Neuromelanin-Sensitive MRI as Candidate Marker for Treatment Resistance in First-Episode Schizophrenia.

OBJECTIVE: Markers for treatment resistance in schizophrenia are needed to reduce delays in effective treatment. Nigrostriatal hyperdopaminergic function plays a critical role in the pathology of schizophrenia, yet antipsychotic nonresponders do not show increased dopamine function. Neuromelanin-sensitive MRI (NM-MRI), which indirectly measures dopamine function in the substantia nigra, has potential as a noninvasive marker for nonresponders. Increased NM-MRI signal has been shown in psychosis, but has not yet been assessed in nonresponders. In this study, the authors investigated whether nonresponders show lower NM-MRI signal than responders. METHODS: NM-MRI scans were acquired in 79 patients with first-episode psychosis and 20 matched healthy control subjects. Treatment response was assessed at a 6-month follow-up. An a priori voxel-wise analysis within the substantia nigra tested the relation between NM-MRI signal and treatment response in patients. RESULTS: Fifteen patients were classified as nonresponders and 47 patients as responders. Seventeen patients were excluded, primarily because of medication nonadherence or change in diagnosis. Voxel-wise analysis revealed 297 significant voxels in the ventral tier of the substantia nigra that were negatively associated with treatment response. Nonresponders and healthy control subjects had significantly lower NM-MRI signal than responders. Receiver operating characteristic curve analysis showed that NM-MRI signal separated nonresponders with areas under the curve between 0.62 and 0.85. In addition, NM-MRI signal in patients did not change over 6 months. CONCLUSIONS: These findings provide further evidence for dopaminergic differences between medication responders and nonresponders and support the potential of NM-MRI as a clinically applicable marker for treatment resistance in schizophrenia.

Exploration of symptom dimensions and duration of untreated psychosis within a staging model of schizophrenia spectrum disorders.

AIM: Clinical staging of schizophrenia entails a new method that identifies clusters of symptoms and variation in level of remission, with the goal to create a framework for early intervention. Additionally, duration of untreated psychosis (DUP) may influence symptom severity in the first episode of psychosis (FEP) and could necessitate refining of the staging model. However, consistent evidence concerning variation in symptom severity and DUP between stages is missing. Therefore, we evaluated the clinical validity of the staging model by investigating differences in symptom severity across stages in schizophrenia spectrum disorders. Second, we assessed if a prolonged DUP is associated with higher symptom severity in FEP. METHODS: We performed a cross-sectional study of 291 acutely admitted patients with a schizophrenia spectrum disorder. Patients were assigned to clinical stages following the definition of McGorry. Symptom severity was evaluated with the new DSM-5 Clinician-Rated Dimensions of Psychosis Symptom Severity (CRDPSS). In FEP, we determined the DUP. RESULTS: Significantly higher severity scores of CRDPSS items hallucinations (H = 14.34, df = 4, P-value = .006), negative symptoms (H = 19.678, df = 4, P-value = .001) and impaired cognition (H = 26.294, df = 4, P-value = <.001) were found in more advanced stages of disease. Moreover, patients with FEP and a DUP longer than 1 year showed significantly more severe negative symptoms (U = 314 000, P = .015) compared to patients with a DUP shorter than 1 year. CONCLUSIONS: The present study found supporting evidence for the clinical validity of the staging model in schizophrenia spectrum disorders. In addition, we found support for refining the stage "first episode" with information concerning the DUP.

Staging and profiling for schizophrenia spectrum disorders: Inter-rater reliability after a short training course.

OBJECTIVE: Clinical staging and profiling have been proposed as a new approach in order to refine the diagnostic assessment of schizophrenia spectrum disorders. However, only limited evidence is available for the inter-rater reliability of the clinical staging and profiling model. The aim of the present study was therefore to determine the inter-rater reliability of the clinical staging and profiling model for schizophrenia spectrum disorders, and to investigate whether a short course can improve inter-rater reliability. METHODS: Consecutively recruited inpatients with schizophrenia spectrum disorders were included between January 2015 and January 2016 (study 1), and between March 2018 and October 2018 (study 2). By contrast with the assessors in study 1, all the assessors in study 2 were trained in clinical staging and profiling. We used the clinical staging model proposed by McGorry and identified profile characteristics. Inter-rater reliability was measured using the Intraclass Correlation Coefficient (ICC). RESULTS: The ICC score for clinical staging in study 1 was moderate (0.578). It improved considerably in study 2 (0.757). In general, the ICC scores for the profile characteristics in studies 1 and 2 ranged from poor to sufficient (0.123-0.781). CONCLUSION: This study demonstrated that inter-rater reliability in clinical staging was sufficient after training. However, inter-rater reliability for clinical profile characteristics was highly variable. The general implementation of the clinical staging model for schizophrenia spectrum disorders is therefore feasible but clinical profile characteristics should be used with caution.

Differential effects of nonselective versus selective ß-blockers on cardiac sympathetic activity and hemostasis in patients with heart failure.

UNLABELLED: Carvedilol, a nonselective ß-blocker, may be more effective than the selective ß-blocker metoprolol in reducing the risk of thromboembolic events in heart failure. The aim of this study was, first, to assess whether there is a differential response in cardiac sympathetic activity by (123)I-meta-iodobenzylguanidine ((123)I-MIBG) imaging when either ß-blocker is used. Second, we assessed whether that response correlates with levels of various serum factors that serve as markers for coagulability. METHODS: In this prospective, randomized, open-label crossover study with masked outcome assessments, stable heart failure patients (left ventricular ejection fraction < 40%) homozygous for the Arg16/Gln27 (n = 13) or Gly16/Glu27 haplotype (n = 8) of the ß2-receptor were randomized to equipotent dosages of carvedilol or metoprolol for two 6-wk periods. Primary outcome was sympathetic activity as measured by (123)I-MIBG myocardial washout. Secondary outcomes included markers of hemostasis. RESULTS: (123)I-MIBG cardiac washout was lower during carvedilol than metoprolol treatment (12.9% ± 3.9% vs. 22.1% ± 2.8%, respectively, P = 0.003), irrespective of ß2-adrenergic receptor haplotype. In addition, treatment with carvedilol resulted in a lower von Willebrand factor than did metoprolol (149% ± 13% vs. 157% ± 13%, respectively, P = 0.01), irrespective of ß2-adrenergic receptor haplotype. CONCLUSION: Compared with metoprolol, carvedilol resulted in greater reduction of sympathetic activity after 6 wk of treatment and lower von Willebrand factor concentrations in both Arg16/Gln27 and Gly16/Glu27 individuals. Therefore, carvedilol may reduce the risk of thromboembolic events in patients with heart failure, irrespective of ß2-receptor haplotype status.

Search for HRV-parameters that detect a sympathetic shift in heart failure patients on ß-blocker treatment.

BACKGROUND: A sympathetic shift in heart rate variability (HRV) from high to lower frequencies may be an early signal of deterioration in a monitored patient. Most chronic heart failure (CHF) patients receive ß-blockers. This tends to obscure HRV observation by increasing the fast variations. We tested which HRV parameters would still detect the change into a sympathetic state. METHODS AND RESULTS: ß-blocker (Carvedilol®) treated CHF patients underwent a protocol of 10 min supine rest, followed by 10 min active standing. CHF patients (NYHA Class II-IV) n = 15, 10m/5f, mean age 58.4 years (47-72); healthy controls n = 29, 18m/11f, mean age 62.9 years (49-78). Interbeat intervals (IBI) were extracted from the finger blood pressure wave (Nexfin®). Both linear and non-linear HRV analyses were applied that (1) might be able to differentiate patients from healthy controls under resting conditions and (2) detect the change into a sympathetic state in the present short recordings. Linear: mean-IBI, SD-IBI, root mean square of successive differences (rMSSD), pIBI-50 (the proportion of intervals that differs by more than 50 ms from the previous), LF, HF, and LF/HF ratio. Non-linear: Sample entropy (SampEn), Multiscale entropy (MSE), and derived: Multiscale variance (MSV) and Multiscale rMSSD (MSD). In the supine resting situation patients differed from controls by having higher HF and, consequently, lower LF/HF. In addition their longer range (τ = 6-10) MSE was lower as well. The sympathetic shift was, in controls, detected by mean-IBI, rMSSD, pIBI-50, and LF/HF, all going down; in CHF by mean-IBI, rMSSD, pIBI-50, and MSD (τ = 6-10) going down. MSD6-10 introduced here works as a band-pass filter favoring frequencies from 0.02 to 0.1 Hz. CONCLUSIONS: In ß-blocker treated CHF patients, traditional time domain analysis (mean-IBI, rMSSD, pIBI-50) and MSD6-10 provide the most useful information to detect a condition change.

Time-trends in treatment and cardiovascular events in patients with heart failure: a pharmacosurveillance study.

AIMS: We assessed, in patients with a first hospitalization for heart failure (HF), the temporal relationship of the incidence of cardiovascular events, all-cause mortality, and cardiovascular drug treatment. METHODS AND RESULTS: Data were obtained from the PHARMO Record Linkage System, a population-based registry of pharmacy records linked with hospital discharge records in The Netherlands. Patients were selected based on a first hospital discharge diagnosis of documented HF. Two time-periods were compared: 1998-2002 and 2003-07. In each time-period, we analysed all prescribed cardiovascular medications, all-cause mortality, and cardiovascular events (rehospitalization for HF and ischaemic events) within the first year after hospitalization, and the occurrence of ischaemic events separately (myocardial infarction and ischaemic stroke). Cox-regression analysis was performed to calculate hazard ratios (HR) with 95% confidence intervals (CI). We identified 8276 patients in 1998-2002 and 9548 patients from 2003-07. There was an increase in almost all cardiovascular medication prescriptions in the second period: in particular, beta-blocker prescriptions rose from 36% in 1998-2002 to 55% in 2003-07. In the first year after hospitalization, there was no difference in all-cause mortality or any cardiovascular event (HR 1.00, 95%CI: 0.95-1.05), as a composite endpoint or when analysed separately. The incidence of ischaemic events decreased from 2.7 to 1.9% in the first and second time-period, respectively (HR 0.74, 95%CI: 0.61-0.90). CONCLUSION: Prescription of cardiovascular medications in patients with a first hospitalization for HF has increased in recent years, particularly for beta-blockers, and the incidence of ischaemic events may have decreased. There was no decrease in all-cause mortality or cardiovascular events.

Non-selective vs. selective beta-blocker treatment and the risk of thrombo-embolic events in patients with heart failure.

AIMS: Heart failure (HF) is associated with a prothrombotic state, resulting in an increased risk for thrombo-embolic events. Studies suggest a reduced prothrombotic state when non-selective beta-blockers relative to selective beta-blockers are given. We studied the influence of non-selective beta-blockers compared with selective beta-blockers on the occurrence of arterial and venous thrombo-embolic events in patients with HF. METHODS AND RESULTS: Data were obtained from the PHARMO Record Linkage System, a population-based registry of pharmacy records linked with hospital discharge records in The Netherlands. In the period of 1998-2007, 20 870 patients were hospitalized for HF. We used Cox regression analysis with time-varying beta-blocker covariate to assess the difference in the incidence of thrombo-embolic events [acute coronary syndrome (ACS), stroke, or pulmonary embolism] among patients. Median follow-up was 2.0 years (inter-quartile range: 0.7-4.1). Directly after discharge, 6558 patients were prescribed a selective beta-blocker and 2202 patients a non-selective beta-blocker. The hazard ratio (HR) for any thrombo-embolic event for non-selective beta-blockers compared with selective beta-blockers was 0.76 [95% confidence interval (CI): 0.64-0.89]. After adjustment, the difference remained (HR 0.84, 95% CI: 0.72-0.99). The effect was most prominent for ACS (HR 0.78, 95% CI: 0.65-0.93), and not clear for stroke (HR 1.00, 95% CI: 0.67-1.50) or pulmonary embolism (HR 1.33, 95% CI: 0.66-2.71). CONCLUSION: In patients with HF, the use of non-selective beta-blockers was associated with a lower risk of thrombo-embolic events than selective beta-blockers. Whether this beneficial effect is caused by the additional beta2-receptor blockade remains to be elucidated. These findings need to be validated in a well-designed randomized study.

Systolic heart failure: a prothrombotic state.

Systolic heart failure is a common syndrome whose incidence is expected to increase. Several treatment modalities, such as beta-blockers and angiotensin-converting enzyme inhibitors, improve survival. Whether antithrombotic treatment is effective remains to be elucidated, although observations suggest a prothrombotic state in heart failure. This article focuses on this prothrombotic state and discusses the risk of thromboembolic events, pathophysiological mechanisms, and the potential role of anticoagulant treatment.