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Introduction: Non-adherence to medication significantly affects bipolar disorder outcomes. Long-Acting Injectable antipsychotics show promise by ensuring adherence and averting relapses., Areas Covered: This narrative review sought to evaluate the efficacy of second-generation injectable antipsychotics in bipolar disorder through searches in Embase, MEDLINE, and PsycInfo for randomized controlled trials and mirror-image studies.Risperidone and aripiprazole Long-Acting Injectables demonstrated effectiveness in preventing mood recurrences compared to placebos in adults with bipolar disorder. They showed superiority in preventing mania/hypomania relapses over placebos but did not appear to significantly outperform active oral controls. Notably, active controls seem to be more effective in preventing depression relapses than Long-Acting Injectables. Mirror-Image studies point toward the reduction of hospitalization rates following LAI initiation., Expert Opinion: The available evidence points thus toward the efficacy of LAIs, especially in managing manic episodes and reducing hospitalizations, The current evidence does not however immediately support prioritizing LAIs over oral medications in bipolar disorder treatment. More high-quality studies, especially comparing LAIs directly with active controls, are crucial to gain a comprehensive understanding of their efficacy. These findings highlight the need for further research to guide clinicians in optimizing treatment strategies for bipolar disorder.

Introduction: Bipolar disorder is a severe, chronic psychiatric disorder with a need for long-term treatment. Patient nonadherence is frequent and poses a major problem in maintenance therapy. Aripiprazole once-monthly long-acting injectable (AOM LAI) is a recently US Food and Drug Administration-approved treatment option for maintenance therapy that could be of great value. Areas covered: This paper reviews the pharmacokinetic, efficacy and safety data for AOM LAI in bipolar disorder. Expert opinion: AOM LAI is a safe and efficacious treatment option in the maintenance therapy of bipolar I disorder. However, further research is still needed to determine the position of AOM LAI relative to other available treatment options.

Introduction: Bipolar I disorder (BD I) is complex with a chronic course that significantly impacts a sufferer's quality of life. As of right now, there are many available treatments that aim to rapidly treat manic or depressive episodes and stabilize mood. The purpose of this report is to provide an up-to-date comprehensive review of the available evidence-based trials of pharmacotherapy for the treatment of BD I., Areas Covered: This paper reviews randomized active comparator-controlled or placebo-controlled trials evaluating the use of current pharmacotherapy in adults with BD I from phase III to clinical practice. Monotherapy and combination therapy for acute and long-term treatment were reviewed for this purpose., Expert Opinion: There are many treatments available for BD mania; however, the depressive and stabilization phases of the illness remain a clinical challenge. Unfortunately, randomized controlled trials do not represent 'real world' patients, as their strict inclusion and exclusion criteria do not allow for different features sometimes present in patients to be considered. Research efforts must also focus on treating cognitive deficits, which adds to lower functional outcome. The authors believe that there is dire need for new, more targeted treatments in BD I, with a critical view of the side effects.

Quetiapine, an atypical antipsychotic drug, is recommended for the treatment of schizophrenia and mood disorders. In addition, given its sedative effects, a low dose of the agent is also widely used in the treatment of anxiety disorders, personality disorders, substance abuse, and sleep disturbances. In this case study, quetiapine was the first effective drug in reducing chronic insomnia in a male patient with a long treatment history. Because its effect declined over time, in the course of two years, a gradual dose increase led to a posology 50 times higher than the off-label dosage used to obtain sedation, i.e. 25-100 mg quetiapine administered once daily. This case raises awareness of the ease with which dose escalation of quetiapine occurs. The risk of side effects and, possibly, dependence and abuse underlines the importance of regular and careful patient monitoring. Given the unexpected effectiveness of the agent and the absence of side effects in the described case, we argue that in treatment-resistant insomnia, a high dose of quetiapine may be justifiable in selected cases but also urge that further research on the long-term effects and potential adverse events of quetiapine for this indication is of the utmost importance.

Objectives: Cytokine level alterations suggest a role for the immune system in the pathophysiology of bipolar disorder (BD). Pharmacotherapy is an important confounding factor in clinical research on cytokine levels. In this systematic review we collate the evidence on blood cytokine levels in medication-free BD and the effects of single mood-stabilizing drugs on these levels., Methods: A systematic review was conducted according to the PRISMA statement. We searched the Pubmed and Embase databases for clinical studies reporting either on cytokine levels in medication-free BD or on the effects of single mood-stabilizing drugs on cytokine levels in BD., Results: Of the 564 articles screened, 17 were included. Fourteen articles report on medication-free patients with BD and indicate state-related cytokine alterations. Six articles discuss the effect of lithium. Whereas no data on short-term effects of lithium were found, ≥2 months lithium use in euthymic populations is associated with normal cytokine levels. Two studies report no effect of valproate and no studies were found on carbamazepine, lamotrigine or antipsychotics., Limitations: The available studies are characterized by a broad methodological heterogeneity and limited replication between studies., Conclusions: This systematic review suggests the presence of state-related cytokine level alterations in medication-free BD with most evidence pointing to a proinflammatory cytokine response in mania. Euthymia and long-term lithium use are associated with normal cytokine levels. To improve our understanding of the impact of mood-stabilizing drugs on cytokine levels, longitudinal studies with medication-free baseline, randomized controlled single-drug treatment protocols and close mood state monitoring are needed., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Oral fluid (OF) is an interesting alternative for conventional blood testing in therapeutic drug monitoring. OF can be used for screening but its value for quantification has to be established., Methods: To evaluate the value of OF for quantification of 11 commonly used antipsychotics (APs) and 5 metabolites, an ultra-high performance liquid chromatography-tandem mass spectrometric method was validated. OF was obtained from psychiatric patients using a Quantisal collection device. OF to serum concentration ratios were determined, taking into account the exact volume of collected OF., Results: Linearity was evaluated at 7 or 8 calibration levels. Accuracy criteria were fulfilled, except for pipamperone (PIP) at quality control (QC) low. The intraday precision ranged 0.88%-14.73% and interday precision ranged 1.92%-16.17%. The mean recovery from the collection pad was 37.1% at QC low and 40.3% at QC high for 1 mL of collected OF; for 0.5 mL collected OF mean recovery was 35.0% at QC low and 37.3% at QC high. When 0.1 mL OF was collected, recovery data were unreliable. Mean absolute matrix effect was 101.1% (82.0%-120.0%). OF patient samples (n = 89) containing 269 APs and metabolites were acquired and the mean volume of collected OF was 0.562 mL (0.057-1.232 mL). The OF to serum ratios were above 1 for all APs (1.54-28.50), except for aripiprazole (0.21) and zuclopenthixol (0.66). A broad range of calculated ratios for all APs was obtained., Conclusions: This validated ultra-high performance liquid chromatography-tandem mass spectrometric method can be used to reliably quantify APs in OF, even when recovery is low. Because the correlation between OF and serum concentrations was low and in addition results were highly variable, it can only be concluded that OF is a potentially interesting matrix, particularly for screening for noncompliance.

Therapeutic drug monitoring of antipsychotics is important in optimizing individual therapy. In psychiatric populations, classical venous blood sampling is experienced as frightening. Interest in alternative techniques, like dried blood spots (DBS), has consequently increased. A fast and easy to perform DBS method for quantification of 16 antipsychotics (amisulpride, aripiprazole, asenapine, bromperidol, clozapine, haloperidol, iloperidone, levosulpiride, lurasidone, olanzapine, paliperidone, pipamperone, quetiapine, risperidone, sertindole and zuclopenthixol) and 8 metabolites was developed. DBS were prepared using 25 μL of whole blood and extraction of complete spots was performed using methanol: methyl-t-butyl-ether (4:1). After evaporation, the extract was reconstituted in the mobile phase and 10 μL were injected on an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Separation using a C18 column and gradient elution with a flow rate of 0.5 mL/min resulted in a 6-min run-time. Ionization was performed in positive mode and a dynamic MRM method was applied. Median recovery was 66.4 % (range 28.7-84.5%). Accuracy was within the acceptance criteria, except for pipamperone (LLOQ and low concentration) and lurasidone (low concentration). Imprecision was only aberrant for lurasidone at low and medium concentration. All compounds were stable during 1 month at room temperature, 4 °C and -18 °C. Lurasidone was unstable when the extract was stored for 12 h on the autosampler. Absolute matrix effects (ME) (median 66.1%) were compensated by the use of deuterated IS (median 98.8%). The DBS method was successfully applied on 25-μL capillary DBS from patients and proved to be a reliable alternative for quantification of all antipsychotics except for olanzapine and N-desmethylolanzapine., (Copyright © 2014 John Wiley & Sons, Ltd.)

Measuring antipsychotic concentrations in human matrices is important for both therapeutic drug monitoring and forensic toxicology. This review provides a critical overview of the analytical methods for detection and quantification of antipsychotics published in the last four years. Focus lies on advances in sample preparation, analytical techniques and alternative matrices. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is used most often for quantification of antipsychotics. This sensitive technique makes it possible to determine low concentrations not only in serum, plasma or whole blood, but also in alternative matrices like oral fluid, dried blood spots, hair, nails and other body tissues. Current literature on analytical techniques for alternative matrices is still limited and often requires a more thorough validation including a comparison between conventional and alternative results to determine their actual value. Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) makes it possible to quantify a high amount of compounds within a shorter run time. This technique is widely used for multi-analyte methods. Only recently, high-resolution mass spectrometry has gained importance when a combination of screening of (un)known metabolites, and quantification is required., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Aim: DBS sampling has been proposed as an alternative for venous blood collection in therapeutic drug monitoring (TDM) of antipsychotics. For implementation in routine practice, a comparison between capillary and venous blood concentrations is mandatory., Results: A DBS method for quantification of antipsychotics was clinically validated. First, whole blood therapeutic ranges were calculated using the blood:serum ratio. Calculation of DBS:blood ratios and Passing-Bablok regression analysis demonstrated that concentrations obtained by DBS analysis were highly comparable to those obtained by conventional whole blood analysis. Clinical interpretation of serum, whole blood and DBS concentrations were highly identical (sensitivity 91.6-97.6%)., Conclusion: This is the first clinical study demonstrating the value of DBS sampling in TDM of antipsychotics.

Background: Therapeutic drug monitoring of antipsychotics is important for optimizing therapy, explaining adverse effects, non-response or poor compliance. We developed a UHPLC-MS/MS method for quantification of 16 commonly used and recently marketed antipsychotics and 8 metabolites in serum., Methods: After liquid-liquid extraction using methyl tert-butyl ether, analysis was performed on an Agilent Technologies 1290 Infinity LC system coupled with an Agilent Technologies 6460 Triple Quadrupole MS. Separation with a C18 column and gradient elution at 0.5 mL/min resulted in a 6-min run-time. Detection was performed in dynamic MRM, monitoring 3 ion transitions per compound. Isotope labeled internal standards were used for every compound, except for bromperidol and levosulpiride., Results: Mean recovery was 86.8%. Matrix effects were -18.4 to +9.1%. Accuracy ranged between 91.3 and 107.0% at low, medium and high concentrations and between 76.2 and 113.9% at LLOQ. Within-run precision was <15% (CV), except for asenapine and hydroxy-iloperidone. Between-run precision was aberrant only for 7-hydroxy-N-desalkylquetiapine, asenapine and reduced haloperidol. No interferences were found. No problems of instability were observed, even for olanzapine. The method was successfully applied on patient samples., Conclusions: The liquid-liquid extraction and UHPLC-MS/MS technique allows robust target screening and quantification of 23 antipsychotics and metabolites., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The aim of this review is to provide information for interpreting outcome results from monitoring of antipsychotics in biological samples. A brief overview of the working mechanisms, pharmacological effects, drug interactions, and analytical methods of classical and atypical antipsychotics is given. Nineteen antipsychotics were selected based on their importance in the worldwide market as follows: amisulpride, aripiprazole, asenapine, bromperidol, clozapine, flupenthixol, haloperidol, iloperidone, lurasidone, olanzapine, paliperidone, perphenazine, pimozide, pipamperone, quetiapine, risperidone, sertindole, sulpiride, and zuclopenthixol. A straightforward relationship between administered dose, plasma or serum concentration, clinical outcome, or adverse effects is often lacking. Nowadays, focus lies on therapeutic drug monitoring and individualized therapy to find adequate treatment, to explain treatment failure or nonresponse, and to check patient compliance. However, extensive research in this field is still mandatory.

Background: Second-generation antipsychotics have gradually replaced first-generation antipsychotics as first-line treatment for patients with schizophrenia. Some positive effects on verbal cognition have been shown for the second-generation antipsychotics, but most studies are based on relatively small numbers of patients., Objective: In the frame of the prospective, multi-centre, open-label study ESCAPE (A Prospective, Multicenter, Open-Label Study to Evaluate the Effectiveness and the Effect on Cognitive Function of a Treatment With Aripiprazole in a Broad Range of Schizophrenic Patients; clinicaltrials.gov identifier NCT00329810) evaluating the effectiveness and effect on cognitive functioning of aripiprazole in schizophrenic patients, we conducted a post hoc analysis to examine changes in verbal cognition and investigate the predictive value of a cognitive improvement on quality of life., Study Design: This was a prospective, multi-centre, non-comparative, open-label study of aripiprazole in schizophrenic patients. At study enrolment, these patients were being treated with various first- or second-generation antipsychotics or were without previous antipsychotic treatment. On entering the study, all patients were treated with aripiprazole (Abilify(®); Otsuka, Tokyo, Japan) monotherapy; those patients who had received prior treatment with antipsychotics had their current drug(s) tapered off over a 2-week period. A post hoc analysis of the effect of aripiprazole on two verbal cognitive measures and their correlation with efficacy measures and quality of life was conducted., Setting: Patients with schizophrenia were recruited in 56 psychiatric hospitals., Patients: A total of 361 patients with schizophrenia, ranging from 18 to 65 years, entered the study., Intervention: Patients were treated with aripiprazole monotherapy at a dosage of 10-30 mg/day. Those who were receiving first- or second-generation antipsychotics at enrolment were switched to aripiprazole monotherapy by tapering off their current drug(s) over a 2-week period., Main Outcome Measure: Physician- and patient-rated parameters were measured to gain a complete view of the effectiveness of aripiprazole on the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) at baseline and at weeks 4, 8 and 12 and on the Clinical Global Impression-Severity of Illness (CGI-S) scale at baseline and at weeks 1, 2, 4, 8 and 12. A secondary endpoint of verbal cognitive function was measured by the California Verbal Learning Test (CVLT) and the Verbal Fluency (VF) test at baseline and at weeks 4 and 12. The hypothesis of an improvement in verbal cognition and its predictive value on the quality of life was formulated during data collection., Results: 238 patients completed the study. A significant improvement in verbal cognition was observed from week 4 with the long term free recall (LTFR) in the CVLT over the scheduled visits in the trial (F(2,519) = 29.67, p < 0.0001). For the phonemic (letter) subtest of the VF test, patients scored significantly better at week 12 in comparison with baseline (F(2,519) = 3.57, p = 0.0289). There was no significant effect on the semantic (categories) subtest of the VF test (F(2,518) = 0.57, p = 0.5614). Improvement in CGI-S scores at a particular moment in time predicted improvement in LTFR scores at that same moment (F(1,519) = 38.38, p < 0.0001) and in the phonemic (F(1,519) = 42.77, p < 0.0001) and semantic (F(1,518) = 67.43, p < 0.0001) subtests of the VF test. Similarly, CGI-S score improvement globally predicted quality-of-life improvement over visits. The Q-LES-Q scales leisure (F(1,144) = 14.03, p < 0.0001) and social relations (F(1,469) = 5.28, p = 0.0220) also directly correlated with verbal cognition., Conclusion: The findings suggest that switching to, or initiating aripiprazole in schizophrenic patients results in improvement in verbal cognitive functioning. The observed improvement on quality of life is explained by the effect of aripiprazole on the CGI-S score, though the leisure and social relations scales of the Q-LES-Q also independently correlated with verbal fluency. Randomized, controlled, clinical trials of this effect of aripiprazole for selected patients are needed.

Background: Neurocognitive impairment and psychiatric symptoms have been associated with deficits in psychosocial and occupational functioning in patients with schizophrenia. This post-hoc analysis evaluates the relationships among cognition, psychopathology, and psychosocial functioning in patients with schizophrenia at baseline and following sustained treatment with antipsychotic drugs., Methods: Data were obtained from a clinical trial assessing the cognitive effects of selected antipsychotic drugs in patients with schizophrenia. Patients were randomly assigned to 24 weeks of treatment with olanzapine (n = 159), risperidone (n = 158), or haloperidol (n = 97). Psychosocial functioning was assessed with the Heinrichs-Carpenter Quality of Life Scale [QLS], cognition with a standard battery of neurocognitive tests; and psychiatric symptoms with the Positive and Negative Syndrome Scale [PANSS]. A path-analytic approach was used to evaluate the effects of changes in cognitive functioning on subdomains of quality of life, and to determine whether such effects were direct or mediated via changes in psychiatric symptoms., Results: At baseline, processing speed affected functioning mainly indirectly via negative symptoms. Positive symptoms also affected functioning at baseline although independent of cognition. At 24 weeks, changes in processing speed affected changes in functioning both directly and indirectly via PANSS negative subscale scores. Positive symptoms no longer contributed to the path-analytic models. Although a consistent relationship was observed between processing speed and the 3 functional domains, variation existed as to whether the paths were direct and/or indirect. Working memory and verbal memory did not significantly contribute to any of the path-analytic models studied., Conclusion: Processing speed demonstrated direct and indirect effects via negative symptoms on three domains of functioning as measured by the QLS at baseline and following 24 weeks of antipsychotic treatment.

Objective: The aim of this review was to discuss data from double-blind, randomized controlled trials (RCTs) that have investigated the effects of oral and long-acting injectable risperidone on cognitive and psychomotor functioning in patients with schizophrenia or schizoaffective disorder., Methods: PubMed/MEDLINE and the Institute of Scientific Information Web of Science database were searched for relevant English-language double-blind RCTs published between March 2000 and July 2008, using the terms schizophrenia, schizoaffective disorder, cognition, risperidone, psychomotor, processing speed, attention, vigilance, working memory, verbal learning, visual learning, reasoning, problem solving, social cognition, MATRICS, and long-acting. Relevant studies included patients with schizophrenia or schizoaffective disorder. Cognitive domains were delineated at the Consensus Conferences of the National Institute of Mental Health-Measurement And Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS). The tests employed to assess each domain and psychomotor functioning, and the within-group and between-group comparisons of risperidone with haloperidol and other atypical antipsychotics, are presented. The results of individual tests were included when they were individually presented and interpretable for either drug; outcomes that were presented as cluster scores or factor structures were excluded., Results: A total of 12 articles were included in this review. Results suggested that the use of oral risperidone appeared to be associated with within-group improvements on the cognitive domains of processing speed, attention/vigilance, verbal and visual learning and memory, and reasoning and problem solving in patients with schizophrenia or schizoaffective disorder. Risperidone and haloperidol seemed to generate similar beneficial effects (on the domains of processing speed, attention/vigilance, [verbal and nonverbal] working memory, and visual learning and memory, as well as psychomotor functioning), although the results for verbal fluency, verbal learning and memory, and reasoning and problem solving were not unanimous, and no comparative data on social cognition were available. Similar cognitive effects were found with risperidone, olanzapine, and quetiapine on the domains of verbal working memory and reasoning and problem solving, as well as verbal fluency. More research is needed on the domains in which study results were contradictory. For olanzapine versus risperidone, these were verbal and visual learning and memory and psychomotor functioning. No comparative data for olanzapine and risperidone were available for the social cognition domain. For quetiapine versus risperidone, the domains in which no unanimity was found were processing speed, attention/vigilance, nonverbal working memory, and verbal learning and memory. The limited available reports on risperidone versus clozapine suggest that: risperidone was associated with improved, and clozapine with worsened, performance on the nonverbal working memory domain; risperidone improved and clozapine did not improve reasoning and problem-solving performance; clozapine improved, and risperidone did not improve, social cognition performance. Use of long-acting injectable risperidone seemed to be associated with improved performance in the domains of attention/vigilance, verbal learning and memory, and reasoning and problem solving, as well as psychomotor functioning. The results for the nonverbal working memory domain were indeterminate, and no clear improvement was seen in the social cognition domain. The domains of processing speed, verbal working memory, and visual learning and memory, as well as verbal fluency, were not assessed., Conclusions: The results of this review of within-group comparisons of oral risperidone suggest that the agent appeared to be associated with improved functioning in the cognitive domains of processing speed, attention/vigilance, verbal and visual learning and memory, and reasoning and problem solving in patients with schizophrenia or schizoaffective disorder. Long-acting injectable risperidone seemed to be associated with improved functioning in the domains of attention/vigilance, verbal learning and memory, and reasoning and problem solving, as well as psychomotor functioning, in patients with schizophrenia or schizoaffective disorder.

Background: Psychomotor slowing is an intrinsic feature of schizophrenia, but little is known about its nature or to what extent it is influenced by antipsychotics. The Symbol-Digit Substitution Test (SDST) is an appropriate tool for assessing reduced processing speed, whereas performance on copying tasks may be more useful in evaluating psychomotor slowing., Objective: The primary aim of this study was to investigate the effects of different antipsychotic agents on psychomotor slowing in patients with schizophrenia., Methods: This cross-sectional study compared performance on line- and figure-copying tasks in schizophrenic inpatients (matched for symptomatology, demographic variables, and duration of illness) treated with risperidone, olanzapine, other atypical antipsychotics (amisulpride, aripiprazole, clozapine, or quetiapine), or conventional antipsychotics (bromperidol, flupentixol, haloperidol, pimozide, or zuclopenthixol) and in healthy controls. Other tests administered included the SDST to assess processing speed, the California Verbal Learning Test to gauge verbal memory, the Letter-Number Sequencing task to assess working memory, and the Wisconsin Card Sorting Test to measure executive function. Comparisons were made between each patient group and healthy controls; between patient groups; and, post hoc, between atypical and conventional antipsychotics., Results: The study included 26 patients treated with risperidone, 24 treated with olanzapine, 25 treated with other atypical antipsychotics, 21 treated with conventional antipsychotics, and 25 healthy controls. The groups were well matched in terms of sex, educational level, mean doses, and duration of illness. The conventional-antipsychotic group was significantly older (P=0.026) and had significantly higher positive symptoms scores (P=0.031) on the Positive and Negative Syndrome Scale compared with the risperidone group. Patients treated with conventional antipsychotics had significantly greater slowing on the copying tasks compared with patients treated with atypical antipsychotics (P

Rationale: Impaired psychomotor function has been shown to be associated with clinical and functional outcome in schizophrenia. However, few studies have investigated the short-term effects of antipsychotics on the cognitive and psychomotor functions of this patient group. Because many confounding factors tend to influence the test results in patient research, this study investigates the drugs' effects in healthy volunteers., Objectives: The short-term effects of haloperidol (2.5 mg), olanzapine (10 mg), and paroxetine (20 mg) on psychomotor function in 15 healthy volunteers are compared with placebo and each other., Methods: In a crossover design, the subjects completed a battery of psychomotor tasks assessing psychomotor speed, sensorimotor accuracy, visuospatial monitoring, and speed of information processing. In addition, peak velocity of saccadic eye movements and subscales of the visual analog scales were analyzed as the objective and subjective measures for sedation, respectively. Finally, the verbal memory test was used to assess the drugs' effects on memory., Results: Apart from affecting the pursuit task where visuospatial monitoring, sensorimotor speed, and sensorimotor accuracy are measured simultaneously, haloperidol has been proven to be not associated with sedative nor with impairing effects on psychomotor function or verbal memory. In contrast, olanzapine had significant sedative effects. Moreover, the subjects displayed a significant impairment on all measures of psychomotor function and verbal memory, which was not attributable to the drug's sedative effects. After administration of paroxetine, no effects were found, with the exception of a single improvement in eye movement velocity., Conclusions: Short-term administration of olanzapine, and not of haloperidol, impedes several aspects of psychomotor function and verbal memory in healthy volunteers.

Humans need to monitor their actions continuously to detect errors as fast as possible and to adjust their performance to prevent future errors. This process of action monitoring can be investigated by measuring the error-related negativity (ERN), an ERP component elicited immediately after an error. In the current study, we investigated action monitoring after administration of the classic antipsychotic haloperidol (2.5 mg), the atypical antipsychotic olanzapine (10 mg), and the antidepressant paroxetine (20 mg), a selective serotonin reuptake inhibitor. Healthy volunteers (N = 14) were administered the three compounds and placebo in a randomized, double-blind, single-dose, four-way cross-over design. All participants performed a speeded two-choice reaction task, while event-related potentials and behavioral measurements were obtained. Both haloperidol and olanzapine significantly reduced ERN amplitudes. After paroxetine, the ERN was not different from placebo. N2 congruency effects were not affected by treatment condition. Only olanzapine demonstrated behavioral effects, namely a slowing of responses, an increase in error rates, and the absence of performance adjustments. The attenuated ERNs after the dopamine antagonist haloperidol are in line with the presumed role of dopamine in action monitoring. Haloperidol is thought to block dopaminergic signaling, thus reducing ERN amplitudes. On the other hand, the effects of olanzapine are mainly caused by its sedative side effects, leading to a decline in motivation and appraisal of errors. Finally, the absence of any effects after paroxetine suggests that serotonin transmission does not play a direct role in regulating mechanisms related to action monitoring.

Purpose: Evidence indicates that classical antipsychotics may aggravate non-malignant and malignant catatonia (MC). Atypical antipsychotics are less likely to cause movement disorders than classical antipsychotics and they are being frequently prescribed in disorders that can be associated with catatonia. Therefore, the important question that arises is whether atypical antipsychotics have a role to play in the treatment of catatonia., Materials and Methods: A Medline search was performed to locate papers on the use of atypical antipsychotics in catatonia published between 1970 and 31st December 2004., Results: The literature on the use of atypical antipsychotics in catatonia consists of case reports and retrospective studies. In most cases of non-MC a reduction of the catatonic symptoms is reported upon treatment with atypical antipsychotics. Cases of MC relate mainly to the neuroleptic malignant syndrome (NMS), which is considered as an iatrogenic stuporous variant of MC caused by antipsychotics., Conclusion: There are indications that atypical antipsychotics may be useful in non-MC. As a consequence, one should not only focus on the possible extrapyramidal and autonomic side effects of these drugs, but also on the possible beneficial effects on certain brain functions and on the catatonic symptomatology. However, randomized controlled trials are needed to evaluate the effect of these drugs, and caution is advisable, since cases of NMS have been linked to treatment with atypical antipsychotics. There is no evidence to prescribe atypical antipsychotics in MC.

Objective: Different patterns of immune system upregulation are present in the acute vs. post-treatment states of psychotic illness. We explored the existence of state and trait markers in the peripheral immune system and two immune-associated neuroendocrine pathways (IDO and GTP-CH1 pathway) in a longitudinal sample of psychosis patients. We also evaluated the association of these markers with neuropsychiatric symptomatology. Method: Plasma concentrations of peripheral blood markers were measured in a transdiagnostic group of 49 inpatients with acute psychosis and 52 matched healthy control subjects. Samples were obtained in patients within 48 h after hospital admission for an acute psychotic episode (before initiation of antipsychotics), after 1–2 weeks and again after 8 weeks of treatment. Kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), phenylalanine, tyrosine, nitrite, and neopterin were measured using HPLC and LC-MS/MS analysis. Concentrations of CRP, CCL2 (MCP1) and cytokines were determined with multiplex immunoassay. PANSS interviews and cognitive tests were performed at baseline and follow-up. Mixed model analyses were used to identify trait and state markers. Results: Patients had significantly higher plasma concentrations of CRP, CCL2, IL1RA, and lower concentrations of KA and KA/Kyn at all time points (F7.5–17.5, all p < 0.001). Increased concentrations of IL6, IL8, IL1RA, TNFα, and CCL2 and decreased QA and 3-HK (F8.7–21.0, all p < 0.005) were found in the acute psychotic state and normalized after treatment. Low nitrite concentrations at admission rose sharply after initiation of antipsychotic medication (F42.4, p < 0.001). PANSS positive scale scores during the acute episode correlated with pro-inflammatory immune markers (r ≥ |0.5|), while negative scale scores correlated inversely with IDO pathway markers (r ≥ |0.4|). Normalization of KA and 3-HK levels between admission and follow-up corresponded to a larger improvement of negative symptoms (r = 0.5, p < 0.030) A reverse association was found between relative improvement of SDST scores and decreasing KA levels (r = 0.5, p < 0.010). Conclusion: The acute psychotic state is marked by state-specific increases of immune markers and decreases in peripheral IDO pathway markers. Increased CRP, CCL2, and IL1RA, and decreased KA and KA/Kyn are trait markers of psychotic illness. [ABSTRACT FROM AUTHOR]

Background: The pharmacotherapeutic management of agitation is a common clinical challenge. Pharmacotherapy is frequently used, the use of published guidelines is not known. The purpose of this study was twofold; to describe the prescribing patterns of psychiatrists and emergency physicians and to evaluate to which extent guidelines are used. Methods: A cross-sectional survey in the Dutch-speaking part of Belgium is carried out in 39 psychiatric hospitals, 11 psychiatric wards of a general hospital and 61 emergency departments. All physicians are asked for demographic information, their prescribing preferences, their use of guidelines and the type of monitoring (efectiveness, safety). For the basic demographic data and prescription preferences descriptive statistics are given. For comparing prescribing preferences of the drug between groups Chi square tests (or in case of low numbers Fisher's exact test) were performed. Mc Nemar test for binomial proportions for matched-pair data was performed to see if the prescription preferences of the participants difer between secluded and non-secluded patients. Results: 550 psychiatrist and emergency physicians were invited. The overall response rate was 20% (n = 108). The number 1 preferred medication classes were antipsychotics (59.3%) and benzodiazepines (40.7%). In non-secluded patients, olanzapine (22.2%), lorazepam (21.3%) and clotiapine (19.4%) were most frequently picked as number 1 choice drug. In secluded patients, clotiapine (21.3%), olanzapine (21.3%) and droperidol (14.8%) were the three most frequently chosen number 1 preferred drugs. Between-group comparisons show that emergency physicians prefer benzodiazepines signiicantly more than psychiatrists do. Zuclopenthixol and olanzapine show a particular proile in both groups of physicians. Polypharmacy is more frequently used in secluded patients. Published guidelines and safety or outcome monitoring are rarely used. Conclusions: Our results show that prescription practice in Flanders (Belgium) in acute agitation shows a complex relationship with published guidelines. Prescription preferences difer accordingly to medical specialty. These indings should be taken into account in future research. [ABSTRACT FROM AUTHOR]

Aims: The aim of the present study was to investigate the predictive value of qualitative psychomotor performance levels and subaspects of the negative syndrome for quantitative motor activity levels in patients with schizophrenia. Methods: Twenty-seven stabilized patients with schizophrenia and 22 age- and sex-matched healthy controls were included in the study. An extensive battery of psychomotor performance tests (Finger Tapping Test, Purdue Pegboard Test, Line Copying Test, Neurological Evaluation Scale, Salpêtrière Retardation Rating Scale), clinical rating scales (Positive and Negative Syndrome Scale) and 24-hour actigraphy were administered to all participants. Results: Correlational analyses showed that motor activity levels were associated with avolition as well as clinically assessed psychomotor slowing. However, in a regression model, only avolition was found to be a significant predictor for motor activity levels in patients with schizophrenia; none of the psychomotor performance tests nor the severity of emotional expressivity deficits contributed to the model. Conclusion: Qualitative and quantitative psychomotor deficits seem to be independent phenomena in stabilized patients with schizophrenia. The diminishing in motor activity in patients with schizophrenia is related to a loss of drive and not to problems in the quality of movement execution. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A correction to the article “Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol" is presented.

Objective Clozapine is an atypical antipsychotic with a narrow therapeutic range and serious toxic side effects. According to AGNP–TDM consensus guidelines, therapeutic drug monitoring (TDM) of clozapine and its metabolite norclozapine is strongly recommended. 330 serum samples, sent to the toxicological laboratory of Ziekenhuis Netwerk Antwerpen for monitoring of clozapine, were tested with a new ultra-high performance liquid chromatography–tandem mass spectrometric method (UHPLC–MS/MS). The aim of this research was to evaluate this method for TDM of clozapine and norclozapine, but also to determine other antipsychotics present in these serum samples. Design and methods Serum samples were taken just prior to the morning dose of the antipsychotic (trough concentration). All samples were, after a simple liquid–liquid extraction with methyl t -butylether, analyzed using a fully validated UHPLC–MS/MS method which is able to quantitate 16 different antipsychotics and 8 of their major metabolites. Serum concentrations were compared with the therapeutic ranges as defined by the AGNP–TDM guidelines. Results For clozapine, only 22.3% of the serum concentrations were within the therapeutic range of 350–600 ng/mL, while 67.9% of the concentrations were below 350 ng/mL. For norclozapine, 68.2% of the serum samples were within the therapeutic range of 100–600 ng/mL. The mean clozapine:norclozapine ratio was 1.7 (SD 0.8). 218 of the 330 serum samples contained other antipsychotics than clozapine. Only 52.5% of these concentrations were within the proposed range. Conclusion This retrospective study highlights the importance of TDM for clozapine and other APs, since many patients show suboptimal serum concentrations. [ABSTRACT FROM AUTHOR]