into four groups according to sex‐specific quartiles of GGT levels. The effect of GGT on stroke recurrence and other vascular events was examined during the 1‐year follow‐up period. Multivariate Cox regression models were performed to evaluate the association. Discrimination tests were used to examine the degree to which incorporating GGT into the conventional model predicted stroke adverse outcomes.ResultsA total of 12,504 patients were enrolled. At both the 3‐month and 1‐year follow‐ups, patients in the highest quartile group of GGT levels exhibited a higher risk of stroke recurrence [HR 1.32 (95% CI 1.07–1.63), HR 1.34 (95% CI 1.13–1.60)], ischemic stroke [HR 1.37 (95% CI 1.10–1.71), HR 1.37 (95% CI 1.14–1.64)], and combined vascular events [HR 1.34 (95% CI 1.09–1.65), HR 1.34 (95% CI 1.13–1.59)] than those in the lowest quartile group. Moreover, the Kaplan–Meier curves revealed that the incidence rates of stroke adverse outcomes were quite different in the four groups. The highest quartile group showed the highest cumulative incidence, while the lowest quartile group showed the lowest cumulative incidence. After applying discrimination tests, adding GGT into the conventional model resulted in slight improvements in predicting stroke adverse outcomes (NRI: 10%–14%).ConclusionThis study demonstrated that elevated GGT levels were positively associated with an increased risk of stroke adverse outcomes, namely, recurrence, ischemic stroke, and combined vascular events.     

Impact of Comorbid Affective Disorders on Longitudinal Clinical Outcomes in Individuals at Ultra-high Risk for Psychosis

IntroductionDiagnoses of anxiety and/or depression are common in subjects at Ultra-High Risk for Psychosis (UHR) and associated with extensive functional impairment. Less is known about the impact of affective comorbidities on the prospective course of attenuated psychotic symptoms (APS).MethodLatent class mixed modelling identified APS trajectories in 331 UHR subjects assessed at baseline, 6, 12, and 24 months follow-up. The prognostic value of past, baseline, and one-year DSM-IV depressive or anxiety disorders on trajectories was investigated using logistic regression, controlling for confounders. Cox proportional hazard analyses investigated associations with transition risk.Results46.8% of participants fulfilled the criteria for a past depressive disorder, 33.2% at baseline, and 15.1% at one-year follow-up. Any past, baseline, or one-year anxiety disorder was diagnosed in 42.9%, 37.2%, and 27.0%, respectively. Participants were classified into one of three latent APS trajectory groups: (1) persistently low, (2) increasing, and (3) decreasing. Past depression was associated with a higher risk of belonging to the increasing trajectory group, compared to the persistently low (OR = 3.149, [95%CI: 1.298–7.642]) or decreasing group (OR = 3.137, [1.165–8.450]). In contrast, past (OR = .443, [.179–1.094]) or current (OR = .414, [.156–1.094]) anxiety disorders showed a trend-level association with a lower risk of belonging to the increasing group compared to the persistently low group. Past depression was significantly associated with a higher risk of transitioning to psychosis (HR = 2.123, [1.178–3.828]).ConclusionA past depressive episode might be a particularly relevant risk factor for an unfavorable course of APS in UHR individuals. Early affective disturbances may be used to advance detection, prognostic, and clinical strategies.     

Sexual Trauma Increases the Risk of Developing Psychosis in an Ultra High-Risk “Prodromal” Population

Studies indicate a high prevalence of childhood trauma in patient cohorts with established psychotic disorder and in those at risk of developing psychosis. A causal link between childhood trauma and development of psychosis has been proposed. We aimed to examine the association between experience of childhood trauma and the development of a psychotic disorder in a large “Ultra High Risk” (UHR) for psychosis cohort. The data were collected as part of a longitudinal cohort study of all UHR patients recruited to research studies at the Personal Assessment and Clinical Evaluation clinic between 1993 and 2006. Baseline data were collected at recruitment to these studies. The participants completed a comprehensive follow-up assessment battery (mean time to follow-up 7.5 years, range 2.4–14.9 years), which included the Childhood Trauma Questionnaire (CTQ), a self-report questionnaire that assesses experience of childhood trauma. The outcome of interest was transition to a psychotic disorder during the follow-up period. Data were available on 233 individuals. Total CTQ trauma score was not associated with transition to psychosis. Of the individual trauma types, only sexual abuse was associated with transition to psychosis (P = .02). The association remained when adjusting for potential confounding factors. Those with high sexual abuse scores were estimated to have a transition risk 2–4 times that of those with low scores. The findings suggest that sexual trauma may be an important contributing factor in development of psychosis for some individuals.Key words: trauma, psychosis, ultra high risk     

The Effect of Clozapine on Premature Mortality: An Assessment of Clinical Monitoring and Other Potential Confounders

Clozapine can cause severe adverse effects yet it is associated with reduced mortality risk. We test the hypothesis this association is due to increased clinical monitoring and investigate risk of premature mortality from natural causes. We identified 14 754 individuals (879 deaths) with serious mental illness (SMI) including schizophrenia, schizoaffective and bipolar disorders aged ≥ 15 years in a large specialist mental healthcare case register linked to national mortality tracing. In this cohort study we modeled the effect of clozapine on mortality over a 5-year period (2007–2011) using Cox regression. Individuals prescribed clozapine had more severe psychopathology and poorer functional status. Many of the exposures associated with clozapine use were themselves risk factors for increased mortality. However, we identified a strong association between being prescribed clozapine and lower mortality which persisted after controlling for a broad range of potential confounders including clinical monitoring and markers of disease severity (adjusted hazard ratio 0.4; 95% CI 0.2–0.7; p = .001). This association remained after restricting the sample to those with a diagnosis of schizophrenia or those taking antipsychotics and after using propensity scores to reduce the impact of confounding by indication. Among individuals with SMI, those prescribed clozapine had a reduced risk of mortality due to both natural and unnatural causes. We found no evidence to indicate that lower mortality associated with clozapine in SMI was due to increased clinical monitoring or confounding factors. This is the first study to report an association between clozapine and reduced risk of mortality from natural causes.Key words: clozapine, mortality, clinician contact, schizophrenia, schizoaffective disorder, bipolar affective disorder