Selected neuroendocrine factors as potential molecular biomarkers of early non-affective psychosis course in relation to treatment outcome: A pilot study.

The aim of this pilot study was to find whether the dysregulation of neuroendocrine biomarker signaling pathways in the first episode of non-affective psychosis is a predictive factor of treatment outcome. Patients with the first episode of non-affective psychosis (N = 29) were examined at admission, at discharge, and at follow-up (N = 23). The biomarkers included serum aldosterone, cortisol, free thyroxine, thyroid stimulating hormone, and prolactin. We revealed lower baseline aldosterone and higher baseline cortisol concentrations in patients with very good outcome compared to those with good outcome after one year. We failed to reveal any significant association between treatment outcome and neurohumoral biomarkers in the whole sample at 1-year follow-up. However, baseline aldosterone concentrations negatively correlated with total PANSS scores at the discharge. Lower baseline aldosterone and higher baseline cortisol concentrations have the potential to predict a more favorable outcome for patients with the first episode of psychosis.

A preliminary choroid plexus volumetric study in individuals with psychosis.

The choroid plexus (ChP) is part of the blood-cerebrospinal fluid barrier, regulating brain homeostasis and the brain's response to peripheral events. Its upregulation and enlargement are considered essential in psychosis. However, the timing of the ChP enlargement has not been established. This study introduces a novel magnetic resonance imaging-based segmentation method to examine ChP volumes in two cohorts of individuals with psychosis. The first sample consists of 41 individuals with early course psychosis (mean duration of illness = 1.78 years) and 30 healthy individuals. The second sample consists of 30 individuals with chronic psychosis (mean duration of illness = 7.96 years) and 34 healthy individuals. We utilized manual segmentation to measure ChP volumes. We applied ANCOVAs to compare normalized ChP volumes between groups and partial correlations to investigate the relationship between ChP, LV volumes, and clinical characteristics. Our segmentation demonstrated good reliability (.87). We further showed a significant ChP volume increase in early psychosis (left: p < .00010, right: p < .00010) and a significant positive correlation between higher ChP and higher LV volumes in chronic psychosis (left: r = .54, p = .0030, right: r = .68; p < .0010). Our study suggests that ChP enlargement may be a marker of acute response around disease onset. It might also play a modulatory role in the chronic enlargement of lateral ventricles, often reported in psychosis. Future longitudinal studies should investigate the dynamics of ChP enlargement as a promising marker for novel therapeutic strategies.

The association of matrix metalloproteinase 9 (MMP9) with hippocampal volume in schizophrenia: a preliminary MRI study.

Matrix metalloproteinases 9 (MMP9) are enzymes involved in regulating neuroplasticity in the hippocampus. This, combined with evidence for disrupted hippocampal structure and function in schizophrenia, has prompted our current investigation into the relationship between MMP9 and hippocampal volumes in schizophrenia. 34 healthy individuals (mean age = 32.50, male = 21, female = 13) and 30 subjects with schizophrenia (mean age = 33.07, male = 19, female = 11) underwent a blood draw and T1-weighted magnetic resonance imaging. The hippocampus was automatically segmented utilizing FreeSurfer. MMP9 plasma levels were measured with ELISA. ANCOVAs were conducted to compare MMP9 plasma levels (corrected for age and sex) and hippocampal volumes between groups (corrected for age, sex, total intracranial volume). Spearman correlations were utilized to investigate the relationship between symptoms, medication, duration of illness, number of episodes, and MMP9 plasma levels in patients. Last, we explored the correlation between MMP9 levels and hippocampal volumes in patients and healthy individuals separately. Patients displayed higher MMP9 plasma levels than healthy individuals (F(1, 60) = 21.19, p < 0.0001). MMP9 levels correlated with negative symptoms in patients (R = 0.39, p = 0.035), but not with medication, duration of illness, or the number of episodes. Further, patients had smaller left (F(1,59) = 9.12, p = 0.0040) and right (F(1,59) = 6.49, p = 0.013) hippocampal volumes. Finally, left (R = -0.39, p = 0.034) and right (R = -0.37, p = 0.046) hippocampal volumes correlated negatively with MMP9 plasma levels in patients. We observe higher MMP9 plasma levels in SCZ, associated with lower hippocampal volumes, suggesting involvement of MMP9 in the pathology of SCZ. Future studies are needed to investigate how MMP9 influences the pathology of SCZ over the lifespan, whether the observed associations are specific for schizophrenia, and if a therapeutic modulation of MMP9 promotes neuroprotective effects in SCZ.

Hemodynamic and white blood cells parameters in patients with first-episode psychosis: a pilot longitudinal study.

OBJECTIVE: Patients with schizophrenia are at higher risk of cardiovascular (CVS) related mortality. Close attention is being paid to the clinical utility of readily available CVS markers. METHODS: A pilot one-year longitudinal study in inpatients with first-episode psychosis (FEP) was carried out to determine markers of inflammation and endothelial dysfunction (monocyte- and neutrophil-to-lymphocyte ratios) and basal blood pressure, pulse, and derived hemodynamic parameters (PP: pulse pressure; RPP: rate pressure product; and MAP: mean arterial pressure). RESULTS: After one year, PP and RPP increased, as did systolic blood pressure and heart rate. Systolic blood pressure, PP, total white blood cells, and neutrophils correlated with weight gain. After one year, correlations between monocyte-to-lymphocyte ratio and RPP and MAP were observed. CONCLUSION: Our study indicates worsening CVS health over the first year of treatment and emphasises the importance of early monitoring of CVS status using easily accessible parameters to prevent CVS-related mortality.Key pointsPatients with schizophrenia are at higher risk of cardiovascular mortality.The CVS risk could be evaluated using affordable, routinely available CVS markers such as monocyte- and neutrophil-to-lymphocyte ratios, blood pressure, and pulse together with the derived parameters.Our pilot study in first-episode psychosis patients indicates worsening of CVS health based on these parameters during the first year of treatment, the early monitoring of CVS status is highly relevant in clinical practice.

Emotional Awareness in Schizophrenia Is Associated With Gray Matter Volume of Right Precuneus.

Objectives: We assessed the relationship between emotional awareness (e.g., the ability to identify and differentiate our own feelings and feelings of others) and regional brain volumes in healthy and in schizophrenia groups. Methods: Magnetic resonance images of 29 subjects with schizophrenia and 33 matched healthy controls were acquired. Brain gray matter was parcellated using FreeSurfer and 28 regions of interest associated with emotional awareness were analyzed. All participants were assessed using the Levels of Emotional Awareness Scale (LEAS) of Self and of Other. LEAS scores were correlated with gray matter volume for each hemisphere on the 14 brain regions of the emotional awareness network. Results: Individuals with schizophrenia showed decreased emotional awareness on both LEAS Self and LEAS Other compared to healthy controls. There were no statistically significant between-group differences in gray matter volumes of the emotional awareness network. The performance on LEAS Other correlated negatively with right precuneus gray matter volume only in the schizophrenia group. Conclusion: Our findings suggest a relationship between gray matter volume of the right precuneus and deficits in understanding of emotional states of others in schizophrenia.

Brain Connectivity and Symptom Changes After Transcranial Magnetic Stimulation in Patients With Borderline Personality Disorder.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) is an innovative method in the treatment of borderline personality disorder (BPD). We hypothesized that prefrontal rTMS in patients with BPD leads to improved BPD symptoms and that these effects are associated with brain connectivity changes. METHODS: Fourteen patients with BPD received 15 sessions of individually navigated prefrontal rTMS over the right dorsolateral prefrontal cortex. Clinical effects were measured by the Borderline Symptom List 23, UPPS-P, the Difficulties in Emotion Regulation Scale (DERS), the Zung Self-Rating Anxiety Scale (SAS), and the Montgomery and Åsberg Depression Rating Scale (MADRS). Effects of rTMS on brain connectivity were observed with a seed correlation analysis on resting-state fMRI and with a beta series correlation analysis on Go/No Go tasks during fMRI. Assessments were made before and immediately after the treatment. RESULTS: The assessments after rTMS showed significant reductions in two subscales of UPPS-P, and in DERS, SAS, and MADRS. The brain connectivity analysis revealed significant decreases in amygdala and insula connectivity with nodes of the posterior default mode network (pDMN; precuneus, posterior cingulate cortex, parietal lobules). Connectivity changes were observed both in the resting state and during inhibition. The decrease of amygdala-pDMN connectivity was positively correlated with reduced depression and lack of premeditation after rTMS. CONCLUSIONS: Despite the study limitations (open single-arm study in a small sample), our findings suggest a possible neural mechanism of rTMS effect in BPD, reduced amygdala connectivity with the pDMN network, which was positively associated with symptom reduction.

Influence of dose, gender, and cigarette smoking on clozapine plasma concentrations.

INTRODUCTION: Therapeutic drug monitoring (TDM) of clozapine is a very useful method for verifying both the correct intake and the interindividual variability of its metabolism, thereby avoiding the risk of toxicity. The purposes of this paper were to discover how many patients using clozapine in common clinical practice have clozapine plasma concentration (PC) levels in the proposed reference range and to identify factors that influence clozapine PC levels. METHODS: Our study included 100 inpatients (diagnosed with schizophrenia or schizoaffective disorder) taking standard doses of clozapine (100-700 mg/day). Clozapine concentration was measured by high-performance liquid chromatography. Correlations between doses and PC levels and the influence of smoking and gender on clozapine PC levels were calculated. RESULTS: A large number of the patients (67%) had PC levels outside the proposed reference range. The clozapine PC levels were influenced by dose, gender, and cigarette smoking. CONCLUSION: The correlations between dose, gender, and cigarette smoking and clozapine PC levels highlighted by our study overlap other research. It was surprising to find such a large number of patients with clozapine PC levels outside the therapeutic range. This result suggests the importance of clozapine TDM due to misunderstood inter- and/or intraindividual variability or misestimated partial therapeutic compliance.

Efficacy and Safety of Intensive Transcranial Magnetic Stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is customarily applied on a daily basis for prolonged periods of time for the treatment of psychiatric diseases. The process is demanding in terms of staff and patient time, and the onset of the effect is slow. Recently, intensive rTMS protocols have been introduced in which stimulation is applied to the same area more than once a day with a higher than standard number of pulses. This article reviews 16 articles to determine the safety and efficacy of such protocols. Intensive rTMS seems to be effective in various mental disorders. It appears to have, in general, the same adverse events as classic, long-term, daily rTMS, and it is largely well tolerated by the patients. One episode of depersonalization, one of increased suicidal thoughts, and two of induced mania were observed in the 16 studies reviewed. The advantages of intensive rTMS are in the possible acute effect of the stimulation and in the possible reduction in the time required to achieve remission in depression (and potentially other disorders). It remains uncertain whether intensive rTMS is more effective than sham stimulation or once-daily, long-term rTMS.

Risperidone increases the cortical silent period in drug-naive patients with first-episode schizophrenia: A transcranial magnetic stimulation study.

OBJECTIVES: Schizophrenia is accompanied by impaired cortical inhibition, as measured by several markers including the cortical silent period (CSP). It is thought that CSP measures gamma-aminobutyric acid receptors B (GABAB) mediated inhibitory activity. But the mutual roles of schizophrenia as a disease and the drugs used for the treatment of psychosis on GABA mediated neurotransmission are not clear. METHODS: We recruited 13 drug-naive patients with first-episode schizophrenia. We used transcranial magnetic stimulation to assess CSP prior to initiating risperidone monotherapy and again four weeks later. At the same time, we rated the severity of psychopathology using the Positive and Negative Syndrome Scale (PANSS). RESULTS: We obtained data from 12 patients who showed a significant increase in CSP, from 134.20±41.81 ms to 162.95±61.98 ms ( p=0.041; Cohen's d=0.544). After the treatment, the PANSS total score was significantly lower, as were the individual subscores ( p<0.05). However, no correlation was found between ΔCSP and ΔPANSS. CONCLUSION: Our study in patients with first-episode schizophrenia demonstrated an association between risperidone monotherapy and an increase in GABAB mediated inhibitory neurotransmission.

Hippocampal volume in first-episode schizophrenia and longitudinal course of the illness.

OBJECTIVES: Several lines of evidence suggest an adverse effect of psychotic episodes on brain morphology. It is not clear if this relationship reflects the cumulative effect of psychotic outbursts on the gradual progressive reduction of hippocampal tissue or an increased tendency toward psychotic episodes in patients with a smaller hippocampus at the beginning of the illness. METHODS: This is a longitudinal 4-year prospective study of patients with first-episode schizophrenia (FES, N = 58). Baseline brain anatomical scans (at FES) were analysed using voxel-based morphometry and atlas-based volumetry of the hippocampal subfields. The effects of first-episode duration on the hippocampal morphology, and the effect of baseline hippocampal morphology on illness course with relapses, number of psychotic episodes and residual symptoms were analysed. RESULTS: A significant negative correlation was detected between first-episode duration and baseline hippocampal morphology. Relapse, number of psychotic episodes and residual symptoms had no correlation with baseline hippocampal volume. CONCLUSIONS: We replicated the effect of psychosis duration on hippocampal volume already at the time first-episode, which supports the concept of toxicity of psychosis. The indices of a later unfavourable course of schizophrenia had no correlation with baseline brain morphology, suggesting that there is no baseline morphological abnormality of the hippocampus that predisposes the patient to frequent psychotic outbursts.

Predictive Motor Timing and the Cerebellar Vermis in Schizophrenia: An fMRI Study.

Abnormalities in both time processing and dopamine (DA) neurotransmission have been observed in schizophrenia. Time processing seems to be linked to DA neurotransmission. The cognitive dysmetria hypothesis postulates that psychosis might be a manifestation of the loss of coordination of mental processes due to impaired timing. The objective of the present study was to analyze timing abilities and their corresponding functional neuroanatomy in schizophrenia. We performed a functional magnetic resonance imaging (fMRI) study using a predictive motor timing paradigm in 28 schizophrenia patients and 27 matched healthy controls (HC). The schizophrenia patients showed accelerated time processing compared to HC; the amount of the acceleration positively correlated with the degree of positive psychotic symptoms and negatively correlated with antipsychotic dose. This dysfunctional predictive timing was associated with BOLD signal activity alterations in several brain networks, especially those previously described as timing networks (basal ganglia, cerebellum, SMA, and insula) and reward networks (hippocampus, amygdala, and NAcc). BOLD signal activity in the cerebellar vermis was negatively associated with accelerated time processing. Several lines of evidence suggest a direct link between DA transmission and the cerebellar vermis that could explain their relevance for the neurobiology of schizophrenia.

Depression and Anxiety after Acute Myocardial Infarction Treated by Primary PCI.

AIMS: The main objective of the study was to find out prevalence of depression and anxiety symptoms in the population of patients with AMI with ST-segment elevation (STEMI), treated with primary PCI (pPCI). Secondary target indicators included the incidence of sleep disorders and loss of interest in sex. METHODS AND RESULTS: The project enrolled 79 consecutive patients with the first AMI, aged <80 years (median 61 years, 21.5% of women) with a follow-up period of 12 months. Symptoms of depression or anxiety were measured using the Beck Depression Inventory II tests (BDI-II, cut-off value ≥14) and Self-Rating Anxiety Scale (SAS, cut-off ≥ 45) within 24 hours of pPCI, before the discharge, and in 3, 6 and 12 months). Results with the value p<0.05 were considered as statistically significant. The BDI-II positivity was highest within 24 hours after pPCI (21.5%) with a significant decline prior to the discharge (9.2%), but with a gradual increase in 3, 6 and 12 months (10.4%; 15.4%; 13.8% respectively). The incidence of anxiety showed a relatively similar trend: 8.9% after pPCI, and 4.5%, 10.8% and 6.2% in further follow-up. CONCLUSIONS: Patients with STEMI treated by primary PCI have relatively low overall prevalence of symptoms of depression and anxiety. A significant decrease in mental stress was observed before discharge from the hospital, but in a period of one year after pPCI, prevalence of both symptoms was gradually increasing, which should be given medical attention.

Repetitive transcranial magnetic stimulation reduces cigarette consumption in schizophrenia patients.

INTRODUCTION: High-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) seemed to decrease tobacco consumption and craving in nicotine-dependent people without psychiatric disorder or otherwise healthy people. Even if the prevalence of cigarette smoking in schizophrenia patients is high and estimated to be between 45% and 88%, this technique has not been systematically studied in this indication in schizophrenia yet. THE AIM OF THE STUDY: The aim of this study was to test the ability of high-frequency (10Hz) rTMS over the left DLPFC to decrease cigarette consumption in schizophrenia patients. METHODS: The study included 35 male schizophrenia patients on stable antipsychotic medication. The patients were divided into two groups: the first (18 patients) were actively stimulated and the second (17 patients) underwent sham (placebo) stimulation. The sham rTMS was administered using a purpose-built sham coil that was identical in appearance to the real coil and made the same noise but did not deliver a substantial stimulus. The rTMS was administered at the stimulation parameters: location (left dorsolateral prefrontal cortex: DLPFC), intensity of magnetic stimulation in % of motor threshold (110%), stimulation frequency (10Hz), number of trains (20), single train duration (10s), inter-train interval (30s), and total number of stimulation sessions (21). In each stimulation session, 2000TMSpulses were given, with a total of 42,000pulses per treatment course. Patients noted the number of cigarettes smoked in the 7days before treatment, during the whole stimulation treatment (21days), and again for a 7-day period after treatment. RESULTS: Cigarette consumption was statistically significantly lower in the actively stimulated patients than in the sham rTMS group as early as the first week of stimulation. No statistically relevant correlations were found in the changes of ongoing negative or depressive schizophrenia symptoms and the number of cigarettes smoked. CONCLUSION: High-frequency rTMS over the left DLPFC has the ability to decrease the number of cigarettes smoked in schizophrenia patients.

A detailed analysis of the effect of repetitive transcranial magnetic stimulation on negative symptoms of schizophrenia: a double-blind trial.

OBJECTIVE: The aim of the study was to assess the effect of rTMS not only on the general severity of negative schizophrenia symptoms, but also particularly on their individual domains, such as affective flattening or blunting, alogia, avolition or apathy, anhedonia, and impaired attention. METHODS: Forty schizophrenic male patients on stable antipsychotic medication with prominent negative symptoms were included in the study. They were divided into two groups: 23 were treated with active and 17 with placebo rTMS. Both treatments were similar, but placebo rTMS was administered using a purpose-built sham coil. Stimulation was applied to the left dorsolateral prefrontal cortex (DLPFC). The stimulation frequency was 10 Hz; stimulation intensity was 110% of the individual motor threshold intensity. Each patient received 15 rTMS sessions on 15 consecutive working days (five working days "on" and two weekend days "off" design). Each daily session consisted of 20 applications of 10-second duration with 30-second intervals between sequences. The patients and raters were blind to condition of stimulation treatment. RESULTS: The active rTMS led to a statistically significantly higher reduction of the Scale for the Assessment of Negative Symptoms (SANS) total score and of all domains of negative symptoms of schizophrenia. After Bonferroni adjustments for multiple testing, the statistical significance disappeared in alogia only. CONCLUSION: High-frequency rTMS stimulation over the left DLPFC at a high stimulation intensity with a sufficient number of applied stimulating pulses may represent an efficient augmentation of antipsychotics in alleviating the negative symptoms of schizophrenia.