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.

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.

[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.

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.

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.

[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.

Brain functional connectivity of male patients in remission after the first episode of schizophrenia.

OBJECTIVES: Abnormal task-related activation and connectivity is present in schizophrenia. The aim of this study was the analysis of functional networks in schizophrenia patients in remission after the first episode. EXPERIMENTAL DESIGN: Twenty-nine male patients in remission after the first episode of schizophrenia and 22 healthy controls underwent examination by functional magnetic resonance during verbal fluency tasks (VFT). The functional connectivity of brain networks was analyzed using independent component analysis. RESULTS: The patients showed lower activation of the salience network during VFT. They also showed lower deactivation of the default mode network (DMN) during VFT processing. Spectral analysis of the component time courses showed decreased power in slow frequencies of signal fluctuations in the salience and DMNs and increased power in higher frequencies in the left frontoparietal cortex reflecting higher fluctuations of the network activity. Moreover, there was decreased similarity of component time courses in schizophrenia­the patients had smaller negative correlation between VFT activated and deactivated networks, and smaller positive correlations between DMN subcomponents. CONCLUSIONS: There is still an abnormal functional connectivity of several brain networks in remission after the first episode of schizophrenia. The effect of different treatment modalities on brain connectivity, together with temporal dynamics of this functional abnormality should be the objective of further studies to assess its potential as a marker of disease stabilization.

Prevalence of remission and recovery in schizophrenia in the Czech Republic.

OBJECTIVE: The aim of the study was to map the point prevalence of remission and recovery in patients with schizophrenia in the Czech Republic. METHOD: The point-symptomatic remission criteria were based on the definition of remission in schizophrenia according to Andreasen, without the time criterion. The definition of complete remission contained, in addition to the point-symptomatic remission criteria, a time aspect which was determined by the absence of psychiatric hospitalisation or a change in antipsychotic medications due to inefficiency in the preceding six months. Functional remission was defined by a total score on the PSP scale in the range between 71 and 100 points. Recovery was defined by the simultaneous fulfilment of the criteria for complete and functional remission. RESULTS: A total of 481 patients with schizophrenia were included in the study. The point-symptomatic remission criteria were fulfilled in a total of 258 patients (54%); complete remission occurred in a total of 214 patients (44%). Functional remission was reached by 124 patients (26%) in total. Recovery was proven in a total of 91 patients (19%). CONCLUSION: The ascertained data are in accordance with the results of methodologically similar studies and confirm the known trajectories of the course of schizophrenia.

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.

Does repetitive transcranial magnetic stimulation have a positive effect on working memory and neuronal activation in treatment of negative symptoms of schizophrenia?

OBJECTIVE: The objective of the study was to find out whether, under the conditions of a double-blind, placebo coil controlled study, high-frequency repetitive transcranial magnetic stimulation (TMS) over the left prefrontal cortex will show positive effects on working memory with simultaneous assessment of respective changes in neuronal activation. RESULTS: Stimulation treatment led to a reduction of seriousness of negative schizophrenia symptoms in both comparative groups. However, mutual comparison of real (n=19) and sham (n=11) rTMS, respectively, has shown that the effect of real rTMS was statistically significantly higher compared with placebo stimulation. During stimulation treatment an improvement in working memory performance was also found. No statistically significant difference between the real and placebo sham rTMS, respectively, was established. The rate of neuronal activation did not change at all during rTMS treatment. CONCLUSIONS: From clinical point of view rTMS seems to be a well-tolerated neurostimulation method for treatment of negative schizophrenia symptoms with favourable of impact on cognitive functions.

Maximum-uncertainty linear discrimination analysis of first-episode schizophrenia subjects.

Recent techniques of image analysis brought the possibility to recognize subjects based on discriminative image features. We performed a magnetic resonance imaging (MRI)-based classification study to assess its usefulness for outcome prediction of first-episode schizophrenia patients (FES). We included 39 FES patients and 39 healthy controls (HC) and performed the maximum-uncertainty linear discrimination analysis (MLDA) of MRI brain intensity images. The classification accuracy index (CA) was correlated with the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning scale (GAF) at 1-year follow-up. The rate of correct classifications of patients with poor and good outcomes was analyzed using chi-square tests. MLDA classification was significantly better than classification by chance. Leave-one-out accuracy was 72%. CA correlated significantly with PANSS and GAF scores at the 1-year follow-up. Moreover, significantly more patients with poor outcome than those with good outcome were classified correctly. MLDA of brain MR intensity features is, therefore, able to correctly classify a significant number of FES patients, and the discriminative features are clinically relevant for clinical presentation 1 year after the first episode of schizophrenia. The accuracy of the current approach is, however, insufficient to be used in clinical practice immediately. Several methodological issues need to be addressed to increase the usefulness of this classification approach.

Suicides in males after the first episode of schizophrenia.

The aim of this study was a retrospective analysis of available data on patients who committed suicide after the first episode of schizophrenia with focus on risk factors for suicide. Seven of 162 patients consecutively hospitalized at the Department of Psychiatry in Brno with first-episode schizophrenia and followed up for 10 years committed suicide by hanging (n = 4), shooting (n = 1), jumping from height (n = 1), and drowning (n = 1). All patients had more known risk factors and had visited a psychiatrist shortly before their suicide. However, according to the documentation, the patients were not asked about their intention to commit suicide and the potentially modifiable risk factors. Under the conditions of routine clinical practice, the prevention of suicide after the first psychotic episode should include early aggressive treatment and careful monitoring for suicidal behaviors in patients with known risk factors.

Effect of electroconvulsive therapy on cortical excitability in a patient with long-term remission of schizophrenia: a transcranial magnetic stimulation study.

The exact effects of electroconvulsive therapy (ECT) on the brain are still not accurately known. Hypotheses considered include the effect of ECT on cortical excitability of the brain. The aim of this trial was to assess the changes in cortical excitability in the brain of a patient with remitted schizophrenia, undergoing maintenance ECT. Three successive ECT applications resulted in significant prolongation of the cortical silent period, which implies augmentation of inhibitory cortical mechanisms in the brain, most likely mediated by the GABAergic (GABA, γ-aminobutyric acid) system with direct involvement of GABAB receptors. The actual therapeutic effect of ECT is therefore probably due to facilitation of cortical inhibitory mechanisms induced by GABAergic neurotransmission.

Safety of amisulpride in combination with antidepressants under common clinical practice conditions.

AIM: The main objective was to identify the occurrence of adverse events associated with amisulpride when combined with antidepressants (ADs). METHODS: A non-interventional questionnaire-based study focussed on identification of occurrence and tolerance of combinations of amisulpride with ADs under common clinical practice conditions. RESULTS: Combinations of amisulpride with ADs were administered to 3178 patients suffering from depression. The average daily dose of amisulpride was 54.8 ± 17 mg (range 50-150 mg/day). The most frequently administered ADs were SSRIs. A total of 4463 adverse events were recorded in 1624 (51%) of all treated patients. The most frequent adverse event was weight gain, followed by headache, fatigue and sleepiness. Only 2% of all adverse events were evaluated as adverse events of medium or high intensity. Higher occurrences of some adverse events were noted for specific combinations. CONCLUSION: The advantages of AD combinations undoubtedly include administration of lower doses and a reduction of adverse events associated with higher doses of individual ADs. On the other hand, adverse events can also sum. Nevertheless it is generally agreed that, in some patients, a combination of ADs, with different mechanisms of action, can be considered safe and effective polypharmacy.

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.

Source-based morphometry of gray matter volume in men with first-episode schizophrenia.

OBJECTIVES: There is a lot of variability between the results of studies reporting the pattern of gray matter volume changes in schizophrenia. Methodological issues may play an important role in this heterogeneity. The aim of the present study was to replicate the better performance of multivariate "source-based morphometry" (SBM) over the mass-univariate approach. EXPERIMENTAL DESIGN: Voxel-based morphometry of Jacobian-modulated gray matter volume images, using voxel and cluster level inference, and SBM were performed in a group of first-episode schizophrenia patients (N = 49) and healthy controls (N = 127). RESULTS: Using SBM we were able to find a significant reduction of gray matter volume in fronto-temporo-cerebellar areas whereas no significant results were obtained using voxel-based morphometry. CONCLUSION: Multivariate analysis of gray matter volume seems to be a suitable method for characterization of the pattern of changes at the beginning of the illness in schizophrenia subjects.