A Randomized, Double-Blind, Controlled Phase II Study of Foliglurax in Parkinson's Disease.

BACKGROUND: Agents targeting the metabotropic glutamate receptor 4 have emerged as a potentially attractive new class of drugs for the treatment of Parkinson's disease (PD). OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of foliglurax in reducing off time and dyskinesia in patients with PD. METHODS: This was a 28-day, multicenter, randomized, placebo-controlled, double-blind clinical trial of foliglurax 10 and 30 mg as adjunct to levodopa in 157 randomly assigned patients with PD and motor complications. RESULTS: Although dose-dependent decreases in daily awake off time were apparent following treatment with foliglurax, the change from baseline to day 28 in off time (primary endpoint) and dyskinesia (secondary endpoint) did not improve significantly compared with placebo for either foliglurax dose. Treatment with foliglurax was generally safe, and there were no relevant safety signals. CONCLUSIONS: There was no evidence in this study that foliglurax has efficacy in improving levodopa-induced motor complications in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9.

PURPOSE: AT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations. METHODS: This phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77-196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks. RESULTS: The most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was -7.2% (95% CI [-10.4 to -3.9], P < 0.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%. CONCLUSIONS: Although both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development. TRIAL REGISTRATION: EudraCT: 2015-001719-11. ClinicalTrials.gov Identifier: NCT02508896.

A Phase 1 Randomized Trial of Specific Active α-Synuclein Immunotherapies PD01A and PD03A in Multiple System Atrophy.

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disease with limited symptomatic treatment options. Aggregation of α-synuclein in oligodendrocytes is believed to be a central mechanism of the neurodegenerative process. PD01A and PD03A are 2 novel therapeutic vaccine candidates containing short peptides as antigenic moieties that are designed to induce a sustained antibody response, specifically targeting pathogenic assemblies of α-synuclein. The objectives of the current study were to evaluate primarily the safety and tolerability of PD01A and PD03A in patients with early MSA. Thirty patients (11 women) were randomized to receive 5 subcutaneous injections of either PD01A (n = 12), PD03A (n = 12), or placebo (n = 6) in this patient- and examiner-blinded, placebo-controlled, 52-week phase 1 clinical trial (ClinicalTrial.gov identifier: NCT02270489). Immunogenicity and clinical scores were assessed as secondary objectives. Twenty-nine patients reported a total of 595 treatment-emergent adverse events (mild or moderate, n = 555; severe, n = 40). Treatment-related adverse events included 190 injection-site reactions typically observed in vaccination trials with similar per-subject incidence in the treatment groups over time. Sustained IgG titers were observed in the PD01A-treated group, and 89% of treated patients developed a PD01-specific antibody response after receiving all injections. Induced antibodies displayed clear reactivity to the α-synuclein target epitope. Titers and antibody responder rate (58%) were lower in the PD03A-treated group. In conclusion, both PD01A and PD03A were safe and well tolerated. PD01A triggered a rapid and long-lasting antibody response that specifically targeted the α-synuclein epitope. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

An mGlu4-Positive Allosteric Modulator Alleviates Parkinsonism in Primates.

BACKGROUND: Levodopa remains the gold-standard treatment for PD. However, it becomes less effective as the disease progresses and produces debilitating side effects, such as motor fluctuations and l-dopa-induced dyskinesia. Modulation of metabotropic glutamate receptor 4 represents a promising antiparkinsonian approach in combination with l-dopa, but it has not been demonstrated in primates. OBJECTIVE: We studied whether a novel positive allosteric modulator of the metabotropic glutamate receptor 4, PXT002331 (foliglurax), could reduce parkinsonism in primate models. METHODS: We assessed the therapeutic potential of PXT002331 in three models of MPTP-induced parkinsonism in macaques. These models represent three different stages of disease evolution: early stage and advanced stage with and without l-dopa-induced dyskinesia. RESULTS: As an adjunct to l-dopa, PXT002331 induced a robust and dose-dependent reversal of parkinsonian motor symptoms in macaques, including bradykinesia, tremor, posture, and mobility. Moreover, PXT002331 strongly decreased dyskinesia severity, thus having therapeutic efficacy on both parkinsonian motor impairment and l-dopa-induced dyskinesia. PXT002331 brain penetration was also assessed using PET imaging in macaques, and pharmacodynamic analyses support target engagement in the therapeutic effects of PXT002331. CONCLUSIONS: This work provides a demonstration that a positive allosteric modulator of metabotropic glutamate receptor 4 can alleviate the motor symptoms of PD and the motor complications induced by l-dopa in primates. PXT002331 is the first compound of its class to enter phase IIa clinical trials. © 2018 International Parkinson and Movement Disorder Society.

Prolonged-release fampridine and walking and balance in MS: randomised controlled MOBILE trial.

BACKGROUND: Mobility impairment is a common disability in MS and negatively impacts patients' lives. OBJECTIVE: Evaluate the effect of prolonged-release (PR) fampridine (extended-release dalfampridine in the United States) on self-assessed walking disability, dynamic/static balance and safety in patients with MS. METHODS: MOBILE was a randomised, double-blind, exploratory, placebo-controlled trial. Patients with progressive/relapsing-remitting MS and Expanded Disability Status Scale score of 4.0-7.0 were treated with PR-fampridine or placebo twice daily for 24 weeks. Efficacy endpoints included change from baseline in the 12-item MS Walking Scale (MSWS-12), Timed Up and Go (TUG) test and Berg Balance Scale (BBS). RESULTS: 132 patients were randomised at 24 sites in six countries. PR-fampridine therapy resulted in greater median improvements from baseline in MSWS-12 score, TUG speed and BBS total score versus placebo over 24 weeks. A higher proportion of patients receiving PR-fampridine versus placebo experienced significant improvements at MSWS-12 improvement thresholds ⩾7 (p = 0.0275), ⩾8 (p = 0.0153) and ⩾9 points (p = 0.0088) and TUG speed thresholds ⩾10% (p = 0.0021) and ⩾15% (p = 0.0262). PR-fampridine was well tolerated. CONCLUSIONS: PR-fampridine therapy resulted in early and sustained improvements in broad measures of walking and balance over six months.

Validation of the World Health Organization Disability Assessment Schedule II (WHODAS-II) in patients with multiple sclerosis.

BACKGROUND: The World Health Organization Disability Assessment Schedule (WHODAS-II) is a widely used generic assessment instrument for health and disability. However, a specific psychometric evaluation for this scale in multiple sclerosis (MS) is lacking. This study is aimed at the assessment of the psychometric properties of the WHODAS-II in MS with Cronbach's α and modern Rasch-model analyses. METHODS: The WHODAS-II was administered to 136 consecutively recruited MS patients. Several indexes of fit to the Rasch model were evaluated in order to assess internal construct validity. Internal consistency was assessed with Cronbach's α and the Person Separation Index (PSI). External validity was evaluated by analyzing correlations between the WHODAS-II and the Multiple Sclerosis Quality of Life-54 (MSQoL-54). RESULTS: Classical reliability indexes (Cronbach's α and intraclass correlation) showed good to excellent reliability for most of the subscales and for the total scale (α = 0.93). The total scale both with (36 items) or without (32 items) work items reached good fit to the Rasch model (PSI = 0.83). However, analysis of the subscales could resolve only four subscales out of seven. CONCLUSIONS: The WHODAS-II is a reliable and valid instrument for the assessment of patient-reported disability in MS, with some limitations including some item redundancy and questionable reliability of some subscales.

Responder definition of the Multiple Sclerosis Impact Scale physical impact subscale for patients with physical worsening.

BACKGROUND: The 29-item Multiple Sclerosis Impact Scale (MSIS-29) was developed to examine the impact of multiple sclerosis (MS) on physical and psychological functioning from a patient's perspective. OBJECTIVE: To determine the responder definition (RD) of the MSIS-29 physical impact subscale (PHYS) in a group of patients with relapsing-remitting MS (RRMS) participating in a clinical trial. METHODS: Data from the SELECT trial comparing daclizumab high-yield process with placebo in patients with RRMS were used. Physical function was evaluated in SELECT using three patient-reported outcomes measures and the Expanded Disability Status Scale (EDSS). Anchor- and distribution-based methods were used to identify an RD for the MSIS-29. RESULTS: Results across the anchor-based approach suggested MSIS-29 PHYS RD values of 6.91 (mean), 7.14 (median) and 7.50 (mode). Distribution-based RD estimates ranged from 6.24 to 10.40. An RD of 7.50 was selected as the most appropriate threshold for physical worsening based on corresponding changes in the EDSS (primary anchor of interest). CONCLUSION: These findings indicate that a ≥7.50 point worsening on the MSIS-29 PHYS is a reasonable and practical threshold for identifying patients with RRMS who have experienced a clinically significant change in the physical impact of MS.

Safety and Tolerability of Active Immunotherapy Targeting α-Synuclein with PD03A in Patients with Early Parkinson's Disease: A Randomized, Placebo-Controlled, Phase 1 Study.

BACKGROUND: Immunotherapies targeting α-synuclein aim to limit its extracellular spread in the brain and prevent progression of pathology in Parkinson's disease (PD). PD03A is a specific active immunotherapy (SAIT) involving immunization with a short peptide formulation. OBJECTIVE: This phase 1 study characterized the safety and tolerability of PD03A in patients with early PD. A key secondary objective was to evaluate immunological activity following immunization. METHODS: This was a phase 1 study of two different doses of PD03A versus placebo in PD patients. Patients were randomized (1:1:1) to receive four priming plus one booster vaccination of PD03A 15µg, PD03A 75µg or placebo and were followed for 52 weeks. RESULTS: Overall, 36 patients were randomized, of which 35 received five immunizations and completed the study. All patients experienced at least one adverse event. Transient local injection site reactions affected all but two patients; otherwise most AEs were considered unrelated to study treatment. A substantial IgG antibody response against PD03 was observed with a maximum titer achieved at Week-12. Differences in titers between both active groups versus placebo were statistically significant from the second immunization at Week-8 until Week-52. CONCLUSION: The safety profile and positive antibody response of PD03A supports the further development of active immunotherapeutic approaches for the treatment of PD.

Treating attention-deficit/hyperactivity disorder beyond symptom control alone in children and adolescents: a review of the potential benefits of long-acting stimulants.

Attention-deficit/hyperactivity disorder (ADHD), one of the most common neuropsychiatric conditions of childhood, often has a chronic course and persists into adulthood in many individuals. ADHD may have a clinically important impact on health-related quality of life in children, a significant impact on parents' emotional health and interfere with family activities/cohesion. To date, the main targets of ADHD treatment have focused on reducing the severity of symptoms during the school day and improving academic performance. However, the treatment of ADHD should reach beyond symptom control to address the issues of social competencies and improvement of health-related quality of life from the perspectives of individuals with ADHD and their families, to support them in reaching their full developmental potential. Methylphenidate (MPH) is recognised as the first-line choice of pharmacotherapy for ADHD in children and adolescents. This paper focuses on the importance and benefits to child development of ADHD symptom control beyond the school day only, i.e. extending into late afternoon and evening and uses the example of an extended-release MPH formulation (OROS((R)) MPH) to demonstrate the potential benefits of active full day coverage (12 h) with a single daily dose. Concerns of long-term stimulant treatment are also discussed.

Safety and immunogenicity of the α-synuclein active immunotherapeutic PD01A in patients with Parkinson's disease: a randomised, single-blinded, phase 1 trial.

BACKGROUND: Robust evidence supports the role of α-synuclein pathology as a driver of neuronal dysfunction in Parkinson's disease. PD01A is a specific active immunotherapy with a short peptide formulation targeted against oligomeric α-synuclein. This phase 1 study assessed the safety and tolerability of the PD01A immunotherapeutic in patients with Parkinson's disease. METHODS: We did a first-in-human, randomised, phase 1 study of immunisations with PD01A, followed by three consecutive study extensions. Patients aged 45-65 years with a clinical diagnosis of Parkinson's disease (≤4 years since diagnosis and Hoehn and Yahr Stage 1 to 2), imaging results (dopamine transporter single photon emission CT and MRI) consistent with their Parkinson's disease diagnosis, and on stable doses of Parkinson's disease medications for at least 3 months were recruited at a single private clinic in Vienna, Austria. Patients were randomly assigned (1:1), using a computer-generated sequence with varying block size, to receive four subcutaneous immunisations with either 15 µg or 75 µg PD01A injected into the upper arms and followed up initially for 52 weeks, followed by a further 39 weeks' follow-up. Patients were then randomly assigned (1:1) again to receive the first booster immunisation at 15 µg or 75 µg and were followed up for 24 weeks. All patients received a second booster immunisation of 75 µg and were followed up for an additional 52 weeks. Patients were masked to dose allocation. Primary (safety) analyses included all treated patients. These four studies were registered with EU Clinical Trials Register, EudraCT numbers 2011-002650-31, 2013-001774-20, 2014-002489-54, and 2015-004854-16. FINDINGS: 32 patients were recruited between Feb 14, 2012, and Feb 6, 2013, and 24 were deemed eligible and randomly assigned to receive four PD01A priming immunisations. One patient had a diagnosis change to multiple system atrophy and was withdrawn and two patients withdrew consent during the studies. 21 (87%) of 24 patients received all six immunisations and completed 221-259 weeks in-study (two patients in the 15 µg dose group and one patient in the 75 µg dose group discontinued). All patients experienced at least one adverse event, but most of them were considered unrelated to study treatment (except for transient local injection site reactions, which affected all but one patient). Serial MRI assessments also ruled out inflammatory processes. Systemic treatment-related adverse events were fatigue (n=4), headache (n=3), myalgia (n=3), muscle rigidity (n=2), and tremor (n=2). The geometric group mean titre of antibodies against the immunising peptide PD01 increased from 1:46 at baseline to 1:3580 at week 12 in the 15 µg dose group, and from 1:76 to 1:2462 at week 12 in the 75 µg dose group. Antibody titres returned to baseline over 2 years, but could be rapidly reactivated after booster immunisation from week 116 onwards, reaching geometric group mean titres up to 1:20218. INTERPRETATION: Repeated administrations of PD01A were safe and well tolerated over an extended period. Specific active immunotherapy resulted in a substantial humoral immune response with target engagement. Phase 2 studies are needed to further assess the safety and efficacy of PD01A for the treatment of Parkinson's disease. FUNDING: AFFiRiS, Michael J Fox Foundation.

Oral versus injectable antipsychotic treatment in early psychosis: post hoc comparison of two studies.

BACKGROUND: Few studies have compared long-acting injectable second-generation antipsychotics with oral antipsychotics. Long-acting injectable antipsychotics-developed specifically to address the problem of adherence-might have an important role to play in treating early psychosis. OBJECTIVE: The effects of oral antipsychotics versus risperidone long-acting injection (RLAI) were compared between 2 similar studies lasting 2 years each that were conducted at our site in South Africa. METHODS: Results of an open-label study in which patients were treated with flexible doses of RLAI were compared with the results of a randomized controlled trial of flexible doses of oral risperidone or haloperidol. Inclusion criteria for both studies were age 16 to 45 years; confirmed diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder;

Remission in patients with first-episode schizophrenia receiving assured antipsychotic medication: a study with risperidone long-acting injection.

Recently proposed criteria for remission by a 'Remission in Schizophrenia Working Group' have generated considerable interest. We assessed rates, predictors, and correlates of remission in a sample of patients with first-episode schizophrenia treated with injectable, long-acting risperidone. This allowed us to examine remission among patients known to be receiving medication. This was a single-site open-label study in which 50 newly diagnosed cases of schizophreniform disorder or schizophrenia aged 16 to 43 years were treated with injectable, long-acting risperidone 25-50 mg every 2 weeks for 2 years. Remission, according to Remission in Schizophrenia Working Group criteria, was achieved in 64% of the patients. Of those achieving remission, 97% maintained this status until study completion. Remission was associated with greater improvements in other symptom domains, insight, and social and occupational functioning. Patients in remission received lower doses of antipsychotic medication, had fewer extrapyramidal symptoms, and a more favorable attitude toward medication. The results of this open-label study suggest that a majority of first-episode patients who receive long-acting injectable antipsychotic medication may achieve sustained remission. Double-blind-controlled studies using long-acting injectable antipsychotics in early psychosis are warranted to further test this.

Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs.

Existing therapeutic strategies for managing Parkinson disease (PD), which focus on addressing the loss of dopamine and dopaminergic function linked with degeneration of dopaminergic neurons, are limited by side effects and lack of long-term efficacy. In recent decades, research into PD pathophysiology and pharmacology has focused on understanding and tackling the neurodegenerative processes and symptomology of PD. In this Review, we discuss the challenges associated with the development of novel therapies for PD, highlighting emerging agents that aim to target cell death, as well as new targets offering a symptomatic approach to managing features and progression of the disease.

Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs.

This corrects the article DOI: 10.1038/nrd.2018.136.

Remission in early psychosis: Rates, predictors, and clinical and functional outcome correlates.

BACKGROUND: Recently, the "Remission in Schizophrenia Working Group" proposed remission criteria consisting of a reduction to mild levels on key symptoms for at least 6 months. AIMS: This study applied these remission criteria to a large first-episode psychosis sample in order to (1) determine the rates of remission; (2) explore predictors of remission; and (3) test the external validity of these criteria. METHODS: We analyzed data from 462 subjects with a first-episode of psychosis who participated in a long-term, multinational, randomized, double-blinded trial of risperidone and haloperidol over 2 to 4 years. RESULTS: At some time point in the study 323 (70%) of the 462 subjects had a reduction to mild levels on the key symptoms as measured by the PANSS although only 109 (23.6%) maintained this level for at least 6 months thereby meeting remission criteria. The two strongest predictors of remission were shorter duration of untreated psychosis (p=0.01) and treatment response at 6 weeks (p=0.001). Compared to non-remitted patients, those in remission experienced greater improvement on all PANSS subscales (p<.0001), CGI-S (p<.0001), better quality of life (p=0.006), fewer relapses (p<.0001), displayed a more favorable attitude towards their medication (p=.002), had lower EPS levels according to the ESRS (p=<.0001) and received lower doses of antipsychotic medication (p=0.003). The remission and non-remission groups did not differ significantly regarding composite cognitive scores, suicidality and body mass index. CONCLUSIONS: The results suggest that the remission criteria, although based solely on core symptom improvement, can effectively identify patients who have a more favorable overall outcome.

Efficacy and safety of risperidone long-acting injectable in stable psychotic patients previously treated with oral risperidone.

This subgroup analysis of symptomatically stable patients with schizophrenia or other psychotic disorders in the StoRMi trial determined the efficacy and tolerability of risperidone long-acting injectable in patients changed from oral risperidone monotherapy. Risperidone long-acting injectable was administered open-label (dosage 25/37.5/50 mg every 2 weeks for 6 months). In total, 568 patients (60% men, mean age 36-40 years) were included and grouped according to pre-trial oral risperidone dosage (56% < or =4 mg; 30% >4 to < or =6 mg; 14% >6 mg). Most patients (71-85% across groups) were diagnosed with schizophrenia. At endpoint, risperidone long-acting injectable dosages partly correlated with the previous oral risperidone dosage. Some patients previously on high dosages of oral risperidone responded well to lower risperidone long-acting injectable dosages. Efficacy significantly improved from baseline to endpoint in all groups; total Positive and Negative Syndrome Scale score improved by > or =20% in 39% of all patients. Clinical global impression symptoms, global assessment of function scores, and the SF-36 mental component summary score significantly improved in all groups. Hospitalizations were reduced by 74-80%. Extrapyramidal symptom rating scale scores were significantly better at endpoint (P< or =0.001). These results indicate that further improvement in symptom control can be seen after a change to risperidone long-acting injectable in clinically stable patients previously treated with oral risperidone.

Time course for antipsychotic treatment response in first-episode schizophrenia.

OBJECTIVE: The authors examined early onset of antipsychotic action and early prediction of nonresponse to antipsychotics in patients with first-episode schizophrenia. METHOD: Time to clinical response (>/=20% improvement in total score on the Positive and Negative Syndrome Scale [PANSS]) was determined in 522 participants in a randomized, controlled trial comparing risperidone and haloperidol. Median treatment length was 206 days. RESULTS: Clinical response was achieved in 77% (N=400) of subjects. Among these patients, clinical response was achieved in 23.3%, 23.3%, 18.5%, and 12.5% at weeks 1, 2, 3, and 4, respectively, after treatment initiation. However, in 22.5% of patients, response was not achieved until after 4 weeks, and in 11.2%, it was not achieved until after 8 weeks. In 45% of patients, response was achieved with a dose of 1-2 mg/day, in 27% with 3 mg/day, in 17% with 4 mg/day, and in the remaining 11% with higher doses. Improvement in the PANSS total score of at least 30%, 40%, and 50%, respectively, were achieved by 63.0%, 44.8%, and 27.5% of patients. CONCLUSIONS: Time to antipsychotic response varied widely, suggesting that, in first-episode schizophrenia, longer treatment trials may be necessary.

Plasma antipsychotic concentration and receptor occupancy, with special focus on risperidone long-acting injectable.

Although effective plasma concentration ranges have been established for some antipsychotics, conventional and atypical, there is considerable inter-patient pharmacokinetic variation. Positron-emission tomography (PET) can be used to estimate D(2)-like receptor occupancy in the brain needed for an antipsychotic effect and the level above which extrapyramidal side effects (EPS) develop. For conventional antipsychotics, the window occupancy is approximately 70-80%. For the atypical antipsychotic risperidone, the antipsychotic effect starts at approximately 60% occupancy, with occupancy above 80% leading to EPS. The new formulation, risperidone long-acting injectable (RLAI), comprises risperidone in a biodegradable polymer. It is effective long-term at doses of 25 or 50 mg injected i.m. every 2 weeks. The constant and slow release of the long-acting formulation leads to less fluctuation in plasma levels and to a D(2)-like receptor occupancy which is below the threshold for EPS.

Orally versus intramuscularly administered antipsychotic drugs in psychiatric emergencies.

High utilization of emergency services by patients at increased risk for agitation and aggression makes the determination of effective therapy a major concern of psychiatric care. Agitated and aggressive behavior needs to be treated rapidly and effectively to minimize the risk to both patients and staff. Traditionally, short-acting intramuscular (IM) formulations of conventional antipsychotic drugs have been preferred in the emergency setting due to their rapid onset of action and the ability to administer them to uncooperative patients. IM injections, however, may not always be the preferred option. Recently, orally administered second generation (atypical) antipsychotics have been shown to be at least as effective in managing acute agitation as conventional antipsychotic drugs, with a superior tolerability profile. The current review evaluates pharmacokinetic parameters, formulation options, and clinical efficacy data for the treatment of acute agitation or aggressive behavior with antipsychotic medications. A synthesis of data from individual clinical trials, meta-analyses, review articles, and expert consensus recommendations is used to develop a working clinical algorithm for the acute management of aggression and agitation.

[Switching from a short-acting to a long-acting methylphenidate preparation: a multicentre, open study in children with ADHD]. / Umstellung von einem unretardierten auf ein retardiertes Methyl phenidatpräparat: Eine multizentrische, offene Studie an Kindern mit ADHS.

OBJECTIVES: The objective was to evaluate the safety and efficacy of a switch in medication to a single daily dose of OROS-Methylphenidate (OROS-MPH, Concerta) in clinically stable children and adolescents with ADHD. METHODS: A prospective, multi-centre open-label study was carried out for a period of three weeks in 213 patients aged 6-16 years with ADHD who had previously been treated with IR-MPH. Their medication was switched to a single daily dose of OROS-MPH. Primary endpoints were changes in the IOWA Conners Inattention/Overactivity Subscale and the global assessment of efficacy as rated by parents and teachers. The safety of the medication was evaluated by means of recording adverse events. The development of weight, sleep quality, and appetite were also observed. RESULTS: Switching the medication from IR-MPH to OROS-MPH resulted in a significant positive effect as evidenced by caregivers' ratings of core symptoms. Corresponding ratings by teachers revealed no significant difference from baseline values. The global efficacy was rated by teachers as "good" or "excellent" for 55% of the cases, by caregivers for 79% thereof, and by investigators in 77% of the cases, respectively. The study medication was well tolerated. The most frequent adverse events were headache (8.9%) and rhinopharyngitis (7.0%). No unexpected adverse events occurred. CONCLUSIONS: Changing patients' medication from IR-MPH to a single daily dose of OROS-MPH resulted in a significant improvement of ADHD symptoms as rated by parents. In a school setting, the efficacy of OROS-MPH was comparable to that of IR-MPH.