Different side effect profiles of risperidone and clozapine in 20 outpatients with schizophrenia or schizoaffective disorder: a pilot study

OBJECTIVE: The purpose of this study was to compare the side effect +profiles of clozapine and risperidone. METHOD: The subjects were 20 outpatients with schizophrenia or schizoaffective disorder who were clinically stable on a regimen of clozapine at the time of screening. They underwent a randomized-order crossover comparison of 6 weeks of risperidone treatment and 6 weeks of clozapine treatment. Clinical and neurocognitive variables were assessed by raters blind to medication status, and severity of side effects was determined from patients' self-reports. RESULTS: Side effect measures, but not clinical ratings, were significantly different after 6 weeks of treatment with the two drugs. Patients required more benztropine for motor effects and complained of more insomnia with risperidone and more sedation with clozapine. Body weight was higher at the end of clozapine treatment than at the end of risperidone treatment. CONCLUSIONS: In this exploratory study, the side effect profiles of clozapine and risperidone were consistent with the different pharmacodynamic profiles of the two drugs.     

CSF neurotensin concentrations and antipsychotic treatment in schizophrenia and schizoaffective disorder

OBJECTIVE: The relationship between CSF neurotensin concentrations and measures of psychopathology in patients with schizophrenia or schizoaffective disorder was examined before and after treatment with antipsychotic drugs. METHOD: CSF neurotensin concentrations were measured in 42 drug-free patients with schizophrenia or schizoaffective disorder. For 18 of these patients, CSF neurotensin was measure again after 4 weeks of antipsychotic treatment. RESULTS: Significantly higher levels of pretreatment psychopathology were observed in the patients with the lowest CSF neurotensin concentrations. Furthermore, improvements in overall psychopathology and, particularly, negative symptoms were correlated with increases in CSF neurotensin concentrations during treatment. CONCLUSIONS: These findings provide further evidence for a role of neurotensin the pathophysiology of psychosis and in the mechanism of action of antipsychotic drugs.     

Association between catechol O-methyltransferase genotype and violence in schizophrenia and schizoaffective disorder

An 18-month-old dog was examined because of ascites of 1 month's duration. Typical causes of ascites, including hepatic failure, heart failure, and protein-losing enteropathy, were ruled out. The dog's history included being hit by a car 6 months earlier, and the caudal vena cava had an S shape on thoracic radiographs. In addition, the abdominal fluid had a high protein concentration and low cellular content. These findings were all consistent with a diagnosis of postsinusoidal hypertension secondary to obstruction of hepatic venous outflow (Budd-Chiari-like syndrome). During exploratory thoracotomy, the pericardium appeared to have been torn from the heart and was partially wrapped around the caudal vena cava, causing a constriction. The pericardium was removed and the dog recovered without any further complications. Blunt trauma has been previously reported to cause kinking of the caudal vena cava and Budd-Chiari-like syndrome in dogs; but in these dogs, clinical signs of ascites developed a few days to several weeks after the traumatic incident. It appears that, depending on the cause of the hepatic venous outflow obstruction, onset of Budd-Chiari-like syndrome may be delayed for months.     

Therapeutic window of serum haloperidol concentration in acute schizophrenia and schizoaffective disorder

Starting from 3-(3-chloro-1H-pyrazol-5-yl)-1H-quinoxalin-2-one (2) a series of substituted [1,2,4]triazolo[4,3-a]quinoxalines (3a-f) was prepared via a multistep reaction sequence. Affinities of the novel derivatives 3a-f for benzodiazepine as well as for adenosine A1- and A2A-receptors of rat brain were determined by radioligand binding assays. 1-Methyl-4-(3-chloro-1H-pyrazol-5-yl) derivative 3a exhibited submicromolar affinity for the benzodiazepine binding site of GABAA receptors (Ki = 340 nM) and was less potent at A1-(Ki = 7.85 microM) and A2A-(Ki = 1.43 microM) adenosine receptors (AR). Derivatives with larger substituents in the 1-position showed reduced binding to benzodiazepine and A2A-AR, but increased A1-AR affinity, the 2-thienylmethyl derivative 3f being the most potent and selective A1-AR ligand of the present series (Ki = 200 nM).     

Cognitive impairments associated with formal thought disorder in people with schizophrenia.

Formal thought disorder (FTD), or disorganized speech, is one of the central signs of schizophrenia. Despite extensive research, the cognitive processes associated with FTD are still unclear. However, the authors' review of FTD theories and research indicates that considerable progress has been made in identifying possible cognitive impairments associated with FTD. Specifically, FTD is strongly associated with impaired executive functioning and with impaired processing of semantic information. Their review indicates that previous research has not yet supported an association between FTD and either an increase in spreading activation or an impairment within the language production system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cardiomyopathy associated with clozapine.

Clozapine is an atypical antipsychotic agent that is more effective than the standard neuroleptics currently used for treating refractory schizophrenia. In addition, clozapine is a drug with few extrapyramidal side effects. However, clozapine is also associated with potentially serious adverse effects, such as cardiac complications as well as agranulocytosis. Clozapine-related cardiomyopathy has not been previously reported in East Asia. This report describes a 31-year-old Korean male patient with schizophrenia who developed dilated cardiomyopathy on treatment with clozapine. The removal of clozapine caused subsequent physical improvement. However, the readministration of clozapine for managing relapse of psychosis caused a recurrence of dilated cardiomyopathy in this patient. Therefore, this is the 1st report showing that the 2nd trial of clozapine caused recurrence of cardiomyopathy associated with clozapine. Thus, this report adds important support for a causal relation between clozapine and cardiac complications. In conclusion, this report attempts to raise awareness of clozapine-related cardiomyopathy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pretreatment plasma homovanillic acid in schizophrenia and schizoaffective disorder: the influence of demographic variables and the inpatient drug-free period

BACKGROUND: The relationship between plasma homovanillic acid (pHVA) and schizophrenic symptoms has not been conclusively determined. We reexamine pHVA levels in a new sample of patients with emphasis on demographic variables and the drug-free period. METHODS: Plasma HVA levels were studied in 54 schizophrenic and schizoaffective-disordered, drug-free inpatients suffering from a psychotic exacerbation. RESULTS: A significant correlation was observed between pHVA levels and the number of inpatient drug-free days in the total sample, as well as the schizophrenic patient subsample. Further, pHVA was significantly and positively correlated with the duration of illness in the schizophrenic patient subsample. Plasma HVA correlations with behavior, as measured by Brief Psychiatric Rating Scale factors (anxiety/depression and hostility/suspiciousness), emerged only when considering schizophrenic patients drug-free for more than 2 weeks. No correlation was found between pHVA and the age of illness onset or the duration of the delay of treatment of the first psychotic episode. CONCLUSIONS: The effects of antipsychotic withdrawal on levels of pHVA in clinical populations may have to be examined and controlled for in future studies attempting to study the relationship between this metabolite and behavior in acutely ill, drug-free schizophrenic patients.     

Twelve-month outcome of patients with DSM-III-R schizoaffective disorder: comparisons to matched patients with bipolar disorder

We examined potential mechanisms by which angiotensin subtype-2 (AT2) receptor stimulation induces net fluid absorption and serosal guanosine cyclic 3',5'-monophosphate (cGMP) formation in the rat jejunum. L-arginine (L-ARG) given intravenously or interstitially enhanced net fluid absorption and cGMP formation, which were completely blocked by the nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine methylester (L-NAME), but not by the specific AT2 receptor antagonist, PD-123319 (PD). Dietary sodium restriction also increased jejunal interstitial fluid cGMP and fluid absorption. Both could be blocked by PD or L-NAME, suggesting that the effects of sodium restriction occur via ANG II at the AT2 receptor. L-ARG-stimulated fluid absorption was blocked by the soluble guanylyl cyclase inhibitor 1-H-[1,2,4]oxadiazolo[4, 2-alpha]quinoxalin-1-one (ODQ). Cyclic GMP-specific phosphodiesterase in the interstitial space decreased extracellular cGMP content and prevented the absorptive effects of L-ARG. Angiotensin II (ANG II) caused an increase in net Na+ and Cl- ion absorption and 22Na+ unidirectional efflux (absorption) from the jejunal loop. In contrast, intraluminal heat-stable enterotoxin of Escherichia coli (STa) increased loop cGMP and fluid secretion that were not blocked by either L-NAME or ODQ. These findings suggest that ANG II acts at the serosal side via AT2 receptors to stimulate cGMP production via soluble guanylyl cyclase activation and absorption through the generation of NO, but that mucosal STa activation of particulate guanylyl cyclase causes secretion independently of NO, thus demonstrating the opposite effects of cGMP in the mucosal and serosal compartments of the jejunum.     

Effects of switching inpatients with treatment-resistant schizophrenia from clozapine to risperidone

A prospective, open-label study in a 400-bed state psychiatric hospital evaluated change in therapeutic response among ten patients with treatment-resistant schizophrenia who were switched from clozapine to risperidone. Drug effects were examined before discontinuation of clozapine and at three, six, nine, and 12 weeks of risperidone treatment. No patients improved, and five discontinued treatment due to exacerbation of psychosis or adverse effects. Changes in scores on the Positive and Negative Syndrome Scale, the Brief Psychiatric Rating Scale, and the Barnes Akathisia Scale indicated clinically significant worsening of symptoms. The findings do not support replacing clozapine with risperidone for patients with treatment-resistant schizophrenia.     

Structural features associated with reactive metabolite formation in clozapine analogues

Clozapine is associated with a high incidence of agranulocytosis. We had previously found that it is oxidized by granulocytes, or simply HOCl, to a reactive metabolite that irreversibly binds to the cells, and we proposed that this reactive metabolite is responsible for clozapine-induced agranulocytosis. The reactive metabolite appeared to be a nitrenium ion formed by chlorination of the nitrogen bridge between the two aromatic rings. If this is correct, analogs that contain this structural feature should also be oxidized to a reactive intermediate while those not possessing this feature would, at least, not form the same type of reactive intermediate and, therefore, may not induce agranulocytosis. We tested the first part of this hypothesis with three clozapine analogs that do contain a nitrogen bridge and three that do not. Consistent with the hypothesis, the three analogs that do contain the nitrogen bridge formed reactive intermediates that could be trapped with glutathione when oxidized by HOCl, myeloperoxidase or activated neutrophils. In contrast, we found no evidence of a reactive intermediate on oxidation of analogs that contained an oxygen or sulfur bridge rather than a nitrogen bridge. If such reactive metabolites are responsible for drug-induced agranulocytosis, it should be possible to use such a simple screening method to test drugs at an early stage in their development for the potential to induce agranulocytosis.     

Trauma and posttraumatic stress disorder in people with schizophrenia.

This study evaluated the hypothesis that trauma and posttraumatic stress disorder (PTSD) severity would be positively associated with schizophrenia symptoms. Forty-seven clients with schizophrenia were assessed for schizophrenia severity and for lifetime trauma history and PTSD symptoms in 2 independent symptom interviews; 35 (74%) participants reported at least 1 event in which there was threat of harm or life threat and subjective distress, and 6 (13%) had current PTSD. Trauma across the life span was associated with greater severity of PTSD. Within the total sample, PTSD symptoms were associated with greater emotional distress, but not with schizophrenia-specific symptoms. Distress among clients with schizophrenia and PTSD suggests the need for routine assessment of PTSD and development of PTSD interventions in this population. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Antisaccade performance in patients with schizophrenia and affective disorder.

The authors examined psychotic patients with schizophrenia, major depression, and bipolar disorder; "normal" participants; and 1st-degree relatives of patients with schizophrenia on an antisaccade task in which participants were instructed to move their eyes in the opposite direction of a target that moved unpredictably and abruptly either to the left or right of central fixation. Patients with schizophrenia were found to make significantly more errors than their relatives, and the latter made more errors than the controls. The poor performance of the relatives could not be attributed to their having a psychiatric disorder. Comparison of the 3 patient groups indicated that antisaccade deficits were more pronounced in schizophrenia and bipolar disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Thought disorder in adolescent-onset schizophrenia

The nature of the thinking disturbances found in adolescent-onset psychotic conditions is not as well-characterized as the thought disorders found in adult psychotic patients. We used the Thought Disorder Index to examine whether schizophrenic patients in whom psychotic symptoms appear in adolescence show the same characteristic features of thought disorder as do adult schizophrenics. Quantitative and qualitative features of thought disorder were assessed in psychiatric inpatients with adolescent-onset schizophrenia, psychotic depression, and nonpsychotic conditions compared with normal control adolescents. Elevated thought disorder occurred in all groups of adolescents hospitalized for an acute episode of psychiatric illness. The magnitude of the elevation and the frequency of occurrence of disordered thinking were greatest in the psychotic adolescents. The qualitative features of the thought disturbances found in the schizophrenic adolescents were distinct from those observed in adolescents with psychotic depression. The thinking of the schizophrenic adolescents resembled that of adult schizophrenics. In both conditions thought disorder is characterized by idiosyncratic word usage, illogical reasoning, perceptual confusion, loss of realistic attunement to the task, and loosely related ideas.     

The use of clozapine in the treatment of aggressive schizophrenia

The effect of coadministration of ritonavir and didanosine (ddI) on the pharmacokinetics of these drugs was investigated in a single-center, three-period, crossover study. Eighteen asymptomatic, HIV-positive men were assigned randomly to 6 different sequences of 3 regimens: ddI (200 mg every 12 hours) alone for 4 days, ritonavir (600 mg every 12 hours) alone for 4 days, and 4 days of ddI with ritonavir under dose-staggering conditions. Although not statistically significant, ritonavir concentrations were slightly higher on average (<10%) with concurrent administration of ddI compared with those of ritonavir alone. In contrast, ddI concentrations were lower with concurrent administration compared with those of ddI alone; maximum concentration and area under the concentration-time curve were reduced by about 15% (p < .05). The ddI elimination rate constant was unaffected by ritonavir, suggesting no change in ddI's systemic metabolism. Adverse events were similar between regimens. The relatively minor changes in ritonavir and ddI pharmacokinetics are probably not clinically relevant; therefore, dosage adjustment of either compound appears unnecessary when administered concurrently. However, the combination regimen of ddI and ritonavir continue to be evaluated clinically.     

Eye tracking disorder in schizophrenia is characterized by specific ocular motor defects and is associated with the deficit syndrome

The objective was to determine the relationships between eye tracking disorder (ETD) in schizophrenia, specific ocular motor measures, and the deficit syndrome. Twenty-five normal comparison subjects and 53 schizophrenic patients had eye movements tested with infrared oculography using a sinusoidal target. Patients were assessed with the Schedule for the Deficit Syndrome. For the patients, the distribution of position root mean square error (a global measure of pursuit) was best fit by a mixture of two normal distributions. This information was used to divide the patients into two subgroups, those with and those without ETD. ETD was almost completely accounted for by several specific ocular motor measures and was significantly associated with the deficit syndrome. The finding that ETD was almost completely accounted for by specific measures bridges a gap of interpretation in this field. ETD and the deficit syndrome of schizophrenia may share a common pathophysiology of cerebral cortical-subcortical circuits.     

Psychoeducation in schizophrenia relapse prevention

Schizophrenia is a chronic disease, with phase course. Most of patients (about 78%) experience more than one episode of the disease in the course of life. Pharmacotherapy is the standard method of troating schizophrenia. Since the middle of the 70 a new orientation of therapy of schizophrenia has been developing. Its main goal is prophylaxis, which combines pharmacotherapy and psychosocial treatment. In the paper we discuss the term "relapse of schizophrenia" and researches concerning the index of relapses and dynamics of the disease. We present theoretical presumptions which are the base of psychoeducational programs, that is, stress-vulnerability model. The main purposes of psychoeducation in schizophrenia are also discussed. The article contains current review of the researches relative to effectiveness of psychoeducational programs in relapse of schizophrenia prevention.     

Relationship between early side effects and therapeutic effects of clomipramine therapy in obsessive-compulsive disorder

Recognizing that the scientific method is as critical to cancer control as it is to basic laboratory research, the National Cancer Institute (NCI) established a well-defined, systematic strategy for attaining its cancer control goals and objectives. This strategy, operationalized in the early 1980s as a five-phase process, emphasized cancer control as a research science rather than a demonstration science. The five phases of NCI's cancer control research strategy progress from hypothesis development, to methods development, to controlled intervention trials, to defined population studies, and finally to demonstration and implementation programs. This research base provides the foundation for nationwide prevention and health services programs. The application of this five-phase approach to NCI's efforts to reduce morbidity and mortality attributable to tobacco use is described, and some of the challenges that faced the Institute in this process are identified. These experiences provide an important framework for other disciplines faced with the challenge of translating science into practice.     

Modal attention asymmetry in patients with schizophrenia and bipolar disorder.

This cross-sectional study examined modal attention asymmetries in patients with schizophrenia (n?=?47) and bipolar disorder (n?=?42), as contrasted to a matched-sample comparison group of normal participants (n?=?89). A test of continuous auditory and visual attention was the primary measure. The data were analyzed from 2 experimental conditions: simple modal responses (auditory and visual) and modal switching responses (ipsimodal and cross-modal switching). In the simple modal condition, patients with schizophrenia demonstrated a visual over auditory asymmetry; patients with bipolar disorder showed no differences. In modal switching conditions, however, patients with bipolar disorder displayed a significant auditory over visual asymmetry. No main effect was detected between medications and attention functioning. Results are discussed in light of differentiating these 2 populations on the basis of modal specificity of attention functioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges

OBJECTIVE: This study sought to determine the relationships between serum clozapine levels and therapeutic response. METHOD: Fifty-six inpatients who met the DSM-III-R criteria for chronic schizophrenia and who had not responded to extended treatment with classical antipsychotics were randomly assigned to 12 weeks of double-blind treatment with clozapine at one of three serum level ranges: low (50-150 ng/ml), medium (200-300 ng/ml), or high (350-450 ng/ml). Baseline clinical assessments were completed before the patients' regular antipsychotic and anticholinergic drugs were discontinued. During clozapine treatment, serum levels were ascertained weekly to allow adjustment of clozapine doses so as to maintain each patient near the midpoint of his or her assigned serum level range. Clinical assessments were completed after 6 and 12 weeks of treatment. RESULTS: The analyses of the results of treatment supported the superior efficacy of the 200-300 ng/ml and 350-450 ng/ml serum clozapine level ranges over the 50-150 ng/ml range, with no advantage for 350-450 ng/ml over 200-300 ng/ml. Sleepiness increased with increasing serum levels. CONCLUSIONS: Serum clozapine levels per unit of daily dose were at the lower end of the range noted in previous reports, possibly reflecting the current study's dosing schedules of twice or three times a day, the 11- to 13-hour postdose sampling time, and the moderate doses given. Serum clozapine levels, if interpreted in relation to daily clozapine dosing schedules, postdose sampling time, and total daily dose, may help to guide dosing to provide adequate opportunities for therapeutic response and to limit certain side effects of clozapine treatment.