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.

Therapeutic drug monitoring in psychiatry.

In medicine, there are two main methods of improving the healthcare provided: perfecting (optimizing) the existing ones and seeking new treatment procedures. Despite of tremendous development in the central nervous system research, current treatment of severe mental illnesses, such as schizophrenia and depressive disorder, is suboptimal. Nowadays, optimization of treatment in psychiatry includes therapeutic drug monitoring (TDM) and pharmacogenomic testing, which examines genetic variation involved in medication metabolism and drug action. The TDM enables to determine drug concentrations in blood and adjust the dose accordingly if clinical effects correlate better with drug blood levels than drug doses. The first international guidelines for TDM in neuropsychopharmacology were published in 2004 and regularly updated. The recent update provides therapeutic reference ranges for a majority of commonly prescribed psychiatric medications and gives example of patients regularly treated in clinical practice profiting from TDM (using antipsychotics and changing their smoking habits). TDM in psychiatry is an underused tool, given its ability to optimize treatment, as well as to improve treatment effectiveness.

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.

From Personalized Medicine to Precision Psychiatry?

Personalised medicine aims to find an individualized approach for each particular patient. Most factors used in current psychiatry, however, depend on the assessment made by the individual clinician and lack a higher degree of reliability. Precision medicine bases decisions on quantifiable indicators available thanks to the tremendous progress in science and technology facilitating the acquisition, processing and analysis of huge amounts of data. So far, psychiatry has not been benefiting enough from the advanced diagnostic technologies; nevertheless, we are witnessing the dawn of the era of precision psychiatry, starting with the gathering of sufficient amounts of data and its analysis by the means of artificial intelligence and machine learning. First results of this approach in psychiatry are available, which facilitate diagnosis assessment, course prediction, and appropriate treatment choice. These processes are often so complex and difficult to understand that they may resemble a "black box", which can slow down the acceptance of the results of this approach in clinical practice. Still, bringing precision medicine including psychiatry to standard clinical practice is a big challenge that can result in a completely new and transformative concept of health care. Such extensive changes naturally have both their supporters and opponents. This paper aims to familiarize clinically oriented physicians with precision psychiatry and to attract their attention to its recent developments. We cover the theoretical basis of precision medicine, its specifics in psychiatry, and provide examples of its use in the field of diagnostic assessment, course prediction, and appropriate treatment planning.

Plasma Levels of Long-Acting Injectable Antipsychotics in Outpatient Care: A Retrospective Analysis.

PURPOSE: Antipsychotic efficacy in schizophrenia depends on its availability in the body. Although therapeutic outcomes remain still far from satisfactory, therapeutic drug monitoring is not a common part of clinical practice during treatment with long-acting injectable antipsychotics (LAI AP). The real effectiveness of LAI AP is thus uncertain. PATIENTS AND METHODS: We made a retrospective evaluation of plasma levels of LAI AP. Collection of blood samples was performed just before the drug application and one week later. Forty patients with a stabilized clinical condition and steady-state plasma levels were included. RESULTS: In the observed cohort of patients, flupentixol decanoate (n = 23) was the most often used drug, followed by fluphenazine decanoate (n = 7), haloperidol decanoate (n = 5), paliperidone palmitate (n = 3), and risperidone microspheres (n = 2). Just 5 of 40 patients were treated with a monotherapy. In the period before the application, 60% of the patients did not reach the therapeutic reference range (TRR) and 20% of the patients had an undetectable plasma level. At the time of collection of the second blood samples performed after 7 days, 24% of the patients were under the TRR. CONCLUSION: We have found a surprisingly high incidence of plasma levels under the TRR in patients treated with LAI AP. Notwithstanding individual variability in pharmacokinetics, it seems that LAI AP may be underdosed in usual clinical practice.

Pharmacological strategies for the management of comorbid depression and schizophrenia.

Introduction: Depressive symptoms may occur in any phase of schizophrenia and can have far-reaching consequences.Areas covered: The author focuses on recent reviews and meta-analyses dealing with the prevalence, importance, etiopathogenesis, and pharmacotherapy of comorbid depression and schizophrenia. Depressive symptoms in acute episodes may improve in parallel with psychosis due to antipsychotic treatment. Therefore, the first step is to evaluate the current antipsychotic treatment of psychotic symptoms and consider changing the dosage. A second step is switching antipsychotic medications, since there are indications that some medications are slightly more effective in reducing depressive symptoms than others. For persistent depressive episodes, additional therapeutic interventions are indicated. Most guidelines recommend the administration of antidepressants as an add-on treatment with a limited evidence level. Immunotherapeutic strategies could be successful, at least in some schizophrenia patients.Expert opinion: In the near future, precision psychiatry should enable clinicians to recognize specific biotypes with unique biosignatures that will guide accurate and prompt clinical management for individual patients.

What Does Antidepressant Drug level Monitoring Reveal About Outpatient Treatment and Patient Adherence?

INTRODUCTION: The evaluation of plasma levels of antidepressants may improve the treatment outcome. The aim was to verify adherence and adequacy of administered doses of antidepressants among patients hospitalized for inadequate outpatient therapeutic response. METHODS: Selective serotonin reuptake inhibitors or venlafaxine plasma levels were assessed on the first day of hospitalization and after 3 days of controlled administration. The patients were considered adherent if the plasma level on admission was within the interval of the minimum and maximum plasma level on the fourth day, expanded by 30%. The adequacy of antidepressant doses used during the outpatient treatment was assessed by comparing the plasma level on the fourth day with the therapeutic reference range. RESULTS: Out of 83 patients, 52 (62.7%) were adherent. The plasma levels of antidepressants on the fourth day were found to be within the therapeutic reference range in 35 (43.2%) patients. The same number manifested levels below the therapeutic reference range. In 11 (13.6%) patients, the levels were higher than recommended. No significant difference in rate of adherence was found among individual antidepressants. CONCLUSION: The results show that antidepressant nonresponders are frequently under-dosed or nonadherent.

Precision psychiatry - a feasible possibility?

Currently, patients are evaluated by a psychiatrist using the phenomenological classification then, first-line treatment is initiated according to the diagnosis; however, this approach is associated with a high rate of etiopathogenetic heterogeneity. The development of mental disorders is likely determined by combined effects of genetic predisposition and environmental adversity. Inter-mutual interaction is regulated by epigenetics processes which determine transcription and translation of gens to corresponding proteins. Choosing the optimal drug among available we strive for individualized approach based upon a patient's clinical characteristics. Personalized medicine including psychiatry considers measurable indicators of pathogenic processes (biomarkers) enabling identification of patients with common biological changes. Although personalized and precision medicine are often used synonymously, they describe two different approaches. Personalized psychiatry refers to the approach to an individual patient, precision psychiatry empowers decision- making process by measurable indicators and becomes the indispensable vehicle to achieve personalized treatment. An example is schizophrenia, the most severe mental disorder and prototype of psychotic disorder. The current definition of schizophrenia lacks a biological validity, which is stimulating an effort to alternatively define the psychotic disorders on the base of biomarkers. The goal of integration knowledge from biomedical research and clinical practice is providing more accurate diagnosis and the tailored treatment for each individual patient.

Once-a-Day Trazodone in the Treatment of Depression in Routine Clinical Practice.

OBJECTIVE: The aim of the study was to evaluate the efficacy, tolerability, and safety of once-a day trazodone tablets (Trittico Prolong® 300 mg) in patients with moderate to severe depression in routine clinical practice. METHODS: Men and women ≥18 years old with Montgomery-Åsberg Depression Rating Scale (MADRS) scores > 21 and Clinical Global Impression - Severity (CGI/S) ≥4 were included in this post-authorization, non-interventional, observational prospective safety study, conducted in 8 psychiatric centers in the Czech -Republic. The acute treatment phase lasted 5 weeks: 1 week of titration and 4 weeks of full-dose treatment. Patients had follow-up visits 9 and 21 weeks after commencing -treatment. RESULTS: Overall, 85 patients were enrolled in the study, of which 80 completed the acute treatment of 5 weeks. There were significant decreases in the overall MADRS score from the baseline mean value of 27.4-21.2 at week 1 (p < 0.001), and a further decrease to 7.9 at week 5 (p < 0.001). The severity of depression according to CGI/S gradually declined. Most patients reported improvement after 6 days of trazodone treatment. The most frequent adverse drug reactions (ADRs) reported were somnolence and fatigue. CONCLUSIONS: Trazodone, in the new extended-release formulation, had very good effects in clinical practice, both in previously untreated depressive episodes and in episodes not responsive to previous antidepressive therapy.

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.

[Current and future pharmacotherapy of severe psychiatric disorders]. / Soucasnost a budoucnost farmakoterapie závazných psychických poruch.

Despite of tremendous development in CNS research, current treatment is suboptimal especially in severe mental disorders. In medicine, there are two main methods of improving the healthcare provided: seeking new treatment procedures and perfecting (optimizing) the existing ones. Optimization of treatment includes not only practical tools such as therapeutic drug monitoring, but also implementation of general trends into the clinical practice. New pharmacological options include drugs aimed at other than monoaminergic systems and old drugs used before the psychopharmacological era. In pharmacoresistant depression promising options include switch to new multimodal/multifunctional antidepressants, augmentation with new atypical antipsychotics (cariprazine and brexpiprazole) and adjunctive treatment with anti-inflammatory and anti-apoptotic agents and nutraceuticals. Ketamine, opioids and psychedelics are in different phases of clinical testing. Recent advances in technology and emerging knowledge about the dysfunctional brain circuits and neuroplasticity have led to the development of different new neuromodulation techniques usually used as add-on therapy. In schizophrenia the cornerstone of the current treatment is still antipsychotic medications. In addition to aripiprazole two new partial dopamine agonists, brexpiprazole and cariprazine are now available. Especially the group of partial dopamine agonists is in the center of interest. Due to severe consequences of partial adherence, new formulations of long-acting injections of the second-generation antipsychotics with longer interval of application have been developed (3- month paliperidone palmitate). New treatment options not yet available include cannabidiol, glutamate modulators and nicotine receptors agonists.

Novel treatment options in depression and psychosis.

In spite of tremendous development in central nervous system research, current treatment is suboptimal, especially in severe mental disorders. In medicine, there are two main methods of improving the health care provided: seeking new treatment procedures and perfecting (optimizing) the existing ones. Optimization of treatment includes not only practical tools such as therapeutic drug monitoring but also implementation of general trends in the clinical practice. New pharmacological options include new more sophisticated forms of monoaminergic drugs, old drugs rediscovered on the base of a better understanding of pathophysiology of mental illnesses, and drugs aimed at new treatment targets. In depression, treatment resistance to antidepressive pharmacotherapy represents one of the most important clinical challenges. Switching to monotherapy with new multimodal/multifunctional antidepressants and augmentation with new atypical antipsychotics (aripiprazole and brexpiprazole) may be promising options. Further, current evidence supports utility and safety of adjunctive treatment of nutraceuticals. Novel approaches being studied include ketamine and opioids. Recent advances in technology and emerging knowledge about dysfunctional brain circuits and neuroplasticity have led to the development of different new neuromodulation techniques usually used as add-on therapy. Antipsychotics are still the cornerstone of the current treatment of schizophrenia. Two new partial dopamine agonists, brexpiprazole and cariprazine, are now available in addition to aripiprazole. Although the mechanisms of action are similar, the two agents differ in terms of their pharmacodynamic profiles. Further, two new formulations of long-acting injections of second-generation antipsychotics (aripiprazole lauroxil and 3-month paliperidone palmitate) were introduced into clinical practice. New treatment options not yet available include cannabidiol, glutamate modulators, and nicotine receptors agonists.

Changes in BMI in hospitalized patients during treatment with antipsychotics, depending on gender and other factors.

OBJECTIVE: To investigate the differences in body mass index (BMI) changes between men and women during hospitalization. METHODS: The retrospective study monitored demographic and clinical data of 462 schizophrenic patients hospitalized 737 times between 2006 and 2011. BMI analysis was performed on patients on antipsychotic medication hospitalized longer than four days. RESULTS: Patients with an initial BMI < 25 gained more weight than patients with a BMI > 25 (3.94% vs. 0.23%, men 4.02% vs. 0.69%, women 3.79% vs. -0.52%, always p < 0.001). Greater BMI gains were reported during the first hospitalization than during subsequent ones (3.94% vs. 1.66%, men 3.97% vs. 1.98%, women 3.88% vs. 1.18%, always p < 0.001). The comparison between men and women showed a higher increase in BMI in men 2.36% vs. 1.54%, p = 0.022. Men also gained significantly more weight than women on polytherapy (+2.55% vs. +1.37%) and during subsequent hospitalizations (1.98% vs. 1.18%). For treatment with various atypical antipsychotics (AP), no significant differences were found in weight changes between men and women; during treatment using a combination of multi-receptor AP and metabolically neutral aripiprazole, a significant increase of BMI occurred in men, but not in women (p = 0.018). CONCLUSIONS: Men appear to be more prone to weight gain than women.

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.

[Psychiatry in everyday life]. / Psychiatrie v realite vsedního dne.

Severe mental disorders including its main representative schizophrenia are chronic lifelong diseases. Most patients like those with somatic disease can live in the society under certain conditions as continuous psychopharmacotherapy and availability of community services. Similarly as in somatic medicine a great attentions is devoted to the individualized treatment.Psychotic disorders have some specific features, like lack of insight associated with poor adherence. Nowadays we have a possibility of an objective adherence evaluation by plasma levels measurement and the depots, long-action injections of antipsychotics (including the second generation antipsychotics), are available. Unfortunately this modern approach is restricted by insurance companies.In spite of the fact that therapeutic drug monitoring is an advantageous tool for treatment optimization this interdisciplinary service is in many faculty and regional hospitals not provided. Providers of health care should realise that accessibility of some services and medication could reduce the danger of untreated psychosis.

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.

Cognitive impairment and cortisol levels in first-episode schizophrenia patients.

Many modalities of cognition are affected in schizophrenia. The most common findings include dysfunctions of episodic and working memory and of executive functions. Although an inverse correlation between cortisol level and memory function has been proven, few studies have focused on the relationship between cortisol level and cognitive impairment in patients with schizophrenia. In an open, naturalistic, prospective study, consecutively hospitalized males diagnosed with first-episode schizophrenia, hypothalamic-pituitary-adrenal axis activity (afternoon cortisol levels, post-dexamethasone cortisol levels) was evaluated before and at the end of acute treatment. Psychopathology was assessed using the positive and negative syndrome scale (PANSS). Cognitive functions (memory, attention, psychomotor, verbal fluency, and executive functions) were tested after symptom alleviation using a neurocognitive test battery. In the total sample (n = 23), significant decreases in total PANSS score (including all subscales), afternoon cortisol levels, and post-dexamethasone cortisol levels occurred during the course of treatment. It was found that higher afternoon cortisol levels at the beginning of treatment were significantly related to impaired performance in memory functions. Afternoon cortisol levels were not significantly associated with other measured cognitive functions. No correlation was discovered between cognitive functions and post-dexamethasone cortisol levels. The determination of afternoon cortisol levels may serve to detect potential candidates for specific cognitive intervention immediately after the first psychotic breakthrough.

Gender differences in the treatment of first-episode schizophrenia: Results from the European First Episode Schizophrenia Trial.

Gender differences in the response to antipsychotic treatment have been detected in the past, but not studied in great detail. The results of the European First-Episode Schizophrenia Trial (EUFEST) were analyzed with a focus on gender differences in the response to randomized treatment of first-episode schizophrenia. A total of 498 patients (298 men and 200 women) were randomly assigned by a web-based online system to open-label treatment with haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone. Treatment response was evaluated using the positive and negative syndrome scale (PANSS). Data were collected at baseline and then prospectively for one year. Baseline characteristics (age and proportion of patients assigned to individual antipsychotics) were the same between the male and female patients with the exception of ziprasidone: significantly fewer men, proportionately, were prescribed ziprasidone. There was no significant difference between genders between the initial total PANSS and subscale scores. A significant interaction between time and gender was found, with more robust PPANSS and TPANSS score improvement in women during the course of treatment. Of all of the antipsychotics used, only olanzapine led to significantly greater improvement in the total PANSS score in women during the follow-up period. Gender differences should be given more attention in research and clinical practice. Their causes require clarification, and future strategies for dealing with them may be considered in early intervention programs and guidelines.