Risperidone as an adjunct to clozapine therapy in chronic schizophrenics

BACKGROUND: Some treatment-resistant schizophrenic patients improve enough to remain out of the hospital but continue to have significant positive or negative symptoms. METHOD: The goal of this study was to assess the safety and potential efficacy of risperidone as an adjunct for schizophrenic patients treated with clozapine. In an open 4-week trial involving 12 DSM-III-R-diagnosed patients, the addition of risperidone to clozapine was well tolerated and did not affect serum clozapine concentrations significantly. RESULTS: Total Brief Psychiatric Rating Scale (BPRS) scores and subscales measuring positive symptoms, negative symptoms, and depressive symptoms were significantly reduced from baseline. Ten of 12 participants had a 20% or greater reduction in the total BPRS score. CONCLUSION: In this open trial, the addition of risperidone to clozapine was well tolerated and produced significant reduction of symptoms, suggesting that this may be a useful clinical approach. Because this was an open trial, the improvement we observed must be replicated in a controlled trial.     

Therapeutic implications of microglia activation by lipopolysaccharide and reactive oxygen species generation in septic shock and central nervous system pathologies: a review

OBJECTIVE: Olanzapine, a potent 5-HT2a/2c, dopamine D1D2D4 antagonist with anticholinergic activity, has a profile of known receptor affinity similar to that of clozapine. This pilot study examined the efficacy of olanzapine for treatment-refractory childhood-onset schizophrenia in eight patients who had received 8-week open-label trials. For comparison, data are included from 15 patients who had received 6-week open-label clozapine trials using identical rating instruments (largely by the same raters) in the same treatment setting. METHOD: Twenty-three children and adolescents with an onset of DSM-III-R schizophrenia by age 12 for whom at least two different typical neuroleptics had been ineffective participated in the two separate studies. Some of the patients were intolerant of clozapine, although it had been effective (n = 4). Patients receiving olanzapine were evaluated over 8 weeks with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms, and the Clinical Global Impressions Scale for Improvement. RESULTS: For the eight patients who received olanzapine trials, at week 8 there was a 17% improvement in the BPRS total score, a 27% improvement in the Scale for the Assessment of Negative Symptoms, and a 1% improvement in the Scale for the Assessment of Positive Symptoms, relative to "ideal" admission status on typical neuroleptics. In contrast, the magnitude of the effect sizes for each of the clinical ratings was larger at week 6 of the previous clozapine trial than for an 8-week olanzapine trial, relative to admission status on typical neuroleptics. For the four children who had received both clozapine and olanzapine, BPRS total scores were significantly lower at week 6 of clozapine treatment compared with week 6 of olanzapine treatment (p = .03). CONCLUSION: These data provide preliminary evidence for the efficacy of olanzapine for some children and adolescents with treatment-refractory schizophrenia, but they also suggest the need for a more rigorous double-blind comparison of these two atypical antipsychotics.     

Differential behavioral response to dopamine D? agonists by sexually naive, sexually active, and sexually inactive male rats.

This study was performed with male rats categorized as sexually active (SN), sexually active (SA). or sexually inactive (SI). In a first experiment the effects of the dopamine (DA) D? agonist SND 919 (0.05, 1, and 10 mg/kg) on the copulatory behavior of SN, SA. and SI rats were assessed. In a second experiment the DA D? agonist B-HT 920 (0.2 mg/kg) was used, and examination was limited to SN and SA rats. The effects exerted on stretching-yawning, penile erection, and sedation by the same compounds at the same doses in these three rat categories were also investigated. The main findings were that SND 919 and B-HT 920 facilitated ejaculation in SA rats, and that the rats that were different as regards level of sexual activity exhibited different behavioral responses to the two DA agonists. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Famotidine adjunctive pharmacotherapy for schizophrenia: preliminary data

The usefulness of the histamine-2 (H2) antagonist famotidine as an adjunct to conventional antipsychotic treatments of idiopathic psychotic disorders (i.e., schizophrenia and schizoaffective disorder) was investigated in an open-label study. After stabilization for at least 1 week with their conventional antipsychotic medication regimen, 10 patients completed a 3-week study period in which famotidine (20 mg twice a day) was added as an adjunctive medication. The 10 patients were all somewhat treatment refractory and had spent a mean of 230 days of the previous 2 years in the hospital. Total Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression scores were significantly lower during the 3 weeks with famotidine compared with the week before and after its administration. Nevertheless, review of the scores revealed that the magnitude of the changes were small. Negative symptoms as measured by the Schedule for the Assessment of Negative Symptoms (SANS) were not significantly different during famotidine treatment, although there was the tendency for total SANS scores to be lower during famotidine treatment. When BPRS items were divided into specific versus nonspecific symptom subscales, only the specific-item subscales had significantly improved during famotidine treatment. The results of this study suggest that famotidine might prove a useful adjunctive agent in certain patients with schizophrenia. Future studies using a double-blind placebo-controlled design and higher doses are needed. Additionally, other H2 receptor antagonists with better penetration across the blood-brain barrier should be pursued.     

Prediction of short-term changes in symptom severity by baseline plasma homovanillic acid levels in schizophrenic patients receiving clozapine

The relationship between pretreatment levels of plasma homovanillic acid (pHVA) and the outcome of clozapine treatment was studied in 18 male patients with schizophrenia who were resistant to treatment with conventional neuroleptics. After 6 months of clozapine treatment, 7 patients demonstrated > or = 20% decrease in the Brief Psychiatric Rating Scale (BPRS) (responders), while 11 patients did not (non-responders). Responders and non-responders did not differ with respect to the baseline pHVA level. The BPRS Positive Symptom scores at 6 weeks and 3 months, but not those at baseline and 6 months, following initiation of clozapine treatment negatively correlated with pHVA levels for all patients. The correlations became stronger when only responders were included. No significant correlation between Positive Symptom scores and pHVA levels was observed for non-responders. The BPRS Total and Negative Symptom scores did not correlate with pHVA for all patients, responders or non-responders at any time. The percent decrease in the BPRS Positive Symptom scores from baseline at 6 weeks following clozapine treatment correlated significantly with pHVA levels in responders. These results suggest that pretreatment levels of pHVA can be used to predict relatively short-term changes in the positive symptoms of patients with schizophrenia receiving clozapine treatment, particularly for clozapine responders.     

The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials

BACKGROUND: In two double-blind trials conducted in North America, 513 patients with chronic schizophrenia received risperidone, haloperidol, or placebo. In the present study, combined data from the two trials were analyzed. METHOD: Patients were randomly assigned to receive placebo, fixed doses of risperidone (2, 6, 10, and 16 mg/day) or 20 mg/day of haloperidol for 8 weeks. Factor analysis of scores on the Positive and Negative Syndrome Scale (PANSS) produced five dimensions (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression), similar to the five dimensions of previous factor-analytic studies of PANSS data. RESULTS: Mean changes (symptom reductions) in PANSS factor scores from baseline to treatment Weeks 6 and 8 were significantly greater in patients receiving 6-16 mg/day of risperidone than in patients receiving placebo or haloperidol. The advantages of risperidone were greatest for negative symptoms, uncontrolled hostility/excitement, and anxiety/depression. Even at the lowest dose, 2 mg/day, risperidone was significantly (p < or = .05) superior to haloperidol in reducing negative symptoms. The differences in outcomes between risperidone and haloperidol on PANSS scores were not related to extrapyramidal symptoms. CONCLUSION: Risperidone produced significantly (p < or = .05) greater improvements than haloperidol on all five dimensions. The large between-group differences on negative symptoms, hostility/excitement, and anxiety/depression suggest that risperidone and other serotonin/dopamine antagonists have qualitatively different effects from those of conventional antipsychotic agents.     

A double-blind, controlled comparison of the novel antipsychotic olanzapine versus haloperidol or placebo on anxious and depressive symptoms accompanying schizophrenia

BACKGROUND: Depressive symptoms are a common feature of schizophrenia and may represent a core part of the illness. Where present, it has been associated with greater overall morbidity and mortality. Monotherapy with conventional dopamine antagonists may either worsen or bestow a limited therapeutic benefit. Accordingly the use of adjunctive thymoleptics has been explored. In contrast, olanzapine (OLZ), an atypical antipsychotic agent, offers a distinctive and pleotropic pharmacology suggestive of a broader efficacy profile than conventional neuroleptic agents. METHODS: In a 6-week placebo- and haloperidol (HAL)-controlled trial with 335 randomized subjects with chronic schizophrenia in an acute exacerbation, three fixed dose ranges of OLZ (5, 10, or 15 +/- 2.5 mg) were evaluated versus HAL (10-20 mg) or placebo. RESULTS: Baseline to endpoint change in the Brief Psychiatric Rating Scale including the anxiety-depression cluster (items 1, 2, 5, 9) was analyzed. Two dose ranges of OLZ (10 +/- 2.5, 15 +/- 2.5) were superior to placebo (p < 05) in improving mood status, whereas HAL was not. CONCLUSION: Contributions from a more selective mesolimbic dopaminergic profile, D1 or D4 activity, the release of dopamine/norepinephrine in the prefrontal cortex, and/or serotonin 5-HT2A,C antagonism may explain the differential benefit seen with OLZ in the treatment of comorbid anxious and depressive symptoms in schizophrenia.     

Prediction of violence and self-harm in mentally disordered offenders: A prospective study of the efficacy of HCR-20, PCL-R, and psychiatric symptomatology.

The efficacy of the Historical, Clinical, and Risk Management Scales (HCR-20; C. D. Webster, D. Eaves, K. S. Douglas, & A. Wintrup, 1995), Psychopathy Checklist--Revised (PCL-R; R. D. Hare, 1991), Beck Hopelessness Scale (BHS; A. T. Beck, A. Weissman, D. Lester, & L. Trexler, 1974), and Brief Psychiatric Rating Scale (BPRS) to predict violence and self-harm in 34 institutionalized mentally disordered offenders was assessed. Both the HCR-20 and BPRS were strong predictors of violence whereas the PCL-R had moderate predictive ability. BHS was the only variable predictive of self-harm. Although risk assessment measures were successful at predicting in-patient violence, a clinical measure of mental state was at least as effective in these mentally disordered offenders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Use of the Brief Psychiatric Rating Scale to measure success in a psychosocial day program

This study contrasted six subscales of the Brief Psychiatric Rating Scale (BPRS) to determine their sensitivity to psychosocial treatment outcome. An expanded version of the BPRS was administered to 216 clients on admission to a day program. The subscale measuring hostility and suspiciousness discriminated at intake clients who were therapeutically discharged from clients who did not complete the program and predicted discharge status after the investigators controlled for the effects of demographic variables. Significant reductions in scores were obtained on five subscales for a subset of clients to whom the BPRS was readministered before discharge. The results support the use of the expanded BPRS as an evaluative tool in psychosocial rehabilitation programs.     

Trial of trazodone for posttraumatic stress disorder using a multiple baseline group design

Six patients with combat-related posttraumatic stress disorder (PTSD) entered a multiple-baseline trial of trazodone, beginning with 50 mg/day and increasing to 400 mg/day until response was maximal. Total Clinician-Administered PTSD Scale scores decreased from a mean of 92 at baseline to 79 at end point, and self-reported PTSD symptoms as measured by the Davidson Trauma Scale paralleled these results (mean of 102 at baseline to 88 at end point). Based on clinician global improvement scores, four patients were rated as much improved and two were rated to be minimally improved. Improvement in social and occupational functioning, and depression was minimal. Available follow-up scores for PTSD symptoms indicated that gains were maintained. Sleep was the first symptom to improve at 2 to 3 months. No dropouts during the treatment period occurred, and reported side effects were quite low. These preliminary data suggest that trazodone may be effective in reducing the three primary clusters of symptoms of PTSD. These findings should be confirmed by using a larger sample in a double-blind, placebo-controlled study.     

Identifying subtypes of schizophrenia by cluster analyses

The existence of two subtypes of schizophrenia (positive and negative) is well established. The evidence in favor of other subtypes, particularly a disorganized subtype, is still the subject of some debate. The aim of the study reported in this article is to investigate the possibility of further subtypes of schizophrenia by applying a particular method of cluster analysis to a particular set of data. Ward's method of cluster analysis was applied to the Positive and Negative syndrome Scale (PANSS) scores of 138 patients, defined as having schizophrenia by one of four diagnostic criteria. The validity of the cluster solution was assessed both by examining differences between clusters on a number of clinical characteristics recorded for each patient and by comparing the results obtained from the PANSS with those derived from a cluster analysis using two other instruments (the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms). Results from the cluster analysis suggest the existence of at least four subtypes of schizophrenia: positive, negative, mixed, and disorganized. A fifth subtype includes patients with few symptoms, suggesting the simple schizophrenia named by Bleuler. Evidence for the validity of these subtypes was provided by the differences observed between the clusters on a number of clinical characteristics and by the similarity of the cluster solution obtained from the different instruments. In conclusion, the negative-positive dichotomy in schizophrenia is an oversimplification, and the existence of a more complex structure needs to be taken into account in future research.     

The role of high- and low-dose corticotropin tests in the diagnosis of secondary adrenal insufficiency

Mini Mental State Examination (MMSE), Brief Psychiatric Rating Scale (BPRS) and subscales of the BPRS were performed on 73 elderly inpatients (mean age: 67.9 years; standard deviation: 7.2; range: 60-89) diagnosed with DSM-III-R chronic schizophrenia. Forty of the subjects were men and 33 were women. A significant negative correlation was observed between MMSE and the age, factor negative, factor depressive, and total score of BPRS. We believe, however, that it is relatively sufficient to screen for demented illness of schizophrenics using MMSE when considering the age and the psychiatric symptoms (especially negative or depressive symptoms ). Forty-eight (66%) of the 73 patients were categorized as 'demented' by MMSE. These results suggest that the aged inpatients with schizophrenia in a hospital showed certain kinds of cognitive deficits (including senile dementia) more frequently than the general population.     

Epithelial removal with the excimer laser (laser-scrape) in photorefractive keratectomy retreatment

1. A study was made relating the involvement of alpha-adrenoceptors in the cardiovascular responses to intracerebroventricular (i.c.v.) injection of B-HT 920, a clonidine-type drug, in conscious sham-operated and sinoaortic-denervated rats. 2. Wistar rats were used, 7 days after the sham operation or sinoaortic denervation. For i.c.v. injection of drugs, a guide cannula had been previously implanted in the left lateral ventricle. 3. In sham-operated rats, cardiovascular responses to B-HT 920 (10-60 microg) were increased blood pressure and bradycardia; but, in sinoaortic-denervated rats, after the pressor response, a decrease in blood pressure also was seen. The responses to this agent were greater in sinoaortic-denervated rats than in sham-operated animals. Treatment with the alpha2-adrenoceptor antagonist yohimbine (30 microg), the imidazoline receptor antagonist idazoxan (15 microg) and the alpha1A-adrenoceptor antagonist 5-methylurapidil (15 microg) blocked the responses to B-HT 920 (30 microg). The alpha1-adrenoceptor antagonist prazosin (15 microg) and the alpha1B-adrenoceptor antagonist chloroethylclonidine (100 microg) did not modify the responses to agonist. 4. Sinoaortic denervation enhances the cardiovascular responses to B-HT 920. Moreover, the effects of i.c.v. administration of B-HT 920 could be mediated by several types of brain receptors: imidazoline receptors and alpha1A- and alpha2-adrenoceptors.     

Health-related quality of life outcomes of omeprazole versus ranitidine in poorly responsive symptomatic gastroesophageal reflux disease

OBJECTIVE: This study evaluated changes in health-related quality of life (HRQL) outcomes of once-daily omeprazole compared with ranitidine for the short-term treatment of patients with poorly responsive symptomatic gastroesophageal reflux disease (GERD). METHODS: A double-blind, randomized clinical trial, compared omeprazole versus ranitidine for the treatment of poorly responsive GERD. Eligible patients had a history of predominant heartburn symptoms with symptomatic heartburn after 6 weeks of ranitidine treatment. Patients were randomized to omeprazole 20 mg once daily (n = 156) or ranitidine 150 mg twice daily (n = 161) and followed for 8 weeks. Assessments were completed at baseline and after 8 weeks with physician-rated symptoms: Gastrointestinal Symptom Rating Scale (GSRS); Psychological General Well-Being (PGWB) Index; Sleep Scale; Impact on Daily Activities Scale, and Overall Treatment Effect. Primary HRQL endpoints were the GSRS reflux scale and PGWB total score. RESULTS: No differences between the 2 treatment groups were observed in baseline demographic, clinical or HRQL measures. After 8 weeks, omeprazole-treated patients had greater improvement in GSRS reflux scale scores (p<0.0001) and PGWB total scores (p = 0. 019) compared with ranitidine-treated patients. Significant between group differences favoring omeprazole were also observed in GSRS total scores (p<0.0001), abdominal pain scale scores (p = 0.003), and indigestion scale scores (p = 0.003), Impact on Daily Activities (p = 0.001), PGWB positive well-being (p = 0.015), anxiety (p = 0. 030), and general health scale scores (p = 0.010). Patient ratings of overall treatment effect demonstrated the significantly (p<0. 0001) greater benefits of omeprazole (mean = 5.26) compared with ranitidine treatment (mean = 3.83). CONCLUSIONS: Omeprazole treatment significantly reduced persistent reflux-related symptoms and normalized psychological well-being compared with ranitidine in poorly responsive symptomatic patients with GERD.     

Switching from clozapine to olanzapine in treatment-refractory schizophrenia: safety, clinical efficacy, and predictors of response

BACKGROUND: In our experience, many of our schizophrenic patients treated with clozapine request the newer atypical antipsychotic agents in order to eliminate the weekly blood monitoring. However, there are few guidelines available to clinicians interested in switching patients successfully treated with clozapine to olanzapine. METHOD: The goal of this study was to collect preliminary data on the safety, clinical effectiveness, and predictors of response of switching clozapine patients to olanzapine. In an open trial, 19 patients receiving clozapine were switched to olanzapine. RESULTS: Eight (42%) of 19 patients were considered responders. Seven patients decompensated seriously enough to require hospitalization. All 7 of these patients were restabilized on clozapine treatment in the hospital, and olanzapine was discontinued. In an additional 4 patients, clinical status worsened, and clozapine doses were titrated upwards and olanzapine was slowly discontinued. Overall, mean total Brief Psychiatric Rating Scale (BPRS) scores increased significantly from baseline to final assessment (p = .02). Responders had been treated for a significantly shorter period of time with clozapine prior to the switch compared to nonresponders (p = .04) and were receiving a lower dose of clozapine (p = .05). The final olanzapine dose did not differ between responders and nonresponders. All responders have remained on olanzapine treatment and are stable. CONCLUSION: In this open trial, the crossover from clozapine to olanzapine was generally well tolerated and resulted in a successful transition for 8 of the 19 patients. However, mean scores on the total BPRS and negative symptom and depressive symptom subscales significantly increased. Caution must be taken in determining which patients may benefit from the switch to olanzapine because of the risk of decompensation and hospitalization. Because this was an open trial, these findings require replication in a controlled trial.     

A comparison of the clinical efficacy and patient acceptability of terbutaline Turbuhaler and salbutamol Rotahaler, in adult patients with asthma

Fifteen Thai patients with Parkinson's disease (7 females, 8 males) were enrolled in an open label trial of pergolide (a new dopamine agonist) to evaluate its safety and efficacy. Inpatients and outpatients from Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand from 1992 to 1994 were included in the study with a total duration of 18 weeks. Both de novo patients and patients who were being treated with levodopa without dopamine agonist and were obtaining a less than optimal response at both visit 1 and visit 2 were all enrolled in this study. At entry into the study, 3 patients had Hoehn and Yahr stage I, 7 patients at stage II, 3 patients at stage III, and 2 patients at stage IV. Pergolide dosage was gradually built up until an optimal dosage was achieved. The average dose of pergolide during the study was 0.94 mg/day (range 0.075 to 8 mg/day). All patients completed the study and no patients dropped out. Two patients (13.33 per cent) experienced nausea (on 0.4 mg/day and 0.075 mg/day), two patients (13.33 per cent) experienced sleepiness (0.50 mg/day and 0.075 mg/day) and one patient (6.67 per cent) unsteadiness on walking (0.50 mg/day). There was one patient who required pergolide up to 8 mg/day which is higher than the recommended dosage (5 mg/day) but this patient experienced no adverse effects and his disabled dyskinesic was abolished. Our study demonstrated the good toleration and efficacy of pergolide treatment for Thai patients with Parkinson's disease. This new dopamine agonist stimulates both D1 and D2 receptors in comparison to other dopamine agonists (bromocriptine and lisuride) which stimulate only D2 receptors.     

Amelioration of methotrexate-induced malabsorption by vitamin A

Since the early 1960s the Brief Psychiatric Rating Scale (BPRS) has been one of the most frequently used standardized methods in international psychiatric research. The BPRS is used mainly for the rating of psychopathological symptoms of schizophrenic subjects. According to the results of factorial analyses, the original version of the BPRS is divided into five subscales, which have been preserved in the German translation. The validity of this original scale structure for the German BPRS version has not been investigated, however. A principal-components analysis of the 18 BPRS items carried out on the data of 301 schizophrenics yielded four factors that are comparable with four of the original subscales: Thought disturbance, Hostility/suspiciousness, Anxiety/depression, and Anergia. These results are compared with earlier findings and similarities and differences are discussed.     

Children's anxiety scales in relation to self, parental, and psychiatric ratings of anxiety.

The CMAS and the General Anxiety Scale for Children were administered to a group of pediatric and psychiatric outpatients and modified forms were given to the parents of the children. The psychiatric group was also given a clinical rating of anxiety and a check list rating of psychiatric symptoms. Significant positive interest correlations were found between the anxiety items, but not the lie items of the 2 scales. Moderate agreement was found between the children's self-ratings of anxiety and those done by their parents. Significant agreement was found between parents' ratings of their children's anxiety. The psychiatric group scored significantly higher on the CMAS than the pediatric group. The number of psychiatric symptoms was found to correlate positively with the anxiety scale scores. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Delayed development of symptomatic improvement by (--)-deprenyl in Parkinson's disease

Twenty de novo patients with Parkinson's disease (Hoehn-Yahr stages I, II, III) were studied in a double blind trial after introducing (--)-deprenyl monotherapy. The parkinsonian symptoms were assessed by a novel graded clinical rating scale, by UPDRS and by the North Western self-rating scale. A significant change was observed in motor behaviour and daily activity (UPDRS) after 3 weeks of treatment with (--)-deprenyl at 10 mg/day. The total scores using UPDRS and the North Western ratings were changed significantly after 4 weeks. The greatest changes observed were in walking and in hypokinesia. Rigidity was not modified by (--)-deprenyl.