Clozapine for substance-abusing schizophrenic patients.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
S R Marder
Publications and source records attributed to S R Marder.
Risperidone in treatment-refractory schizophrenia.
OBJECTIVE: The purpose of this study was to evaluate the clinical safety and efficacy of risperidone compared to haloperidol in patients with treatment-refractory schizophrenia. METHOD: Sixty-seven medication-unresponsive subjects were randomly assigned to treatment with risperidone (N = 34) or haloperidol (N = 33). After a 3-7 day-placebo washout period, there was a 4-week, double-blind, fixed-dose comparison trial that was followed by a 4-week, flexible-dose phase. Measures of clinical change were quantified by standard psychopathologic and neuromotor instruments. RESULTS: Risperidone demonstrated clinical efficacy superior to that of haloperidol on the total Brief Psychiatric Rating Scale (BPRS) after the first 4 weeks of treatment. Risperidone did not show any advantage over haloperidol after an additional 4 weeks. Overall improvement on the BPRS at 4 weeks was significantly better for the risperidone group (24%) than for the haloperidol group (11%). Risperidone-treated subjects were significantly less likely than haloperidol-treated subjects to require concomitant anticholinergic medication after 4 weeks (20% versus 63%); they also had significantly les observable akathisia (24% versus 53%) and significantly less severe tardive dyskinesia. Baseline characteristics that correlated significantly with risperidone response were positive symptoms, conceptual disorganization, akathisia, and tardive dyskinesia. CONCLUSIONS: Risperidone was better tolerated and more effective in a subset of patients with treatment-refractory schizophrenia. Positive psychotic symptoms and extrapyramidal side effects at baseline appear to be powerful predictors of subsequent response to risperidone.
Adult↗
An approach to treatment resistance in schizophrenia.
Currently, patients with schizophrenia are usually considered refractory to treatment if they continue to be floridly symptomatic despite receiving treatment with conventional antipsychotic agents. Attempts to improve their response by increasing the dosage, adding supplementary drugs, or switching to agents of another class have not been very successful, and may increase side-effects. Clozapine can be effective, but it is a difficult drug to administer and has therefore been reserved for patients who are doing poorly. With the recent introduction of newer, safer antipsychotic agents, however, even patients who have milder refractory symptoms that persist after treatment with conventional antipsychotics can now be treated.
Antipsychotic Agents↗
Novel antipsychotics: comparison of weight gain liabilities.
BACKGROUND: We performed a retrospective analysis of 122 clinical records of 92 male patients with DSM-III-R schizophrenia to examine the relative weight gain liabilities of clozapine, risperidone, olanzapine, and sertindole compared with haloperidol. We hypothesized that the unique pharmacodynamic profiles of these agents would contribute to different amounts and patterns of weight gain. METHOD: Data were analyzed to determine differences in weight gain during treatment among patients receiving 5 different drug treatments (clozapine [N = 20], olanzapine [N = 13], risperidone [N = 38], haloperidol [N = 43], and sertindole [N = 8]). Measures of maximal weight gain, final weight, and duration to maximal weight gain were calculated. RESULTS: Repeated measures analyses of variance controlling for age, treatment duration, and initial weight revealed statistically significant differences between groups on all 3 measures. Clozapine and olanzapine had the greatest maximal weight gain liability (F = 4.13, df = 4,23; p = .01). Weight gain with clozapine, but not olanzapine or risperidone, appears to persist (as reflected by final weight) despite behavioral interventions (e.g., nutritional consultation, suggested exercise regimen; F = 5.69, df = 4,23; p = .003). Clozapine- and olanzapine-treated subjects appeared to gain weight over a prolonged period of time, whereas risperidone-and sertindole-treated subjects had a more limited period of weight gain (F = 2.95, df = 4,25; p = .04). CONCLUSION: Clozapine and olanzapine caused the most weight gain, risperidone was intermediate, and sertindole had less associated weight gain than haloperidol. The relative receptor affinities of the novel antipsychotics for histamine H1 appear to be the most robust correlate of these clinical findings.
Adult↗
Risperidone vs. haloperidol on reaction time, manual dexterity, and motor learning in treatment-resistant schizophrenia patients.
BACKGROUND: The present study compared the effects of risperidone vs. haloperidol on reaction time, manual dexterity, and two types of motor learning in a sample of treatment-resistant schizophrenia patients. METHODS: Fifty-six DSM-III-R diagnosed schizophrenia inpatients participated in a randomized, double-blind comparison of risperidone vs. haloperidol. Measures of reaction time, manual dexterity, motor sequence learning, and gross motor learning were administered at baseline, after 4 weeks of fixed-dose medication, and after 4 weeks of flexible-dose medication. RESULTS: The results indicated that patients receiving risperidone showed greater improvement in reaction time and manual dexterity than patients receiving haloperidol. After covarying symptom changes and movement disorder ratings, the results remained significant. The two treatment groups did not differ on either measure of motor learning. CONCLUSIONS: The differences in performance in reaction time and manual dexterity may be due to a specific beneficial effect of risperidone, as opposed to a general reduction in extrapyramidal symptom liability, compared to haloperidol.
Adult↗
Novel antipsychotics and new onset diabetes.
BACKGROUND: The new antipsychotics induce minimal extrapyramidal side effects, probably due to their relatively greater affinity for certain nondopaminergic receptors than their older, conventional counterparts; however, this polyreceptor affinity may be responsible for the development of other adverse effects. One serious adverse effect that may be linked to these effects is non-insulin-dependent diabetes mellitus. METHODS: We summarize 6 new cases of clozapine- and olanzapine-associated diabetes that we have documented in our clinic. We compare our cases to previous reports and tabulate the pertinent similarities among cases. RESULTS: Two of the cases were olanzapine-associated and 4 were clozapine-associated diabetes. Five of our 6 patients had risk factors for diabetes, as have 7 of the 9 previously reported in the literature. Four of our 6 patients, and 2 of the 4 prior cases in which such data were reported, experienced substantial weight gain after starting their antipsychotics. CONCLUSIONS: Novel antipsychotics should be administered with great care to patients with risk factors for diabetes. Although the precise mechanism of the novel antipsychotic-associated diabetes is unclear, we hypothesize that histaminic and possibly serotonergic antagonism induces weight gain, which in turn leads to changes in glucose homeostasis. Additionally, serotonin1A antagonism might decrease pancreatic beta-cell responsiveness, resulting in inappropriately low insulin and hyperglycemia.
Adult↗
Tardive dyskinesia and serum iron indices.
BACKGROUND: This study was undertaken to evaluate whether peripheral (serum) markers of iron status are associated with severity of the choreoathetoid movements seen in tardive dyskinesia (TD). METHODS: Serum iron indices (ferritin, iron, and total iron binding capacity) and fluphenazine levels were measured in a group of 30 male DSM-III diagnosed schizophrenic patients chronically treated with fluphenazine decanoate. The severity of choreoathetoid movements was assessed with the Abnormal Involuntary Movement Scale (AIMS), and akathisia was assessed with the Barnes scale. RESULTS: A significant positive correlation was observed between AIMS scores and serum ferritin. This relationship remained significant after controlling for age and plasma fluphenazine levels. No significant correlations were observed between serum iron or total iron binding capacity and choreoathetoid movement ratings. There were no significant associations between serum iron indices and akathisia ratings. CONCLUSIONS: The data suggest that choreoathetoid movements are associated with serum ferritin levels in chronically medicated male schizophrenic patients. This relationship does not seem to be caused by an association of these variable with age or plasma fluphenazine levels. In addition, the relationship seems to be specific, since other iron indices and another extrapyramidal side effect (akathisia) do not demonstrate a similar relationship. In view of reports that antipsychotic medications change normal iron metabolism and increase iron uptake into the brain, the current results could be interpreted to suggest that serum ferritin levels may be a risk factor for TD in patients treated with "classic" antipsychotic medications.
Adult↗
Design of organic molecules with large two-photon absorption cross sections.
A strategy for the design of molecules with large two-photon absorption cross sections, delta, was developed, on the basis of the concept that symmetric charge transfer, from the ends of a conjugated system to the middle, or vice versa, upon excitation is correlated to enhanced values of delta. Synthesized bis(styryl)benzene derivatives with donor-pi-donor, donor-acceptor-donor, and acceptor-donor-acceptor structural motifs exhibit exceptionally large values of delta, up to about 400 times that of trans-stilbene. Quantum chemical calculations performed on these molecules indicate that substantial symmetric charge redistribution occurs upon excitation and provide delta values in good agreement with experimental values. The combination of large delta and high fluorescence quantum yield or triplet yield exhibited by molecules developed here offers potential for unprecedented brightness in two-photon fluorescent imaging or enhanced photosensitivity in two-photon sensitization, respectively.
Aniline Compounds↗
Infrared photorefractive polymers and their applications for imaging.
Photorefractive polymers with high diffraction efficiency in the visible and near-infrared regions of the electromagnetic spectrum have been developed. These polymers, which have a large dynamic range because of their high orientational birefringence, incorporate a dye designed to have a large dipole moment and a high linear polarizability anisotropy. Such polymers have enabled demonstrations of imaging through scattering media, using a holographic time-gating technique at a wavelength that is compatible with the transparency of biological tissues and with the emission of low-cost semiconductor laser diodes.
Birefringence↗
Distribution after repeated oral administration of different dose levels of risperidone and 9-hydroxy-risperidone in the brain and other tissues of rat.
Rats were treated with daily oral doses of 1, 4, and 6 mg/kg risperidone (RSP) and its metabolite, 9-hydroxy-risperidone (9-OH-RSP), for 15 consecutive days. Concentrations of RSP and 9-OH-RSP were measured in plasma, brain, liver, kidney, lungs and fat tissue by high-performance liquid chromatography with electrochemical detection. Non-specific distribution of RSP and 9-OH-RSP in various brain regions was also studied after administration of 6 mg/kg per day oral dose for 15 days. After RSP treatment, concentrations of 9-OH-RSP were higher than those of RSP in plasma and tissues except in brain, where both compounds were present in nearly equal concentrations. Similarly, after 9-OH-RSP treatment, levels of 9-OH-RSP were higher than levels of either RSP or 9-OH-RSP or the sum of RSP and 9-OH-RSP levels measured after treatment with RSP. There was a moderate relationship between RSP dose and tissue levels of RSP and 9-OH-RSP (all rs > or = 0.62, P < 0.01), except in fat. There was also a strong relationship between the dose and tissue levels of 9-OH-RSP (all rs > or = 0.68, P < 0.005). A significant relationship was found between plasma levels of RSP and brain levels of RSP and 9-OH-RSP (all rs > or = 0.57, P < 0.03) after treatment with RSP. After 9-OH-RSP treatment, a much stronger relationship was observed between plasma and brain 9-OH-RSP levels (rs > or = 0.90, P < 0.005). The plasma concentrations of RSP and 9-OH-RSP appear to reflect their concentrations in brain. The tissue-to-plasma ratios of RSP and 9-OH-RSP were relatively low compared to other antipsychotics. In liver, kidney and lung the tissue to plasma ratio for RSP and 9-OH-RSP after treating with RSP ranged from 0.85 to 3.4. The brain to plasma ratio for RSP and 9-OH-RSP was several-fold lower than that in peripheral tissues. After RSP administration, the mean brain to plasma level ratio for RSP was 0.22, and for 9-OH-RSP to it was 0.04. The brain to plasma ratio of 9-OH-RSP after giving 9-OH-RSP was similarly low (0.04). The low brain/plasma ratio of high potency RSP and 9-OH-RSP may in part be due to their low lipophilicity, log P = 3.04 and 2.32, respectively, resulting in limited non-specific accumulation in brain tissue.
Animals↗
Plasma concentrations of risperidone and its 9-hydroxy metabolite and their relationship to dose in schizophrenic patients: simultaneous determination by a high performance liquid chromatography with electrochemical detection.
A simple, sensitive and accurate method for the simultaneous determination of risperidone (RSP) and its 9-hydroxy metabolite (9-OH-RSP) in human plasma is described. The relationship between dose of RSP and the plasma concentration of RSP and 9-OH-RSP in a clinical situation is discussed. Both compounds were isolated from plasma by a simple one-step liquid-liquid extraction with 15% methylene chloride in pentane. High-performance liquid chromatography separations were made on a cyano column and the compounds were detected by electrochemical detector. The method had sufficient sensitivity to determine RSP and 9-OH-RSP accurately at concentrations as low as 0.25 ng/ml when 1 ml of plasma is used for the analysis. The assay determinations were accurate, precise and consistent with a coefficient of variation less than 15%. Commonly co-administered drugs and other antipsychotics did not interfere with the analysis of either RSP or 9-OH-RSP There were large variations in inter- and intra-individual values of plasma concentrations of RSP and 9-OH-RSP. The 9-OH-RSP appears to be the major circulating active moiety and its plasma concentrations were, on the average 22 fold higher than that of RSP in schizophrenic patients treated with RSP. The ratio of RSP/9-OH-RSP concentrations suggested that three of the patients may have deficiency in cytochrome P450 enzyme CYP 2D6. The plasma concentrations of RSP showed a weak relationship with the administered daily oral dose (r = 0.4684, p = 0.01, n = 215). However, there was a good relationship between the daily dose of RSP and the plasma concentration of 9-OH-RSP (r = 0.6654, p = 0.01, n = 280) or the total active moiety, sum of RSP and 9-OH-RSP concentrations (r = 0.7041, p = 0.0005, n = 280). The measurement of the total active moiety in plasma of schizophrenic patients may be useful for assessing the relationship between dose and plasma concentration and dose and clinical outcome of patients rather than measuring RSP alone.
Antipsychotic Agents↗
Informed consent: assessment of comprehension.
OBJECTIVE: The authors designed and evaluated a structured and rigorous informed consent procedure involving subjects with schizophrenia. METHOD: Informed consent forms were read and explained to 49 schizophrenic patients participating in ongoing clinical treatment research trials. The subjects answered a questionnaire relating to each research protocol. Protocol procedures were reiterated until the patients answered 100% of the questions correctly. Subjects were asked the same questions 7 days later to ascertain how much of the information they had retained. RESULTS: The patients' median score on the first trial of the informed consent questionnaire was 80% correct. To achieve 100% correct responses, 53% of the patients required a second trial of the questionnaire, and 37% of them required three or more trials. Scores improved between the first trial and the trial on day 7. Ninety-six percent of the subjects felt adequately informed, 66% reported participating in the research protocol for personal reasons, and 34% reported participating at the suggestion of others. CONCLUSIONS: These findings demonstrate that when adequate informed consent procedures are established, schizophrenic research subjects are able to understand and retain critical components of informed consent information.
Adult↗
Facilitating compliance with antipsychotic medication.
Noncompliance with medication is common among patients who have schizophrenia and is a leading cause of rehospitalization in this population. Both standard and subjective risk-factor assessments have been used to identify patients who are likely to refuse or discontinue treatment. Noncompliant patients who have schizophrenia commonly have been treated with potent D2 dopamine-receptor antagonists and therefore may have experienced extrapyramidal side effects. The newer antipsychotics (i.e., serotonin-dopamine antagonists) are efficacious in reducing the symptoms of schizophrenia without associated dysphoria and motor side effects. Clozapine and other newer antipsychotics may improve certain aspects of cognition. The improved psychiatric state and cognitive function may facilitate "involved compliance" as a result of increased insight, awareness, and judgment. These cognitive faculties allow patients to appreciate their improved state and take steps to maintain it. The periodic visits for blood monitoring mandated for clozapine therapy also facilitate the formation of a therapeutic alliance that allows the clinician to monitor compliance. Facilitating involved compliance this way among patients who have schizophrenia may reduce the cost of this disorder to society.
Antipsychotic Agents↗
Management of acute extrapyramidal effects induced by antipsychotic drugs.
The management of acute extrapyramidal effects (EPEs) induced by antipsychotic drugs is reviewed. EPEs associated with antipsychotics include acute dystonias, pseudoparkinsonism, and akathisia. Acute dystonias consist of abnormal muscle spasms and postures and usually occur three to five days after antipsychotic therapy begins or the dosage is increased. Acute dystonias should be treated with anticholinergic medications or benzodiazepines. Antipsychotic-induced pseudoparkinsonism has the same clinical appearance as idiopathic parkinsonism. Symptoms generally appear within the first three months. Pseudoparkinsonism is managed by lowering the anti-psychotic dosage or by adding an anticholinergic agent or a mantadine; switching to a low-potency agent or an atypical antipsychotic may also help. Akathisia is characterized by subjective feelings of restlessness and anxiety and objective signs of motor activity, such as inability to sit still. This EPE appears days to weeks after antipsychotic exposure begins and can be difficult to manage. If reduction of the antipsychotic dosage or a switch to a less potent antipsychotic is not practical or effective, an anticholinergic, beta-blocker, or benzodiazepine may be added. Lipophilic beta-blockers, especially propranolol and metoprolol, appear to be the most effective treatments. Anticholinergic agents are commonly given to prevent acute dystonias, especially in high-risk patients, but long-term prophylaxis is controversial. Atypical antipsychotics may have less potential to induce EPEs. Options in the management of antipsychotic-associated EPEs include using the lowest effective dosage of antipsychotic, treating the reactions with medications, and changing the antipsychotic to one with less potential for inducing EPEs.
Adrenergic beta-Antagonists↗
Large molecular third-order optical nonlinearities in polarized carotenoids.
Garito and co-workers have suggested a mechanism to dramatically increase the second hyperpolarizability, gamma, in linear pi-electron-conjugated molecules. Polarization is introduced that leads to a difference between the dipole moments of the molecule's ground state and excited state. Here a series of carotenoids was examined that had increasing intramolecular charge transfer (ICT) from the polyenic chain to the acceptor moiety in the ground state, and gamma was measured for these compounds as a function of wavelength by third-harmonic generation. The compound with the greatest ICT exhibited a 35-fold enhancement of gammamax (the gamma measured at the peak of the three-photon resonance) relative to the symmetric molecule beta-carotene, which itself has one of the largest third-order nonlinearities known. Stark spectroscopic measurements revealed the existence of a large difference dipole moment, Delta mu, between the ground and excited state. Quantum-chemical calculations underline the importance of interactions involving states with large Delta mu.
Carotenoids↗
MR evaluation of age-related increase of brain iron in young adult and older normal males.
The purposes of this study were to extend the investigation of age-related increases in brain iron to a younger age group, replicate previously published results, and further evaluate the validity of a novel noninvasive magnetic resonance (MR) method for measuring tissue iron (ferritin) levels with specificity. The method consists of measuring the dependence of tissue transverse relaxation rates (R2) on the field strength of MR instruments. Two MR instruments operating at 1.5 and 0.5 T were used to measure the field-dependent R2 increase (FDRI) in the frontal white matter, caudate, putamen, and globus pallidus. A group of 13 normal adult males (ages 21-77), with seven subjects below and six above age 35, was examined. As expected from postmortem and prior FDRI data, robust and significant age-related increases in FDRI were observed in the caudate, putamen, and globus pallidus, with the globus pallidus FDRI increasing sharply in the second decade and reaching a plateau after age 30. In addition, we replicated previous reports showing very high correlations between FDRI and published brain iron levels for the four regions examined. The data replicate and extend previous FDRI observations on brain aging and are consistent with postmortem data on age-related increases in brain iron. These results are relevant to the investigation of age-related neurodegenerative diseases in which iron may catalyze toxic free radical reactions.
Adult↗
Plasma level monitoring of olanzapine in patients with schizophrenia: determination by high-performance liquid chromatography with electrochemical detection.
A sensitive high-performance liquid chromatography method with electrochemical detection for the determination of olanzapine in human plasma is described. Olanzapine from plasma samples was isolated by a simple one-step liquid--liquid extraction with 15% methylene chloride in pentane with an extraction recovery of approximately 94% of the total olanzapine in plasma. The compound was separated on a cyano column. Under the conditions described, commonly coadministered drugs and other common antipsychotic drugs did not interfere with the analysis of olanzapine. The lower limit of determination of the assay was 0.25 ng of olanzapine per ml when 1 ml of plasma was used for the analysis. The interaassay and intraassay variance was (CV%) less than 10%. The standard curve was linear within the range of 0.25 to 50 ng/ml of olanzapine. This method has been used for the determination of plasma levels of olanzapine in patients with schizophrenia who were treated with daily oral doses of 10, 15, and 20 mg of olanzapine. The results indicate that the plasma level of olanzapine increases linearly with the administered daily oral dose (r = 0.6889, p = 0.01).
Adult↗