Long-acting risperidone improves negative symptoms in stable psychotic patients.

The aim of this paper was to evaluate the efficacy of risperidone long-acting injectable (RLAI) for reducing negative symptoms of schizophrenia in patients with predominantly negative symptoms at baseline. A subanalysis was performed on data from the 6-month, open-label Switch to Risperidone Microspheres trial. Patients with Positive and Negative Syndrome Scale (PANSS) negative subscale score > or = 21, which was higher than their PANSS positive subscale score, were included in this subanalysis. Improvement in negative symptoms was measured by assessing change in the PANSS negative subscale and a negative factor score. Additional outcome variables included measures in general functioning, quality of life and patient satisfaction. A total of 842 patients were eligible for inclusion in this subanalysis. Six months of treatment was completed by 631 (74.9%) patients. Forty-three (5.1%) patients discontinued treatment due to an adverse event. Negative symptoms were significantly reduced by 6.1 +/- 6.3 points for the PANSS negative score and 6.1 +/- 6.4 points for the negative factor score (P < 0.0001 for both). Significant improvements were also noted for total PANSS and other PANSS subscale scores, general functioning, quality of life and patient satisfaction (P < 0.0001). The most common treatment-emergent adverse events (>5%) were: anxiety (6.8% of patients), exacerbation of disease (6.2%) and insomnia (5.7%). Overall, RLAI was well tolerated and associated with significant reductions in movement disorder severity. The treatment resulted in a significant improvement in negative symptom severity and was well tolerated in patients with predominantly negative symptoms, who switched from a stable antipsychotic regimen

Long-term remission in schizophrenia and related psychoses with long-acting risperidone: results obtained in an open-label study with an observation period of 18 months.

OBJECTIVE: To monitor long-term symptomatic tolerability and remission in patients with stable but suboptimally treated psychoses after switching to risperidone long-acting injectable (RLAI). METHOD: This subgroup analysis of the Switch to Risperidone Microspheres (StoRMi) open-label trial followed up patients with psychoses who were converted to RLAI for a period of 18 months or until RLAI became commercially available in their country of residence. It included patients from seven European countries. Dosage adjustments were performed as clinically necessary. The efficacy endpoint was achieving and maintaining remission, defined as absent to mild core schizophrenia symptoms for > or = 6 months. A schizophrenia assessment was also completed and patients were monitored for the development of adverse events (AEs). Discontinuation rates were calculated based on Kaplan-Meier estimates where patients switching to commercial RLAI were used as censored observations. RESULTS: A total of 529 patients were followed for up to 18 months. At 18 months, the discontinuation rate was 55.7% based on Kaplan-Meier estimates. The median time to discontinuation was 15.7 months (95% CI (14.0; 17.5)). RLAI was generally well tolerated with most AEs mild-to-moderate in severity. 13% of patients discontinued treatment because of an AE. Body weight of patients increased by a mean A+/- SD of 1.0 A+/- 6.1 kg from treatment initiation to endpoint (p = 0.0001). Glucose-related AEs occurred in four patients (0.8%). Among those patients not meeting severity remission criteria at baseline, 44.8% were in remission at endpoint. Among those patients meeting severity criteria for remission at baseline, 84.2% were in remission at endpoint. A total of 93.7% of the patients who achieved or maintained remission at 6 months were in remission at endpoint. CONCLUSIONS: RLAI is safe during long-term treatment up to 18 months in adults requiring antipsychotics. Conversion to RLAI resulted in improved symptom control. Most patients achieved and maintained a sustained remission (> or = 6 months) after conversion to RLAI.

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.

Long-acting risperidone in stable patients with schizoaffective disorder.

Oral and long-acting risperidone has been shown to be effective for acute and maintenance treatment of patients with schizoaffective disorders. The present analysis investigated the efficacy and tolerability of direct transition from other antipsychotics to risperidone long-acting injectable in patients with schizoaffective disorder. Patients aged > or = 18 years with schizoaffective disorder (DSM-IV), who required a change of medication, received risperidone long-acting injectable 25 mg (increased to 37.5 or 50 mg, if necessary) every 2 weeks for 6 months. The analysis included 249 patients (47% male; mean age 43 years), of whom 74% completed the 6-month study. Mean scores for the total Positive and Negative Syndrome Scale (PANSS) and all three subscales were significantly reduced from baseline to week 4 (p < 0.001), with further improvements until treatment endpoint. Significant improvements from baseline to endpoint were seen in the mood symptom domains of anxiety/depression (10.4+/-4.1 vs 8.7+/-3.9) and uncontrolled hostility/excitement (7.6+/-3.6 vs 6.9+/-3.8). Mean Global Assessment of Function (GAF) score improved significantly from 59.4+/-15.6 at baseline to 66.4+/-17.7 (p < 0.001) at endpoint. Of 87 patients hospitalized at baseline, 67% were discharged at endpoint. Both quality of life (SF-36) and satisfaction with treatment were improved significantly at endpoint. Total ESRS scores fell progressively throughout the study, and the reduction was already statistically significant (p < 0.001) at 4 weeks. Small but statistically significant (p < 0.001) mean shifts of 1.8% were seen in body weight and Body Mass Index (BMI). Patients with schizoaffective disorder derived several benefits from a change to risperidone long-acting injectable, including reductions in psychiatric symptoms (particularly the mood symptom domains) and a reduction in the severity of drug-induced neurological movement disorders.

Sustained improvement of clinical outcome with risperidone long-acting injectable in psychotic patients previously treated with olanzapine.

The efficacy and tolerability of risperidone long-acting injectable were investigated in patients with schizophrenia or other psychotic disorders who had previously been symptomatically stable on olanzapine treatment. Patients received risperidone long-acting injectable, 25 mg, by intramuscular injection every 2 weeks; the dose could be increased to 37.5 or 50 mg if necessary. Patients were transferred directly from their previous medication to risperidone long-acting injectable without a run-in period of oral risperidone treatment. Of 192 patients recruited, 134 patients (70%) completed the study. The principal reasons for discontinuation were withdrawal of consent (8%), adverse events (6%), insufficient response (5%) and non-compliance (4%). Risperidone long-acting injectable produced a significant improvement (p = 0.0001) in Positive and Negative Syndrome Scale (PANSS) total scores, from 74.2+/-21.3 at baseline to 65.8+/-21.4 at endpoint. There were also significant reductions in PANSS subscales (positive symptoms, negative symptoms, general psycho-pharmacology) and Marder factor scores. The Clinical Global Impression increased significantly from baseline to endpoint (p = 0.0001), as reflected by the increase in the proportion of patients rated as 'not ill' or 'borderline ill' from 10% at baseline to 21% at endpoint. Risperidone long-acting injectable was also associated with significant improvements in Global Assessment of Function, patient satisfaction with treatment, and quality of life, measured on the SF-36 scale. Movement disorders, measured on the Extrapyramidal Symptom Rating Scale, were significantly reduced following the change to risperidone long-acting injectable. Treatment with risperidone long-acting injectable was well tolerated, and no significant weight gain occurred during the study. This open study suggests that risperidone long-acting injectable produces symptomatic improvement in schizophrenia patients previously considered symptomatically stable with olanzapine, along with improvement in movement disorders. The combination of improved efficacy and good tolerability may have important implications for patient adherence to therapy and subsequent long-term outcomes.

Patients in the early phases of schizophrenia and schizoaffective disorders effectively treated with risperidone long-acting injectable.

The efficacy and safety of risperidone long-acting injectable (RLAI) was investigated in patients in the early phases of schizophrenia and schizoaffective disorders (< or = 3 years). Patients who required a treatment change received RLAI (2-weekly gluteal injections of 25, 37.5 or 50 mg, per clinical judgement), without an oral risperidone run-in phase.A total of 382 patients were included in this 6-month open-label study; 73% of patients completed the study. A total of 84% had schizophrenia with a median duration of 1.0 year since diagnosis. Previous medications were mainly atypical antipsychotics (70%) and depot neuroleptics (24%). The main reasons for treatment change were non-compliance (42%) and insufficient efficacy (31%) of previous medication. The total Positive and Negative Syndrome Scale (PANSS) and all its subscale scores improved significantly (p < or = 0.0001), with 40% of patients showing a 20% improvement on total PANSS. Global Assessment of Functioning, quality of life, patient satisfaction and movement disorders also improved significantly. Tolerability of RLAI was generally good and no unexpected adverse events were reported. The ensured delivery of medication with RLAI resulted in significant symptom improvement in this patient population. Direct initiation of RLAI is well accepted by patients. RLAI might represent a novel option for patients in the early phases of psychosis.

Mitochondrial DNA alterations as a source of human disorders.

The mitochondrial genome has an underdeveloped "DNA repair repertoire" compared with the nuclear genome, making the mitochondrial DNA more susceptible to mutations by endogenous factors such as defects of the mitochondrial polymerase itself, and by exogenous factors such as radiation and UV light. Increased sensitivity to mutagenic factors may account for the mitochondrial DNA polymorphism within ethnic groups and the mitochondrial diseases associated with all mitochondrial DNA mutations, including DNA depletion. The presence in highly developed organisms of a DNA repair repertoire less organized in the mitochondria than in the nuclei might be a source of biologic dysfunction relevant also to aging and cell death. Uncorrected mitochondrial DNA modifications may determine lethal and severe diseases or asymptomatic biochemical dysfunctions. Considering the long life span and the complex metabolism of highly developed cells, the tendency to produce and accumulate mitochondrial DNA mutations may assume a pathogenetic role with aging.

Two dissimilar brothers with Becker's dystrophy have an identical genetic defect.

Becker's muscular dystrophy is phenotypically heterogeneous, but the clinical expression is usually similar in patients within the same family. We report here 2 brothers affected with Becker's muscular dystrophy in whom the disease followed completely different courses. The disease started in both patients before their teens. However, the oldest sibling died at 37, following many years of severe disability, whereas the other sibling, now 26, has normal muscle strength. In addition, since the age of 13, the younger brother has had epilepsy and has been treated with phenytoin combined with other antiepileptic drugs. Analysis of the DNA from each of the 2 brothers revealed a similar deletion at the 5' end of the dystrophin gene. The different clinical courses despite the similar mutational event suggest that intrinsic muscle factors due to modified genes or environmental phenomena such as prolonged treatment with phenytoin or other antiepileptic agents may have influenced the clinical course.

Genetic abnormalities in Duchenne and Becker dystrophies: clinical correlations.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are two allelic forms of an X-linked muscle disorder exhibiting phenotypic heterogeneity. We studied 49 individuals clinically diagnosed as having classic DMD, female DMD, mild DMD "outliers," and BMD. The patients' DNA was analyzed and alterations detected were correlated with particular phenotypes. We found that 14 of 32 classic DMD patients have an internal deletion in the same, relatively small, region of the gene; therefore this region may undergo deletions at a higher rate than the remainder of the gene. We could detect no alterations in the DNA in the remaining 18 patients. Selected patients from both groups failed to show muscle dystrophin. Seven of 11 patients with a mild DMD or BMD phenotype showed deletions at the 5' end of the gene. The other 4 patients failed to show deletions. Three of the patients with both a mild phenotype and a deletion at the 5' end had normal or low amounts of a dystrophin of smaller molecular weight. Patients with classic DMD who had a detectable deletion had a milder clinical course than those without. Contrary to a previous report, no patient in the population of clinically precisely defined DMD boys showed a deletion at the 5' end; thus, the outlier and BMD patients may be genetically different from boys with classic DMD. This correlation may be of diagnostic and prognostic significance.

Changes in axon size and slow axonal transport are related in experimental diabetic neuropathy.

In the sciatic system of rats with streptozocin (SZ)-induced diabetes, delay of axonal transport of neurofilament (NF) proteins, tubulin, and other proteins is associated with a change in axonal caliber, which increases by 40% in lumbar motor roots and decreases by 36% in tibial nerves. Since in large myelinated axons caliber is a function of the number of NF, which, in turn, is regulated by axonal transport, we studied the correlation of the number of NF and microtubules (MT) with axonal cross-sectional area in the sciatic system of SZ-treated rats to investigate whether the changes in caliber could be attributed to the impairment of transport. Despite the changes in cross-sectional area, diabetic axons in both proximal motor roots and distal tibial nerves maintained the ratios of number of NF and MT to cross-sectional area found in controls. Our findings suggest that, in rats with SZ-induced diabetes, the proximal and distal alterations of axonal caliber are an adjustment to the change in number of NF and/or MT that results from the impairment of the slow axonal transport.

Dystrophin deficiency in young girls with sporadic myopathy and normal karyotype.

We studied dystrophin in three young girls with a sporadic myopathy of early onset, manifested by mild to severe limb weakness, calf hypertrophy, high serum creatine kinase, normal karyotype, and morphologic features in muscle consistent with muscular dystrophy. DNA analysis did not reveal a deletion of the dystrophin gene. Immunohistochemical studies of dystrophin in muscle biopsies showed a mosaic of fibers with and without dystrophin, and immunoblot analysis showed partial dystrophin deficiency in all three patients, more severe in the patient with the highest proportion of dystrophin-deficient fibers. These observations suggest that the patients are Duchenne muscular dystrophy carriers. The data also support the concept that uneven lyonization in muscle is responsible for the clinical myopathy in these patients. We suggest that any girl with sporadic proximal limb weakness should be evaluated as a possible Duchenne carrier by dystrophin studies.

MELAS syndrome: characteristic migrainous and epileptic features and maternal transmission.

Severe prolonged migrainous symptoms and prolonged partial status epilepticus are characteristic features of the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Maternal transmission previously found in myoclonus epilepsy and ragged-red fibers (MERRF), another mitochondrial disease, is suggested in this disorder as well.

Fatal familial insomnia: a second kindred with mutation of prion protein gene at codon 178.

Fatal familial insomnia (FFI), a condition characterized by inability to sleep, dysautonomia, motor disturbances, and selective thalamic atrophy is a prion disease linked to a GAC----AAC mutation at codon 178 of the prion gene. These data were obtained from one kindred. We now report a second kindred affected by FFI and carrying the same mutation. The finding of the same disease phenotype and genotype in a second family further validates FFI as a distinct disease entity and a phenotype of the GAC----AAC mutation at codon 178 of the prion gene.

Fatal familial insomnia: clinical and pathologic study of five new cases.

In 1986, we reported two anatomoclinical observations of a familial condition that we called "fatal familial insomnia" (FFI). We now present the pedigree as well as the clinical and neuropathologic findings in five new subjects. The pedigree includes 288 members from six generations. Men and women are affected in a pattern consistent with an autosomal dominant inheritance. The age of onset of the disease varies between 37 and 61 years; the course averages 13 months with a range of 7 to 25 months. Progressive insomnia (polygraphically proven in two cases); autonomic disturbances including hyperhidrosis, hyperthermia, tachycardia, and hypertension; and motor abnormalities including ataxia, myoclonus, and pyramidal dysfunction, were present in every case, but with variable severity and time of presentation. Sleep and autonomic disorders were the earliest signs in two subjects, motor abnormalities were dominant in one, and others had intermediate clinical patterns. Pathologically, all the cases had severe atrophy of the anterior ventral and mediodorsal thalamic nuclei. Other thalamic nuclei were less severely and inconsistently affected. In addition, most of the cases had gliosis of the cerebral cortex, a moderate degree of cerebellar atrophy with "torpedoes," and severe atrophy of the inferior olivary nuclei. One case also showed spongy degeneration of the cerebral cortex. We conclude that all the lesions were primary, and that FFI is a multisystem disease in which the different structures are primarily affected with different severity. The insomnia appears to correlate best with the major thalamic pathology. The possibility that FFI belongs to the group identified as prion diseases or diseases transmitted by unconventional agents is examined.

A randomized controlled study of pergolide in patients with restless legs syndrome.

BACKGROUND: Open clinical trials indicate that low doses of pergolide, a long-acting D1 and D2 dopamine agonist, lead to a reduction in the symptoms of restless legs syndrome (RLS) with subjective improvement in sleep quality. OBJECTIVE: To assess the therapeutic efficacy of pergolide in improving sleep and subjective measures of well-being in patients with idiopathic RLS using polysomnography and clinical ratings. METHODS: In a randomized, double-blind, placebo-controlled crossover design we enrolled 30 patients with idiopathic RLS according to the criteria of the International RLS Study Group. All patients were free of psychoactive drugs for at least 2 weeks before the study. Patients were monitored using polysomnography, clinical ratings, and sleep diaries at baseline and at the end of a 4-week pergolide or placebo treatment period. The initial dosage of 0.05 mg pergolide was increased to the best subjective improvement paralleled by 20 mg domperidone tid. RESULTS: At a mean dosage of 0.51 mg pergolide as a single daily dose 2 hours before bedtime, there were fewer periodic leg movements per hour of time in bed (5.7 versus 54.9, p < 0.0001), and total sleep time was significantly longer (373 versus 261 minutes, p < 0.0001). Ratings of subjective sleep quality, quality of life, and severity of RLS were improved significantly without relevant adverse events. CONCLUSION: Pergolide given as a single low-to-medium bedtime dose in combination with domperidone provides a well-tolerated and effective treatment of sensorimotor symptoms and sleep disturbances in patients with primary RLS.

Partial dystrophin deficiency in monozygous twin carriers of the Duchenne gene discordant for clinical myopathy.

We studied monozygous twin women, age 63. One, asymptomatic, had a serum creatine kinase (CK) level of 191 units (normal, 1 to 50); her son died of typical Duchenne muscular dystrophy (DMD) at age 18. Her twin sister had symptomatic limb weakness from about age 40. Her serum CK was 495 units. EMG and muscle biopsy were compatible with myopathy. In the asymptomatic twin, the peripheral blood lymphocyte karyotype was 46,XX. In the affected twin, 18% of cells were 45,X, and the others 46,XX, without X/autosome translocation. DNA analysis did not reveal a deletion at the DMD locus. Immunologic studies of dystrophin showed a partial deficiency of the protein that was more severe in the symptomatic twin. The clinical discordance and the different severity of dystrophin deficiency may have resulted from the effects of lyonization.

Becker muscular dystrophy or spinal muscular atrophy?--Dystrophin studies resolve conflicting results of electromyography and muscle biopsy.

We studied a 29-year-old man with slowly progressive proximal leg weakness, calf hypertrophy, and high serum levels of creatine kinase activity. Clinically, it was not possible to identify his as a sporadic instance of Becker muscular dystrophy (BMD) or one of spinal muscular atrophy. The problem arose because electromyography and elevated creatine kinase suggested a myopathy whereas changes in the muscle biopsy resembled a neurogenic disorder. The diagnosis of BMD was made by DNA analysis which detected a deletion at Xp21 and by immunoelectrophoresis and immunohistochemical tests that identified an abnormal form of gene product, dystrophin. These studies were important for genetic counselling, identifying an X-linked disease instead of one that is autosomal recessive.

Dystrophin and its isoforms in a sympathetic ganglion of normal and dystrophic mdx mice: immunolocalization by electron microscopy and biochemical characterization.

In normal mouse superior cervical ganglion, dystrophin immunoreactivity is present in ganglionic neurons, satellite cells and Schwann cells. It is associated with several cytoplasmic organelles and specialized plasma membrane domains, including two types of structurally and functionally different intercellular junctions: synapses, where it is located at postsynaptic densities, and adherens junctions. Dystrophin immunostaining can be ascribed to the 427,000 mol. wt full-length dystrophin, as well as to the several dystrophin isoforms present in superior cervical ganglion, as revealed by western immunoblots. In mdx mouse superior cervical ganglion, which lacks the 427,000 mol. wt dystrophin, the unchanged pattern of dystrophin immunolabelling observed at several subcellular structures indicates the presence of dystrophin isoforms at these sites. Moreover, the absence of labelled adherens junctions indicates the presence of full-length dystrophin at this type of junction in the normal mouse superior cervical ganglion. The lower number of immunopositive postsynaptic densities in mdx mouse superior cervical ganglion than in normal mouse ganglion suggests the presence, in the latter, of postsynaptic densities with differently organized dystrophin cytoskeleton: some containing dystrophin isoforms alone or together with 427,000 mol. wt dystrophin, and others containing 427,000 mol. wt dystrophin alone.

Production of single-stranded DNA for sequencing: an alternative approach.

We describe a simple procedure for the direct sequencing of single-stranded, PCR-amplified, target regions of human genomic DNA. At variance with previously reported procedures, purification of the desired double-stranded DNA was introduced. This additional step allowed the single-stranded amplification and sequencing of the target gene. This step is required for direct sequencing of some amplified regions of human genomic DNA. However, no individual technique seems suitable to generate and sequence all single-stranded DNA.

Dystrophin deficiency in a case of congenital myopathy.

We studied a 5-year-old boy who had the "floppy infant syndrome" and a dystrophic pattern on muscle biopsy. According to the clinical presentation and the histopathological findings the diagnosis of congenital muscular dystrophy with associated intellectual retardation was made. Immunohistochemical and immunoblot studies using anti-dystrophin antibodies showed complete absence of the protein in the patient's muscle. DNA analysis using cDNA probes showed a deletion at the 5' end of the dystrophin gene. Our observations on this patient suggest a new phenotypical variant of Duchenne muscular dystrophy.