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.

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.

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.

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.

Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs.

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

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.

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.

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.

Assessing clinical correlates of self-rated disability in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is associated with significant impairment. OBJECTIVE: The objective of this article is to identify and compare clinical measures that can predict self-rated disability in patients with MS using the World Health Organization Disability Assessment Schedule II (WHODAS-II). METHODS: Patients with MS and healthy controls were consecutively recruited at one center. Patients were evaluated for cognitive function assessment, neurological status, perceived disability, mood, fatigue and disease duration. Controls underwent neuropsychological evaluation only. Data were analyzed using multivariate regression. RESULTS: WHODAS-II total score was predicted by fatigue (p < 0.001) and neurological status (p < 0.05). Student's t test comparisons between published WHODAS-II normative data and the enrolled cohort of patients with MS showed significantly worse (p < 0.05) scores for patients on mobility, self-care, life activities, participation and total score domains, but not in cognition. Group differences between patients with MS (n = 61) and controls (n = 61) were significant in all cognitive measures except one verbal memory test subscale. Memory function correlated best with the social participation domain of the WHODAS-II. CONCLUSIONS: Self-reported disability in patients with MS was most strongly influenced by fatigue and to a lesser extent by physical disability. Although cognitive function does affect self-assessment of disability, this is not captured by patients on the WHODAS-II cognitive domain.

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.

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 tolerability of flexible dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder.

The osmotic release oral system (OROS) methylphenidate formulation is a prolonged-release medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. We conducted a seven-week open-label extension of a double-blind study to assess the safety and tolerability of OROS methylphenidate in a flexible dose regimen (18-90 mg daily) for the treatment of adults diagnosed with ADHD (N =370). Medication was adjusted to optimize efficacy and tolerability for each patient. Adverse events, vital signs, and laboratory parameters were assessed. Most patients (337; 91%) completed the seven-week treatment and the final dispensed dose was 18 mg (8%), 36 mg (29%), 54 mg (34%), 72 mg (20%), or 90 mg (9%). Adverse events were reported in 253 (68%) patients and most were mild or moderate in severity; most frequently reported included headache (17%), decreased appetite (13%), and insomnia (11%). Adverse events were rarely serious (<1%; 2/370). Small mean increases in systolic and diastolic blood pressure (both 2.4 mmHg) and pulse (3.2 bpm) were observed. Body weight decreased slightly (-1.5 kg). The results provide additional support for the safety and tolerability of prolonged-release OROS methylphenidate in a flexible dose regimen (18-90 mg/day) for the treatment of adults with ADHD.

Dosing patterns in Europe: Efficacy and safety of risperidone long-acting injectable in doses of 25, 37.5 and 50 mg.

Objective. To assess the dose prescription patterns for risperidone long-acting injectable (RLAI) in patients with schizophrenia who participated in the 6-month, open-label Switch to Risperidone Microspheres (StoRMi) trial. Methods. Clinically stable patients requiring a change in medication were converted to RLAI prescribed using clinically-appropriate doses, as determined by treating clinicians. RLAI 25 mg was recommended as the starting dose, although higher initiation doses were permitted if deemed necessary. RLAI was administered intramuscularly every 2 weeks, with dosage adjustments permitted, and continued for a total of 6 months. Efficacy outcomes included Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S). Treatment-emergent adverse events (AEs) were monitored. Results. A total of 1,849 patients were included. Modal dose was 25 mg for 52.9% of patients. At baseline, patients treated with lower RLAI doses were more likely to be female, have shorter disease duration, milder symptoms, and be using less polypharmacy. The strongest predictors that a patient would remain on 25 mg RLAI were baseline PANSS hallucinatory behaviour item score (odds ratio [OR]=0.78), baseline CGI-S score (OR=0.69), female gender (OR=1.56), and country of residence (P<0.001 for all). Efficacy measures improved in all dose groups, with the greatest improvement seen in patients treated with lower doses. AEs were more common in patients treated with 50 mg RLAI (68 vs. 57% with lower doses; P<0.0001), although most AEs were mild to moderate in severity. Conclusion. In this study, 25 mg RLAI was the most commonly prescribed dose. RLAI was effective and well tolerated over the full range of doses.

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.

Long-acting injectable risperidone in the treatment of subjects with recent-onset psychosis: a preliminary study.

Using a long-acting antipsychotic to improve adherence early in the illness may reduce relapse rates and promote sustained remission, thereby improving the long-term outcome of schizophrenia. We assessed whether risperidone long-acting injection (RLAI) could be used safely and effectively in the treatment of recent-onset psychosis. Fifty patients aged 15 to 43 years with newly diagnosed schizophreniform disorder or schizophrenia were treated with RLAI 25 to 50 mg every 2 weeks for 2 years. Thirty-six patients (72%) completed the trial. Of 39 (78%) who showed a clinical response of 50%, 4 relapsed. Thirty-two patients (64%) achieved remission. Mean maximum increase in Extrapyramidal Symptoms Rating Scale total score was 1.4 (95% confidence interval, 0.61-2.10; n = 50); 10 patients required anticholinergic medication, and 1 subject developed persistent dyskinesia. Prolactin levels were elevated in 18 patients, 4 of whom reported possible prolactin-related adverse events. Mean increase in body mass index to last visit for all patients was 4.8 kg/m (SD, 3.8 kg/m). The final RLAI dose was 25 mg for 54% of patients, 37.5 mg for 30%, and 50 mg for 16%. This preliminary study suggests that RLAI was overall well tolerated and appears to be effective in recent-onset psychosis. Further investigation is warranted.

A randomized, placebo-controlled trial of three fixed dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder.

BACKGROUND: There is increasing recognition of attention-deficit/hyperactivity disorder (ADHD) in adults and the need to evaluate efficacy and safety of methylphenidate treatment in these patients. METHODS: In this double-blind trial, 401 adults with ADHD (218 men; 18-63 years) were randomly assigned to receive prolonged-release osmotic release oral system (OROS) methylphenidate (18 mg, 36 mg, or 72 mg/day) or placebo for 5 weeks. Primary outcome was change in total score on Conners' Adult ADHD Rating Scale (CAARS: investigator-rated) at end point compared with baseline. Adverse events, vital signs, and laboratory parameters were assessed. RESULTS: Treatment with 18-mg, 36-mg, and 72-mg/day prolonged-release methylphenidate, compared with placebo, was associated with significantly larger improvement in CAARS total symptom score from baseline to end point than placebo: mean change -10.6 (p = .01), -11.5 (p = .01), and -13.7 (p < .001) versus -7.6, respectively. Responders (> or = 30% decrease) were 50.5%, 48.5%, and 59.6% versus 27.4% (p < .001). Other efficacy measures also showed improvements. Incidence of adverse events was 75%, 76%, and 82% in 18-mg, 36-mg, and 72-mg/day groups, respectively, and 66% in placebo; most frequent included decreased appetite (25% methylphenidate; 7% placebo) and headache (21% methylphenidate; 18% placebo). In methylphenidate-treated patients, 4.3% discontinued due to adverse event; one serious adverse event was possibly related to study drug. Blood pressure and pulse increased at week 1 and then remained stable through week 5. CONCLUSIONS: Prolonged-release methylphenidate is an effective treatment of ADHD in adults, with a safety profile consistent with methylphenidate use in pediatrics.

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;