Improved symptom control, functioning and satisfaction in French patients treated with long-acting injectable risperidone.

OBJECTIVE: To investigate the efficacy and tolerability of direct initiation of long-acting injectable risperidone (LAIR) in adults with schizophrenia or other psychotic disorders requiring a change of treatment. METHODS: Patients clinically stable for one month or more on their previous medication received 25 mg of LAIR (increased to 37.5 or 50 mg, if necessary) every 14 days for six months. RESULTS: Of 202 patients (70% male, mean age 38 years), the majority (86%) had DSM-IV schizophrenia (mainly paranoid). Previous treatments were atypical antipsychotics (65%), depot (34%) and oral (9%) conventional neuroleptics. Mean total positive and negative syndrome scale (PANSS) score was significantly reduced from baseline to treatment endpoint (79.4 versus 68.3, P<0.001), as were all subscale and symptom factor scores. The clinical global impression-disease severity (CGI-S), general assessment of functioning (GAF), health-related quality of life (SF-36) and patient satisfaction with treatment were also improved significantly. At endpoint, 31% rated the treatment as 'very good' compared with 8% at baseline. The total extrapyramidal symptoms rating scale (ESRS) and Parkinsonism subscale scores were reduced significantly (P<0.001) from baseline at one month and further improved until treatment endpoint. CONCLUSION: LAIR significantly improved disease symptoms, patient functioning, movement disorders, health-related quality of life and treatment satisfaction. It therefore provides a useful option for the management of patients with psychotic disorders.

Direct transition to long-acting risperidone--analysis of long-term efficacy.

This report presents data from the extension phase of a 6-month trial that evaluated the efficacy of risperidone long-acting injectable (RLAI) in stable psychotic patients requiring a treatment change. Patients continued to receive RLAI every 2 weeks for a maximum of 12 months from study entry. Symptoms were assessed using the PANSS after 1, 3, 6, 9 and 12 months of treatment (or treatment endpoint). Remission of severity criteria were defined as < or =3 points in all PANSS items suggested by the Remission in Schizophrenia Working Group.715 patients (63% male) entered the extension phase and 508 completed the 12-month study. The mean PANSS total score at Day 0 was 74.9+/-22.7. This was significantly reduced after 1 month (67.7 +/-22.3, p< or =0.001), with continued improvements over the 12 months of the study until treatment endpoint (59.7+/-21.9). Significant improvements from Day 0 to endpoint were also seen in the scores for all PANSS subscales and symptom factors. The proportion of patients who met the PANSS severity criteria for remission increased from 29% at Day 0 to 60% at endpoint, and the proportion of patients who met these criteria for < or = 6 months increased from 24% at Month 6 to 45% at endpoint. Treatment with RLAI for up to 12 months provided significant and sustained improvements in symptom control in patients with schizophrenia. These improvements may help patients to achieve and remain in remission.

Pharmacokinetic profile of long-acting injectable risperidone at steady-state: comparison with oral administration.

The single dose pharmacokinetic profiles of long-acting injectable (LAI) risperidone and oral risperidone were extrapolated to steady-state. Plasma concentrations of the active moiety (unchanged risperidone + 9-hydroxy-risperidone) were measured by radioimmunoassay up to 72 h after a single oral 1 mg dose of risperidone in healthy volunteers (n = 12), and up to 84 days after a single intramuscular injection of 50 mg LAI risperidone in schizophrenic patients (n = 26). These data were projected to multiple dose regimens (4 mg/day for the oral formulation and 50 mg every 2 weeks for LAI formulation) using the software package WinNonlin, and average steady-state pharmacokinetic profiles were predicted. The most interesting results, obtained at steady-state, were a lower predicted peak plasma level (46 vs. 62 ng/ml) and a lower predicted degree of fluctuation between Cssmax and Cssmin (53 vs 145%) with LAI compared to oral administration, which is in line with actual steady state data on LAI risperidone. In conclusion, the pharmacokinetic profile of LAI risperidone administered every 2 weeks ensures a steady-state profile with concentrations falling in the interval observed with an equivalent oral dose but with lower and less fluctuations (i.e. 1/2 weeks vs 1/day).

Effects of risperidone on psychometric and cognitive functions in healthy elderly volunteers.

RATIONALE: Dementia includes not only cognitive deficit but may also include psychiatric and behavioral symptoms. These psychological symptoms of dementia require specific treatment without deleterious effects on cognitive functions. OBJECTIVE: The aim of the present study was to assess the effects of a single dose of risperidone (0.25 or 0.5 mg) on psychomotor performances and cognitive functions compared to a placebo and to a positive control, lorazepam 1 mg, in 12 healthy elderly subjects. METHODS: This study was a randomized, double-blind, four-way crossover clinical trial involving four 8-h long treatment periods. The pharmacodynamic assessment criteria included a battery of psychomotor tests, a subjective evaluation and an electroencephalogram. Safety was evaluated by clinical laboratory tests, electrocardiogram and recording of adverse events. Concentrations of risperidone, 9-hydroxy-risperidone and lorazepam were determined before and 2 h after dosing. RESULTS. Few significant effects were observed on psychomotor tests with risperidone at all dosages. Risperidone was devoid of any deleterious effects on speed of reaction, vigilance and sustained attention, working and long-term memory and increased cortical arousal. Risperidone demonstrated minor impairment on motor activity (decreased finger taping), postural stability, and information processing (impaired digit symbol substitution). Contentedness subjective evaluation was decreased with risperidone 0.5 mg, 6 h after dosing. No significant difference was observed on EEG frequencies and no sedative activity was detected with risperidone. At 2 h after dosing, risperidone plasma concentrations were 1.54+/-0.99 ng/ml and 2.80+/-1.41 ng/ml; 9-hydroxy-risperidone concentrations were 0.77+/-0.46 ng/ml and 1.54+/-0.85 ng/ml after intake of 0.25 mg and 0.5 mg doses, respectively. Well-known detrimental effects of lorazepam on psychomotor performances were observed and sedative effects were confirmed by the EEG findings. At 2 h following lorazepam 1 mg administration, plasma concentrations were 13.40+/-2.17 ng/ml. None of both compounds induced serious adverse events. CONCLUSION: The results of this clinical trial conducted on healthy subjects demonstrated that low doses of risperidone, but not low doses of lorazepam, did not disturb the cognitive functions in the elderly.

Correlation of clinical response (PANSS) and plasma levels of haloperidol and reduced haloperidol in schizophrenia.

1. The authors attempted to correlate plasma concentrations in H/rH and clinical efficacy from 8 schizophrenic patients (DSM IIIR) on H. 2. No significant correlations were found between H, rH plasma levels and positive and negative subscale for each patient. 3. The authors observed an opposite evolution concerning the mean results between plasma concentrations and PANSS total score.

Comparative study of the psychomotor and antistress effects of ritanserin, alprazolam and diazepam in healthy subjects: some trait anxiety-independent responses.

The new potential anxiolytic ritanserin was studied in a double-blind manner vs. alprazolam, diazepam and placebo in 23 healthy subjects. The subjects belonged either to a high anxiety level group or a low anxiety level group, in order to study the effect of the anxiety level on the pharmacodynamic responses. The assessments included cognitive function (memory tests), psychomotor performance [Critical Flicker Fusion (CFF), Choice Reaction Time (CRT)], subjective ratings of alertness and overnight sleep and stress paradigm. Ritanserin (10 mg), alprazolam (0.75 mg), diazepam (10 mg) and placebo were given as single oral doses following a latin square design. Groups were well contrasted on the Cattell anxiety scale and were not overlapping. On no psychometric variable have there been any interactions between the anxiety level and the drug factor. At baseline an anxiety-related difference between the two groups was observed: lower CFF value in the high anxiety group (-1.4 Hz). Both benzodiazepines impaired psychomotor assessment and memory function and increased sleepiness. Ritanserin decreased CFF values without significantly affecting CRT on which nevertheless a trend to impairment was observed. Memory tests, and subjective ratings of alertness were unaffected by ritanserin. A trend to an antistress effect was observed on electrodermogram after ritanserin. Both benzodiazepines decreased central nervous system arousal and memory while ritanserin was inactive except on CFF. Recent data support the hypothesis that 5-HT2 blockers decrease pupil diameter which is a well known covariate of flicker frequency.

[Memory, attention and evoked potentials during aging and in Alzheimer type senile dementia]. / Mémoire, attention, potentiels évoqués au cours du viellissement et dans la démence sénile de type Alzheimer.

A study of event-related brain potentials (ERPs) in Alzheimer type dementia has been performed on 6 elderly subjects (mean age: 67.5). Patients were included if they met DSM-III criteria for primary degenerative dementia. They presented important loss of memory function (in short-term memory-STM and long-term memory-LTM) and impairment of attention. They were compared to two groups: normal elderly subjects with no memory trouble and no attention dysfunction (12 subjects, mean age: 66) and elderly subjects with minor trouble in STM and little attention disturbance (6 subjects, mean age: 68.5). The chosen procedure is a dichotic listening and selective attention paradigm. Three series of tone bursts occurred in counterbalanced order (frequent tones: 1,000 Hz, 2,000 Hz; rare tones: 1,450 Hz). Rare/frequent ratio was 10/90. Subjects were asked to press a key to the rare tones. During the task, ERPs are recorded with 16 electrodes (cross montage), using 2 different reference electrodes sites: nasion and 7th vertebra. Results are displayed with the use of chronograms, spatio-temporal maps, reaction time histograms. In Alzheimer's group compared to the 2 others: N100, N200, P300 are significantly delayed in latency. P300 has a smaller amplitude. In Alzheimer's, P300 distribution on the scalp is more frequently founded of greater amplitude on the frontal region than on the centro-parietal region while the opposite is found in normal subjects. These results suggest that memory trouble or attention dysfunction are well correlated with the abnormalities of the ERPs.

[An application of balloon probes. Preoperative electrophysiological test of the tolerance to temporal occlusion of the artery of cervical enlargement]. / Une application des sondes à ballonnets. Test pré-opératoire par méthode électrophysiologique de la tolérance à l'occlusion temporale de l'artére du renflement cervical.

The authors report a case of testing of the temporary occlusion of origin of the radiculo-medullar artery for the cervical enlargement by balloon occlusion and both testing by clinical evaluation and evaluation of somesthesic evoked potentials and F wave. This testing allowed the surgical removal of a malignant tumor of the cervical vertebra including the vertebral artery and the origin of the radiculo-medullar artery for the cervical enlargement. About this case, they discuss possibilities and the theorical value of these pre-operative tests.

Preattentional processes and disorganization in schizophrenia: Influence of a 6-week risperidone treatment.

INTRODUCTION: Visual orientation and attention are impaired in schizophrenia. Engagement and disengagement of attention and the ability to prompt responses to a stimulus in patients before and after six weeks of risperidone were compared to controls. METHODS: Ten unmedicated (nine naïve) schizophrenic patients, and eleven controls performed 1) A visual orienting task, the Cued Target Detection task (CTD), with the detection of a visual stimulus in valid, invalid, no cue and double cue trials, two conditions for fixation offset for a modulation of visual fixation: Gap: 200 ms before target; No Gap: simultaneous with target, 2) Choice Reaction Time (CRT 0.5 and 2 s delays). RESULTS: At baseline, patients showed longer RT than controls in CRT, but not in CTD, with in CTD, no facilitation of RT with the gap procedure. The alertness index was almost null in CTD-Gap and comparable to controls in CTD-No Gap. Efficiency to detect attended stimuli (CTD-No Gap) and warning effect (CRT 0.5 s) were negatively correlated to disorganization. After treatment, readiness to act in CRT had decreased. In CTD-No Gap, change in PANSS disorganization was correlated to an increased validity index, change in negative sub-score was correlated to decreased attention cost. CONCLUSION: Untreated patients displayed a deficit of Gap effect and a slowing in sustained attention. Disorganization interfered with warning and visual detection. After treatment, its improvement and negative symptoms improvement were associated with better visual detection. These alterations in visual orienting provide new evidence for an oculomotor dysregulation of attentional engagement in schizophrenia.

Antipsychotic and anxiolytic properties of risperidone, haloperidol, and methotrimeprazine in schizophrenic patients.

The subjects were 62 patients hospitalized for acute exacerbations of schizophrenia and were randomly assigned to receive risperidone (mean dose, 7.4 mg/day), haloperidol (7.6 mg/day), or methotrimeprazine (100 mg/day) for 4 weeks. Clinical improvement, defined a priori as a 20% reduction in total Positive and Negative Syndrome Scale (PANSS) scores at end point, was attained by 81% of the risperidone patients, 60% of the haloperidol patients, and 52% of the methotrimeprazine patients (p < 0.05). The reductions in total PANSS and Clinical Global Impression Scale severity scores from baseline to end point were significantly greater in the risperidone patients than in the other two groups. Reductions in scores on the Psychotic Anxiety Scale were significantly greater in the risperidone patients than the methotrimeprazine patients; the difference between haloperidol and methotrimeprazine was not significant. Extrapyramidal symptoms (scores on the Extrapyramidal Symptom Rating Scale) were more severe in the haloperidol patients than in the other two groups, but few differences were apparent between risperidone and methotrimeprazine patients. It is concluded that risperidone is an effective antipsychotic and anxiolytic agent in schizophrenic patients.

Pharmacokinetics of sabeluzole and dextromethorphan oxidation capacity in patients with severe hepatic dysfunction and healthy volunteers.

AIMS: The primary objective of this study was to determine how the pharmacokinetics of sabeluzole, an investigational drug with specific effects on memory and learning abilities, are affected by chronic liver disease. Since sabeluzole is metabolised by CYP2D6, a secondary objective was to study the correlation between CYP2D6 activity (as assessed by the dextromethorphan dextrorphan metabolic ratio) and hepatic dysfunction. METHODS: The single-dose pharmacokinetics of sabeluzole (10 mg) was compared in 10 healthy Caucasian subjects and 10 patients with severe hepatic dysfunction. The urinary dextromethorphan/dextrorphan (DMP/DRP) metabolic ratio was determined after intake of 20 mg dextromethorphan (NODEX capsules). RESULTS: The terminal half-life of sabeluzole was significantly prolonged in subjects with severe hepatic dysfunction vs healthy subjects (respectively 39.3 +/- 11.5 h; 17.5 +/- 10.2 h (mean +/- s.d.)). The areas under the curve (AUC) were significantly higher in subjects with severe hepatic dysfunction than in healthy volunteers (681 +/- 200 ng ml(-1) h vs 331 +/- 282 ng ml(-1) h). There was a significant correlation between the AUC(0,infinity) and the DMP/DRP metabolic ratio in healthy volunteers and subjects with severe hepatic dysfunction. AUC was greater and elimination of sabeluzole slower in poor metabolizers compared with extensive metabolizers. CONCLUSIONS: These results suggest that a) sabeluzole dose should be reduced in patients with severe hepatic dysfunction and b) the AUC of sabeluzole is linked to individual CYP2D6 activity.