Expanding the range of ZNF804A variants conferring risk of psychosis.

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).

P300 deficits in adults with attention deficit hyperactivity disorder: a meta-analysis.

BACKGROUND: The P300 (P3) event-related potential (ERP) component, a possible endophenotype for attention deficit hyperactivity disorder (ADHD), has been widely examined in children, but received little attention in adults. Our objective was to conduct a meta-analysis of P3 studies in adults with ADHD. METHOD: We searched the Medline and PsycINFO databases for controlled studies examining both adult ADHD and matched healthy controls. Six relevant publications were identified for the meta-analysis, which had comparable data across studies with regard to the amplitude of ERP components related to target detection (P3, P3b). Pooled effect size (ES) for P3 amplitude as well as the association of the ES with age and gender were investigated using meta-regression. RESULTS: Comparing the ADHD group versus controls, the pooled effect size for a decrease in P3 amplitude was in the medium range (Cohen's d=-0.55, p=0.0006). Additionally, meta-regression revealed that decrease in P3 amplitude significantly varied with the mean age of ADHD patients (p=0.0087), with a gradual increasing of the difference at higher ages. Results also showed a significant association between the ES and gender, indicating a more pronounced reduction of P3 amplitude in the ADHD group versus controls when females were predominantly represented in the sample. CONCLUSIONS: To our knowledge, this is the first meta-analysis of P3 characteristics in adults with ADHD. It reveals a significantly decreased P3 amplitude during target detection. Our result that the reduction in P3 amplitude increases with age is interpreted in a neurodevelopmental context.

EPA guidance on treatment of negative symptoms in schizophrenia.

Negative symptoms of schizophrenia remain a major therapeutic challenge. The progress in the conceptualization and assessment is not yet fully reflected by treatment research. Nevertheless, there is a growing evidence base regarding the effects of biological and psychosocial interventions on negative symptoms. The importance of the distinction between primary and secondary negative symptoms for treatment selection might seem evident, but the currently available evidence remains limited. Good clinical practice is recommended for the treatment of secondary negative symptoms. Antipsychotic treatment should be optimized to avoid secondary negative symptoms due to side effects and due to positive symptoms. For most available interventions, further evidence is needed to formulate sound recommendations for primary, persistent, or predominant negative symptoms.However, based on currently available evidence recommendations for the treatment of undifferentiated negative symptoms (including both primary and secondary negative symptoms) are provided. Although it has proven difficult to formulate an evidence-based recommendation for the choice of an antipsychotic, a switch to a second-generation antipsychotic should be considered for patients who are treated with a first-generation antipsychotic. Antidepressant add-on to antipsychotic treatment is an option. Social skills training is recommended as well as cognitive remediation for patients who also show cognitive impairment. Exercise interventions also have shown promise. Finally, access to treatment and to psychosocial rehabilitation should be ensured for patients with negative symptoms. Overall, there is definitive progress in the field, but further research is clearly needed to develop specific treatments for negative symptoms.

EPA guidance on assessment of negative symptoms in schizophrenia.

BACKGROUND: During the last decades, a renewed interest for negative symptoms (NS) was brought about by the increased awareness that they interfere severely with real-life functioning, particularly when they are primary and persistent. METHODS: In this guidance paper, we provide a systematic review of the evidence and elaborate several recommendations for the conceptualization and assessment of NS in clinical trials and practice. RESULTS: Expert consensus and systematic reviews have provided guidance for the optimal assessment of primary and persistent negative symptoms; second-generation rating scales, which provide a better assessment of the experiential domains, are available; however, NS are still poorly assessed both in research and clinical settings.This European Psychiatric Association (EPA) guidance recommends the use of persistent negative symptoms (PNS) construct in the context of clinical trials and highlights the need for further efforts to make the definition of PNS consistent across studies in order to exclude as much as possible secondary negative symptoms. We also encourage clinicians to use second-generation scales, at least to complement first-generation ones.The EPA guidance further recommends the evidence-based exclusion of several items included in first-generation scales from any NS summary or factor score to improve NS measurement in research and clinical settings. Self-rated instruments are suggested to further complement observer-rated scales in NS assessment.Several recommendations are provided for the identification of secondary negative symptoms in clinical settings. CONCLUSIONS: The dissemination of this guidance paper may promote the development of national guidelines on negative symptom assessment and ultimately improve the care of people with schizophrenia.

Attention deficit hyperactivity disorder (ADHD): gender- and age-related differences in neurocognition.

BACKGROUND: Despite the growing recognition that the clinical symptom characteristics associated with attention deficit hyperactivity disorder (ADHD) persist into adulthood in a high proportion of subjects, little is known about the persistence of neurocognitive deficits in ADHD. The objective was twofold: (1) to conduct a meta-analysis of neuropsychological studies to characterize attentional performance in subjects with adult ADHD by examining differences in ADHD versus normal control subjects; and (2) to investigate whether these differences vary as a function of age and gender. METHOD: Twenty-five neuropsychological studies comparing subjects with adult ADHD and healthy controls were evaluated. Statistical effect size was determined to characterize the difference between ADHD and control subjects. Meta-regression analysis was applied to investigate whether the difference between ADHD and control subjects varied as a function of age and gender across studies. RESULTS: Tests measuring focused and sustained attention yielded an effect size with medium to large magnitude whereas tests of simple attention resulted in a small to medium effect size in terms of poorer attention functioning of ADHD subjects versus controls. On some of the measures (e.g. Stroop interference), a lower level of attention functioning in the ADHD group versus the controls was associated with male gender. CONCLUSIONS: Adult ADHD subjects display significantly poorer functioning versus healthy controls on complex but not on simple tasks of attention, and the degree of impairment varies with gender, with males displaying a higher level of impairment.

Comparative effectiveness of second generation long-acting injectable antipsychotics based on nationwide database research in Hungary.

BACKGROUND: Schizophrenia is a severe condition that affects approximately 1% of the population. Certain elements of antipsychotic treatment can only be examined in large population, thus the need for population-based real-world analyses has been increasing. PATIENTS AND METHODS: Hungarian National Health Fund database includes all healthcare data of the population of Hungary. All patients diagnosed with schizophrenia between 01.01.2006 and 31.12.2015 were included in the study. We analyzed all patients with newly initiated second-generation antipsychotic during the inclusion period (01.01.2012-31.12.2013). Patients were followed for 2 years. All-cause treatment discontinuation served as the primary outcome of the study. Patients with newly initiated long-acting injectable treatments were further investigated in stratified analyses based on their previous treatment. RESULTS: 106,624 patients had schizophrenia diagnosis during the study period. 12,232 patients met the inclusion criteria for newly initiating second-generation antipsychotic during the inclusion period. The proportion of patients still on treatment after 1 year for oral treatments varied between 17% (oral risperidone) and 31% (oral olanzapine) while the analogous data for long acting injectables were between 32% (risperidone long acting) and 64% (paliperidone long acting one monthly). The 2-year data were similarly in favor of long-actings. Median time to discontinuation in the oral group varied between 57 days (clozapine) and 121 days (olanzapine). The median time to discontinuation for long-actings was significantly longer: between 176 and 287 days; in case of paliperidone long acting, median was not reached during the observation period. Patients receiving long-acting treatment switched from another long-acting remained on the newly initiated treatment significantly longer than those switched from orals. CONCLUSION: Our results indicate the superiority of second generation long-acting antipsychotics with regard to rates of treatment discontinuation and periods of persistence to the assigned medication.

Updated European Consensus Statement on diagnosis and treatment of adult ADHD.

Background Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that often persists into adulthood and old age. Yet ADHD is currently underdiagnosed and undertreated in many European countries, leading to chronicity of symptoms and impairment, due to lack of, or ineffective treatment, and higher costs of illness. Methods The European Network Adult ADHD and the Section for Neurodevelopmental Disorders Across the Lifespan (NDAL) of the European Psychiatric Association (EPA), aim to increase awareness and knowledge of adult ADHD in and outside Europe. This Updated European Consensus Statement aims to support clinicians with research evidence and clinical experience from 63 experts of European and other countries in which ADHD in adults is recognized and treated. Results Besides reviewing the latest research on prevalence, persistence, genetics and neurobiology of ADHD, three major questions are addressed: (1) What is the clinical picture of ADHD in adults? (2) How should ADHD be properly diagnosed in adults? (3) How should adult ADHDbe effectively treated? Conclusions ADHD often presents as a lifelong impairing condition. The stigma surrounding ADHD, mainly due to lack of knowledge, increases the suffering of patients. Education on the lifespan perspective, diagnostic assessment, and treatment of ADHD must increase for students of general and mental health, and for psychiatry professionals. Instruments for screening and diagnosis of ADHD in adults are available, as are effective evidence-based treatments for ADHD and its negative outcomes. More research is needed on gender differences, and in older adults with ADHD.

Dynamics of phosphatidylinositol 4,5-bisphosphate in actin-rich structures.

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) is known to regulate a wide range of molecular targets and cellular processes, from ion channels to actin polymerization [1] [2] [3] [4] [5] [6]. Recent studies have used the phospholipase C-delta1 (PLC-delta1) pleckstrin-homology (PH) domain fused to green fluorescent protein (GFP) as a detector for PI(4,5)P(2) in vivo [7] [8] [9] [10]. Although these studies demonstrated that PI(4,5)P(2) is concentrated in the plasma membrane, its association with actin-containing structures was not reported. In the present study, fluorescence imaging of living NIH-3T3 fibroblasts expressing the PLC-delta1 PH domain linked to enhanced green fluorescent protein (PH-EGFP) reveals intense, non-uniform fluorescence in distinct structures at the cell periphery. Corresponding fluorescence and phase-contrast imaging over time shows that these fluorescent structures correlate with dynamic, phase-dense features identified as ruffles and with microvillus-like protrusions from the cell's dorsal surface. Imaging of fixed and permeabilized cells shows co-localization of PH-EGFP with F-actin in ruffles, but not with vinculin in focal adhesions. The selective concentration of the PH-EGFP fusion protein in highly dynamic regions of the plasma membrane that are rich in F-actin supports the hypothesis that localized synthesis and lateral segregation of PI(4,5)P(2) spatially restricts actin polymerization and thereby affects cell spreading and retraction.

Mortality and the relationship of somatic comorbidities to mortality in schizophrenia. A nationwide matched-cohort study.

AIM: We conducted a matched-cohort study to assess mortality in schizophrenia and the relationship of mortality with comorbid somatic conditions and suicide attempts. METHOD: A full-population register-based prospective matched-cohort study was performed including all eligible patients with schizophrenia in Hungary between 01/01/2005 and 31/12/2013. Control subjects were individually matched to patients with schizophrenia at a 5:1 ratio. The principal outcome measure was death due to any reason. A non-parametric approach was used for descriptive statistical purposes, the Kaplan-Meier model for survival analysis, and the Cox proportional-hazards regression model for inferential statistics. RESULTS: Patients with schizophrenia (n=65,169) had substantially higher risk of all-cause mortality than the control subjects (n=325,435) (RR=2.4; P<0.0001). Comorbidities and suicide attempts were associated with significantly increased mortality in both groups. As compared to the controls, 20-year old males with schizophrenia had a shorter life expectancy by 11.5years, and females by 13.7years; the analogous numbers for 45-year old schizophrenics were 8.1 and 9.6years, respectively. CONCLUSIONS: A significant mortality gap - mainly associated with somatic comorbidities - was detected between patients with schizophrenia and individually matched controls. Improved medical training to address the disparity in mortality, and many other factors including lack of resources, access to and model of medical care, lifestyle, medication side effects, smoking, stigma, need for early intervention and adequate health care organization could help to better address the physical health needs of patients with schizophrenia.

A systematic review of the efficacy and safety of second generation antipsychotics in the treatment of mania.

Second generation antipsychotic agents are increasingly used in the management of acute mania. A systematic review of the efficacy and safety of these agents, as both monotherapy and in combination with mood stabilisers, was performed to establish the evidence for their use. Randomised controlled trials (RCTs) were critically appraised in more detail than studies that presented lower levels of evidence such as case reports, case series and open label follow up studies. We found 11 RCTs reporting on patients treated with second generation antipsychotics for acute bipolar mania, of which three included randomisation between the second generation antipsychotic and placebo, and eight between a mood stabiliser combined with either the second generation antipsychotic or placebo. Data from non-randomised trials is also presented.

Once-monthly paliperidone palmitate in recently diagnosed and chronic non-acute patients with schizophrenia.

OBJECTIVE: To explore the treatment response, tolerability and safety of once-monthly paliperidone palmitate (PP1M) in non-acute patients switched from oral antipsychotics, stratified by time since diagnosis as recently diagnosed (≤3 years) or chronic patients (>3 years). RESEARCH DESIGN AND METHODS: Post hoc analysis of a prospective, interventional, single-arm, multicentre, open-label, 6-month study performed in 233 recently diagnosed and 360 chronic patients. MAIN OUTCOME MEASURES: The proportion achieving treatment response (defined as ≥20% improvement in Positive and Negative Syndrome Scale [PANSS] total score from baseline to endpoint) and maintained efficacy (defined as non-inferiority in the change in PANSS total score at endpoint [Schuirmann's test]). RESULTS: 71.4% of recently diagnosed and 59.2% of chronic patients showed a ≥20% decrease in PANSS total score (p = 0.0028 between groups). Changes in PANSS Marder factors, PANSS subscales, and the proportion of patients with a Personal and Social Performance scale (PSP) total score of 71-100 were significantly greater in recently diagnosed compared with chronic patients. PP1M was well tolerated, presenting no unexpected safety findings. CONCLUSION: These data show that recently diagnosed patients treated with PP1M had a significantly higher treatment response and improved functioning, as assessed by the PSP total score, than chronic patients.

Haloperidol blood levels and clinical effects.

This study explored the relationships between plasma levels and the clinical effects of haloperidol in 176 acutely exacerbated schizophrenic or schizoaffective patients. After a single-blind placebo period of 1 week (period 1), they entered the double-blind period 2 randomly assigned to one of three plasma levels of haloperidol: low (2 to 13 ng/mL), medium (13.1 to 24 ng/mL), or high (24.1 to 35 ng/mL). Patients whose conditions did not improve in period 2 continued on one of the three haloperidol levels (period 3). Periods 2 and 3 lasted 6 weeks each. Only minor differences in clinical responses were noted among the three levels of haloperidol. These results imply that low or moderate doses of neuroleptics are appropriate for many acutely psychotic patients.

Nitrogen bridgehead compounds. 38. New antiallergic 4H-pyrido[1,2-a]pyrimidin-4-ones. 3.

The weak antiallergic activity of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (4) on the rat reaginic passive cutaneous anaphylaxis test was enhanced by the introduction of appropriate functional groups into position 9 of the pyridopyrimidine ring. The most active 9-substituted pyridopyrimidinecarboxylic acids contained an oxime, a phenylamino, or a (phenylamino)thioxomethyl group in position 9. The 9-phenylcarboxamido and 9-phenylhydrazono moieties may be regarded as bioisosteric groups in the pyridopyrimidinone series. In the series of 9-(arylamino)dihydropyridopyrimidines, the structure-activity relationship study revealed similar relationships as found for the 9-(arylhydrazono)tetrahydropyridopyrimidines. The biological activity was due to the 6S enantiomers. A monosubstituted arylamino moiety in position 9 was necessary for the intravenous activity. The most active compound, 9-[(3-acetylphenyl)amino]-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H- pyrido[1,2-a]pyrimidine-3-carboxylic acid (40) was three times as active as the reference sodium chromoglycate (DSCG) in the passive cutaneous anaphylaxis (PCA) test.

Relationship between the Brief Psychiatric Rating Scale and the Scale for the Assessment of Negative Symptoms: a study of their correlation and redundancy.

Because overlapping psychometric scales are used frequently in psychiatric research, examination of the relationship between scales has become increasingly important. The concept of relationship is the focus of this article. By way of illustration, the Brief Psychiatric Rating Scale (BPRS) and the Scale for the Assessment of Negative Symptoms (SANS) were compared for correlation and redundancy. Since these scales are frequently represented by derived summary variables (e.g., factors, total scores), it is also important to assess the effect of such representation on measures of relationship. The SANS and the BPRS were found to be highly intercorrelated. Nevertheless, the individual items and the subscale scores of the SANS contain information independent from the BPRS: the best BPRS predictor variates can explain only approximately half of the total variance of the SANS. When the SANS, however, is represented by a single variable (composite score), it becomes highly redundant with the anergia factor of the BPRS.

Electrodermally differentiated subgroups of anxiety patients. I. Automatic and vigilance characteristics.

A total of 32 anxiety patients (agoraphobia, panic syndrome, generalized anxiety syndrome) selected according to the DSM-III criteria were compared with 16 controls to determine distinguishing features of autonomic response patterns to a sequence of verbal and acoustic stimuli. In addition sensorimotor tasks were performed. The anxiety patients were classified into electrodermally stabile and labile subgroups on the basis of two reliably measurable psychophysiological parameters: the rate of electrodermal habituation to neutral stimuli and non-specific electrodermal activity. The electrodermally labile anxiety group was characterized by a high degree of variability in respiratory and pulse rate during the autonomic activation procedure. Within the control group the electrodermally labile subjects were characterized by a significantly higher pulse rate during the entire autonomic activation procedure. The reduced habituation capacity of the labile subgroup of anxiety patients compared to the controls was reflected in both retarded habituation and long durations of electrodermal responses to all verbal stimuli. This group also tolerated monotony; their performance did not drop during the 256 sensorimotor reaction time tasks and even exceeded the performance of the control group by the end of the test. The stabile anxiety subgroup had a significantly longer reaction time in all reaction time tasks than the labile subgroup of anxiety patients.

Chromogenic calix[4]arene as ionophore for potentiometric and optical sensors.

Chromogenic calix[4]arene derivative was synthesized and tested as an ionophore for potentiometric and optical sensors. Distinct sodium selectivity was observed with this ionophore based, plasticized PVC membranes in potentiometric measurements suggesting their utility for biological applications. Optode membranes exhibited sodium sensitivity in the 5 x 10(-2) -10(-4)M concentration range. The optical sensitivity was improved by the use of an internal, lipophilic base (TDDA). The operation of the optical sensor is in accordance with the ion-exchange theory.

Prevalence of subthreshold forms of psychiatric disorders in persons making suicide attempts in Hungary.

BACKGROUND: Suicide and suicide attempts have been associated to psychiatric illnesses; however, little is known about the role in suicide risk of those symptoms that do not meet the full criteria for a DSM-IV disorder. The aim of this study was to examine the prevalence of subthreshold psychiatric disorders among suicide attempters in Hungary. METHODS: Using a modified structured interview (Mini International Neuropsychiatric Interview) determining 16 Axis I psychiatric diagnoses and their subthreshold forms defined by the DSM-IV and a semistructured interview collecting background information, the authors examined 140 consecutive suicide attempters, aged 18-65 years. RESULTS: Eighty-three-point-six percent of the attempters had one or more current threshold diagnoses on Axis I and in addition more than three-quarters (78.6%) of the subjects had at least one subthreshold diagnosis. Six-point-four percent of the subjects (N = 9) had neither subthreshold nor threshold diagnoses at the time of their suicide attempts. Ten percent of the subjects (N = 14), not meeting the full criteria for any DSM-IV diagnoses, had at least one subthreshold diagnosis. In 68.6% of the subjects (N = 96), both subthreshold and threshold disorders were diagnosed at the time of their suicide attempts. The number of subthreshold and threshold diagnoses were positively and significantly related (chi2 = 5.12, df = 1, P < 0.05). Sixty-three-point-six percent of the individuals received two or more current threshold diagnoses on Axis I and 44.3% of the individuals (N = 62) had two or more subthreshold diagnoses at the time of their suicide attempts. LIMITATIONS: The subthreshold definitions in this study included only those forms of the disorders which required the same duration as the criteria DSM-IV disorder with fewer symptoms. Conclusions - Suicide attempts showed a very high prevalence of subthreshold disorders besides psychiatric disorders meeting the full criteria required according to the DSM-IV. Subthreshold forms of mental disorders need to be taken into account in suicide prevention.

[Pharmacotherapy of anxiety disorders]. / A szorongásos betegségek farmakoterápiája.

The pharmacotherapy of anxiety disorders has revolutionary changed in the last few years. This ICD-10 based review of the literature provides help for general practitioners and other specialists in the short and long term treatment of anxiety as well as in the discontinuation of pharmacologic treatment. The author describes the use of high potency benzodiazepines, selective serotonin reuptake inhibitors and 5 HT1A partial agonists and summarizes the disadvantages of some older drugs still in use for the treatment of anxiety disorders.

Is ADHD severity in adults associated with the lifetime prevalence of comorbid depressive episodes and anxiety disorders?

PURPOSE: The objective of the present study was to examine the association between ADHD severity and the lifetime prevalence of comorbid depressive episodes and anxiety disorders in adults with ADHD. SUBJECTS/MATERIALS AND METHODS: Analyses were based on data of the Conner's Adult ADHD Rating Scale (CAARS) and a parent study examining the epidemiology of adult ADHD in 17 GP practices in Budapest, Hungary. Subjects between 18 and 60 years were included in the screening phase (n=3529). Out of 279 positively screened subjects 161 participated in a clinical interview and completed the CAARS to confirm the diagnosis. We applied four diagnostic criteria: "DSM-IV"; "No-onset" (DSM-IV criteria without the specific requirement for onset); "Symptoms-only" (DSM-IV symptom criterion only); and "Reduced symptoms-only" (DSM-IV symptom criterion with a reduced threshold for symptom count). The MINI PLUS 5.0 was used to assess psychiatric comorbidity. RESULTS: ADHD severity, as measured by the CAARS ADHD Index, showed a significant positive association with the prevalence of comorbid depressive episodes in all but the "ADHD_No-onset" group ("DSM-IV": F[1.23]=8.39, P=0.0081; "No-onset": F(1.27)=0.97, P=0.3346; "Symptoms-only": F[1.55]=30.79, P<0.0001; "Reduced symptoms-only": F(1.62)=26.69, P<0.0001). DISCUSSION AND CONCLUSION: Results indicate that ADHD symptom severity increases in association with lifetime comorbidity with depression.

Position statement of the European Psychiatric Association (EPA) on the value of antidepressants in the treatment of unipolar depression.

This position statement will address in an evidence-based approach some of the important issues and controversies of current drug treatment of depression such as the efficacy of antidepressants, their effect on suicidality and their place in a complex psychiatric treatment strategy including psychotherapy. The efficacy of antidepressants is clinically relevant. The highest effect size was demonstrated for severe depression. Based on responder rates and based on double-blind placebo-controlled studies, the number needed to treat (NNT) is 5-7 for acute treatment and four for maintenance treatment. Monotherapy with one drug is often not sufficient and has to be followed by other antidepressants or by comedication/augmentation therapy approaches. Generally, antidepressants reduce suicidality, but under special conditions like young age or personality disorder, they can also increase suicidality. However, under the conditions of good clinical practice, the risk-benefit relationship of treatment with antidepressants can be judged as favourable also in this respect. The capacity of psychiatrists to individualise and optimise treatment decisions in terms of 'the right drug/treatment for the right patient' is still restricted since currently there are no sufficient powerful clinical or biological predictors which could help to achieve this goal. There is hope that in future pharmacogenetics will contribute significantly to a personalised treatment. With regard to plasma concentration, therapeutic drug monitoring (TDM) is a useful tool to optimize plasma levels therapeutic outcome. The ideal that all steps of clinical decision-making can be based on the strict rules of evidence-based medicine is far away from reality. Clinical experience so far still has a great impact.