Treatment-refractory Schizophrenic Patients Research Articles

Efficacy of Asenapine in Schizophrenia Resistant to Clozapine Combined with Electroconvulsive Therapy: A Case Report.

Schizophrenic patients resistant to antipsychotics are diagnosed as having treatment-refractory schizophrenia, and they are treated with clozapine. However, clozapine is sometimes combined with electroconvulsive therapy (ECT) if clozapine monotherapy fails. In this report, a severe treatment-refractory schizophrenic patient who did not respond to clozapine even with ECT, but who recovered with asenapine monotherapy, is presented. Asenapine, considered a serotonin spectrum dopamine modulator, is a new atypical antipsychotic with unique pharmacological features that is used not only for schizophrenia, but also for bipolar disorder. The unique features of asenapine may be effective for some treatment-refractory schizophrenic patients.

P.3.a.019 Efficacy and safety of ziprasidone and clozapine in treatment refractory schizophrenic patients:results of a randomized, double-blind, 18-week trial

Composition of Indian Russell's viper (Daboia russelii russelii) venom, a medically important snake and member of “Big Four” snakes of India was done by gel filtration chromatography followed by tandem mass spectrometry. The MS/MS analyses of tryptic digested gel filtration peaks divulged the presence of 63 different proteins belonging to 12 families. Phospholipase A2 (PLA2), serine proteases, metalloproteases, cysteine-rich secretory proteins, l-amino acid oxidase, C-type lectin-like proteins, kunitz-type serine protease inhibitor, disintegrin, nucleotidase, phosphodiesterase, vascular endothelial growth factor and vascular nerve growth factor families were identified. PLA2 enzymes with isoforms of N-, S- and H-type based on their first N-terminal amino acid residue were observed. The venom is also found to be rich in RVV-X, RVV-V and thrombin-like enzymes. Homologues of disintegrins with RGD and RTS motifs were also observed. The high percentage of PLA2 and proteases in the venom proteome could be responsible for the observed coagulopathy, haemorrhage and edema which can be correlated with the clinical manifestations of Russell's viper envenomation. This is the first proteomic analysis of Indian D. russelii venom which might assist in understanding the pathophysiological effects of viper envenomation. Such study will also be important for developing more effective antivenom for viper bite management.

Association Analysis of the Genetic Variants of the N-Methyl D-Aspartate Receptor Subunit 2b (NR2b) and Treatment-Refractory Schizophrenia in the Chinese

Several pieces of evidence showed that N-methyl D-aspartate (NMDA)-receptor-mediated decreases in function may be a causative factor for schizophrenia. The NMDA receptors are composed of a common glutamate receptor, an ionotropic NMDA 1 (GRIN1) subunit and one of four GRIN2 subunits (GRIN2A–GRIN2D), combined in an undetermined ratio to make up the receptor complex. In this study, we tested the hypothesis of whether the GRIN2B 366C/G and 2664C/T genetic polymorphisms are related to Chinese treatment-refractory schizophrenic patients. 193 treatment-refractory schizophrenic patients and 176 normal subjects were recruited for this study. The results demonstrated that the genotype distribution was similar between schizophrenic patients and control subjects in 366C/G (p = 0.88) and 2664C/T (p = 0.336), but we found a higher mean clozapine dosage in 2664C/C genotype patients. These results show that GRIN2B genetic variations were not a major risk factor for treatment-refractory schizophrenic patients, but may influence the effect of clozapine during treatment.

Benzodiazepines in Schizophrenia: Prefrontal Cortex Atrophy Predicts Clinical Response to Alprazolam Augmentation

Summary: Benzodiazepines augment clinical responses to neuroleptics in some, but not all, treatment-refractory schizophrenic patients; however the biological predictors of response have remained unclear. Since patients with prefrontal cortex (PFC) volume loss demonstrate exaggerated subcortical dopamine responses to stress, and since benzodiazepines curtail stress-induced subcortical dopamine release in PFC-lesioned animals, we reasoned that patients with PFC volume loss might show preferential clinical responses to benzodiazepine augmentation. Five patients, who were participating in a larger four-week double-blind study of alprazolam augmentation of neuroleptics in treatment-resistant or partially treatment-resistant schizophrenia, had brain MRI scans prior to entry into the study. MRI scans were morphometrically analyzed to yield estimates of PFC grey and white matter volumes and PFC cerebrospinal fluid (CSF) volume, and these were correlated with clinical responses to alprazolam augmentation. PFC grey matter volume (adjusted for overall cranial capacity) was significantly correlated (r = 0.96, p < 0.01), in the predicted direction, with alprazolam-associated changes in total Brief Psychiatric Rating Scale ratings. PFC volume loss may represent a biological marker for benzodiazepine responsivity in schizophrenia, although the present findings are considered preliminary because of the small sample size. Mechanistic considerations and suggestions for future research are discussed.

Short-term clinical efficacy and safety of clozapine in schizophrenia: A study with plasma levels

Clozapine has proven to be more effective than typical antipsychotics in treatment-refractory schizophrenic patients, and some evidence suggests that it may be particularly useful in treating the negative symptoms of schizophrenia. However, it is unclear whether this observation reflects improvement in “primary” or “secondary” negative symptoms. We hypothesized that a portion of clozapine's effect on negative symptoms would be related to an improvement in positive (psychotic and disorganization) symptoms, a decrease in extrapyramidal side effects (EPSE), and/or a decrease in depressive symptoms. The remainder of its effect would be related to a direct effect on the neural circuits or pathologic processes responsible for the negative symptoms. Twenty-nine treatment-refractory schizophrenics treated with clozapine for 6 weeks were studied. The core negative symptoms measured by the Scale for the Assessment of Negative Symptoms ([SANS] affective flattening, anhedonia/asociality, avolition/apathy, and alogia) all improved with clozapine treatment. Overall, there was a 31% improvement in negative symptoms, a 32% improvement in psychotic symptoms, and a 35% improvement in disorganization. The improvement in negative symptoms was correlated with improvement in disorganization, but not with improvement in psychotic symptoms, depression, or drug-induced EPSE. Although there was a correlation between improvement in negative symptoms and improvement in disorganization, there was a suggestion that the two are changing in parallel, but are independent of each other. It appears that at least a portion of clozapine's effect on core negative symptoms is mediated through a direct effect on the underlying pathophysiology of schizophrenia associated with negative symptoms.

Another use of silica gel and aqueous eluent for HPLC analysis of clozapine and desmethylclozapine.

A procedure that involves a high-performance liquid chromatographic system with silica-bonded columns and reversed-phase eluents was fitted from a previously described method to measure clozapine and desmethylclozapine plasma levels. Clozapine and its demethylated metabolite were extracted from alkalinized serum by a liquid-liquid extraction, separated in 10 min, then quantitated at 254 nm at a minimum concentration of 20 ng/mL. The standard curves were linear over the range of 50-3000 ng/mL (r > 0.99) both for clozapine and desmethylclozapine and the assay had good sensitivity and recovery. Intra- and interday coefficients of variation for 200 and 800 ng/mL controls were less than 11.5% for clozapine and desmethylclozapine. This simple and efficient assay was used to monitor clozapine and desmethylclozapine levels from some treatment-refractory schizophrenic patients.

Auditory P50 in Schizophrenics on Clozapine: Improved Gating Parallels Clinical Improvement and Changes in Plasma 3-Methoxy-4-Hydroxyphenylglycol

Schizophrenic patients have decreased inhibition of the P50 auditory evoked potential response to the second of two paired click stimuli delivered 500 ms apart. This deficit in inhibitory gating does not change during treatment with typical neuroleptics. We recently reported that neuroleptic-resistant schizophrenics had enhanced P50 gating after 1 month of clozapine treatment, if they responded with decreased clinical symptoms. This study reports the outcome of more prolonged treatment. Ten treatment-refractory schizophrenic patients were studied at baseline, after 1 month on clozapine, and again after 15 ± 6.1 (SD) months of clozapine treatment. Eight subjects reached a clinically stable improved state, at which time they had significantly improved P50 auditory gating. One patient had a return of impaired gating after stopping clozapine, as did another during a clinical relapse. Decreasing plasma 3-methoxy-4-hydroxyphenylglycol levels with clozapine treatment were correlated with improved P50 gating and improved Brief Bsychiatric Rating Scale-positive scores. This study provides further evidence that improved P50 gating in schizophrenic patients treated with clozapine coincides with clinical improvement and that this improvement can be sustained for at least 1 year.

A one-year study with determination of levels of clozapine in plasma of treatment-refractory schizophrenic patients

A one-year study with determination of levels of clozapine in plasma of treatment-refractory schizophrenic patients

Olanzapine response in treatment-refractory schizophrenic patients with a history of substance abuse

As many as half of all schizophrenic patients have abused alcohol or illicit drugs. This study determines the extent of substance abuse in a treatment-resistant population and assesses the response of this population to olanzapine treatment. Sixty patients with a DSM-III-R diagnosis of schizophrenia were included in an open 7-week trial of up to 25 mg/day of olanzapine. A history of substance abuse as present in 23 (38%) of the patients. At baseline evaluation, patients with a history of substance abuse had lower CGI scores and less negative symptomatology while having a higher rate of tardive dyskinesia. The overall group improved significantly over time. There were no differences in response between the substance-abusing (SA) and non-substance-abusing (NSA) patients as measured by the total BPRS, GGI and SANS ratings. The NSA group had significantly greater improvement in negative symptoms as measured by the BPRS negative symptom factor. Sixty-nine per cent (16/23) of the SA group and 60% (22/37) of the NSA were considered olanzapine responders by a priori criteria ( p = NS). Extrapyramidal symptoms declined significantly in the overall group, but did not significantly differ between the SA and NSA groups. Treatment-refractory patients with prior substance abuse had a comparable outcome on olanzapine therapy to those with no history of abuse, as well as no increase in adverse effects. This suggests that olanzapine may be of benefit to SA patients who have a greater tendency for antipsychotic side effects and tardive dyskinesia.

Mediating effects of gender differences at 3 year follow-up in a cohort of first onset psychoses

Clozapine has proven to be more effective than typical antipsychotics in treatment-refractory schizophrenic patients, and some evidence suggests that it may be particularly useful in treating the negative symptoms of schizophrenia. However, it is unclear whether this observation reflects improvement in “primary” or “secondary” negative symptoms. We hypothesized that a portion of clozapine's effect on negative symptoms would be related to an improvement in positive (psychotic and disorganization) symptoms, a decrease in extrapyramidal side effects (EPSE), and/or a decrease in depressive symptoms. The remainder of its effect would be related to a direct effect on the neural circuits or pathologic processes responsible for the negative symptoms. Twenty-nine treatment-refractory schizophrenics treated with clozapine for 6 weeks were studied. The core negative symptoms measured by the Scale for the Assessment of Negative Symptoms ([SANS] affective flattening, anhedonia/asociality, avolition/apathy, and alogia) all improved with clozapine treatment. Overall, there was a 31% improvement in negative symptoms, a 32% improvement in psychotic symptoms, and a 35% improvement in disorganization. The improvement in negative symptoms was correlated with improvement in disorganization, but not with improvement in psychotic symptoms, depression, or drug-induced EPSE. Although there was a correlation between improvement in negative symptoms and improvement in disorganization, there was a suggestion that the two are changing in parallel, but are independent of each other. It appears that at least a portion of clozapine's effect on core negative symptoms is mediated through a direct effect on the underlying pathophysiology of schizophrenia associated with negative symptoms.

Pharmacoeconomic Assessment of Olanzapine in the Treatment of Refractory Schizophrenia Based on a Pilot Clinical Study

The objective of this study was to assess the pharmacoeconomic impact of olanzapine in the treatment of schizophrenic patients resistant to conventional antipsychotic drugs. The study was an open-label, multicentre, 'mirror-image', pilot study. Resource utilisation during the 6 months prior to starting olanzapine treatment was retrospectively collected for all patients (period A) at the beginning of the study. Use of direct medical resources was collected after 6 months of olanzapine treatment initiation (period B). The study was conducted in the psychiatric research units of general hospitals, and included 25 treatment-refractory schizophrenic patients. Olanzapine therapy was initiated at 15 mg/day on a single daily dose from day 1. The dosage could be adjusted at any time within the range of 10 to 25 mg/day, targeting the optimum balance between response and adverse effects. Patients were evaluated using the following efficacy rating scales: PANSS in its Spanish validated version, BPRS, CGI severity and improvement scales and Patient Global Impression of Improvement. Medical resource use was collected at the beginning of the study for the 6 months prior to treatment, and at the end of the study for the 6 months of olanzapine treatment. The response rate according to the previously defined response criteria was 36% (9 of 25) at 6 weeks and 48% (12 of 25) at 6 months. Despite the higher costs (given in pesetas; Pta) of medication in period B compared with period A, total direct medical costs were higher in period A (Pta884 098) compared with period B (Pta850 974), although the difference did not reach statistical significance. The difference in acute psychiatric hospitalisation days was the main contributor to the difference in total hospitalisation costs (31 +/- 37 in period A compared with 21 +/- 30 in period B) [p = NS]. The results suggest that olanzapine may be effective in a significant number of neuroleptic-resistant schizophrenic patients, and that the efficacy obtained does not necessarily imply an increase in the cost of the treatment.

Fronto-striato-thalamic perfusion and clozapine response in treatment-refractory schizophrenic patients. A 99mTc-HMPAO study

Several studies with functional and structural brain-imaging techniques support the hypothesis that responders and non-responders to clozapine could show a different pattern of cerebral dysfunction. Thirty-nine neuroleptic-refractory schizophrenic patients were studied with 99Tc-labelled hexamethyl-propylene-arninoxime (HMPAO) and SPECT, while on classical neuroleptics and after 6 months of treatment with clozapine. The perfusion differences between responders and non-responders to clozapine were studied in the regions included within the dorsolateral and orbitofrontal fronto-striato-thalamic circuits, as well as the predictive value of these parameters. These values were compared to those of a normal database, and between both treatments within the two groups. On-neuroleptic perfusion in non-responders was lower in the thalamus, basal ganglia and dorsolateral prefrontal cortex. Thalamus and right prefrontal perfusion regions were selected as response predictors by a discriminant analysis. Thalamic and left basal ganglia activities while on neuroleptics were lower only in non-responders with respect to the normal subjects. Perfusion changes were only observed in the responder group in thalamus and basal ganglia. Study of regional perfusion may contribute to the prediction of clozapine response.

Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients.

The purpose of this study was to determine if plasma clozapine levels were associated with treatment response. To examine this question, neuroleptic nonresponsive patients with schizophrenia or schizoaffective disorder were given clozapine, which was titrated to 500 mg/day by day 14 of treatment, and the dose was held fixed at least through day 21. Subsequently, clozapine doses were adjusted as clinically indicated, up to a maximum of 900 mg/day. Plasma clozapine levels were obtained at weeks 3 and 6, and standard clinical ratings (Brief Psychiatric Rating Scale [BPRS] and Clinical Global Impression) were done at baseline and at weeks 3 and 6. Data from 45 subjects were analyzed. There were no correlations between plasma clozapine levels and change in BPRS scores at treatment weeks 3 and 6. However, when the subjects were classified as responders or nonresponders, therapeutic response was associated with clozapine blood levels above 350 ng/ml. This study suggest that clozapine blood levels are correlated with clinical response.

Optimal drug and behavior therapy for treatment-refractory schizophrenic patients

Thirteen treatment-refractory schizophrenic patients (10 men and three women) who were receiving more than 50 mg/day of haloperidol and who had been hospitalized for more than 1 year successfully tolerated a mean dose reduction of 63% with consequent improvement in psychopathology and side effects. The addition of intensive behavior therapy to the optimal dose of haloperidol yielded further improvements in functional behavior, such as self-care and social interaction.

Clozapine's effect on negative symptoms in treatment-refractory schizophrenics

Clozapine has proven to be more effective than typical antipsychotics in treatment-refractory schizophrenic patients, and some evidence suggests that it may be particularly useful in treating the negative symptoms of schizophrenia. However, it is unclear whether this observation reflects improvement in “primary” or “secondary” negative symptoms. We hypothesized that a portion of clozapine's effect on negative symptoms would be related to an improvement in positive (psychotic and disorganization) symptoms, a decrease in extrapyramidal side effects (EPSE), and/or a decrease in depressive symptoms. The remainder of its effect would be related to a direct effect on the neural circuits or pathologic processes responsible for the negative symptoms. Twenty-nine treatment-refractory schizophrenics treated with clozapine for 6 weeks were studied. The core negative symptoms measured by the Scale for the Assessment of Negative Symptoms ([SANS] affective flattening, anhedonia/asociality, avolition/apathy, and alogia) all improved with clozapine treatment. Overall, there was a 31% improvement in negative symptoms, a 32% improvement in psychotic symptoms, and a 35% improvement in disorganization. The improvement in negative symptoms was correlated with improvement in disorganization, but not with improvement in psychotic symptoms, depression, or drug-induced EPSE. Although there was a correlation between improvement in negative symptoms and improvement in disorganization, there was a suggestion that the two are changing in parallel, but are independent of each other. It appears that at least a portion of clozapine's effect on core negative symptoms is mediated through a direct effect on the underlying pathophysiology of schizophrenia associated with negative symptoms.

Improvement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine

Cognitive functions and psychopathology were assessed in 36 treatment-refractory schizophrenic patients before initiation of clozapine, and at 6 weeks and 6 months, thereafter. Before treatment, cognitive impairment was found in each measure of memory, attention, and executive function as compared with 26 normal controls. After both 6 weeks and 6 months of treatment, significant improvement occurred in the Controlled Oral Word Association Test, a measure of retrieval from reference memory. Improvement was also noted as 6 months in the Category Instance Generation Test, another measure of retrieval from reference memory, and in some, but not all, tests of executive function, attention, and recall memory. Clozapine treatment also resulted in significant improvement in Brief Psychiatric Rating Scale (BPRS) Total and Positive symptom scores at both 6-week and 6-month assessment points. There was some evidence for a relationship between improvement in psychopathology and cognitive function. The improvement in cognitive function during clozapine treatment could have consequences for capacity to work and social function.

Prediction of response to haloperidol dose reduction by Span of Apprehension measures for treatment-refractory schizophrenic patients.

Thirteen treatment-refractory schizophrenic patients participated in a haloperidol reduction study. Two of the subjects were unable to tolerate medication reduction. These subjects were comparable to the other patients in terms of initial clinical variables but were outliers on baseline accuracy and reaction time measures from the Span of Apprehension. The results suggest that aspects of basic visual processing and motor response speed may identify patients who require higher neuroleptic doses.

Clozapine's effect on negative symptoms in treatment-refractory schizophrenics

Abstract Clozapine has proven to be more effective than typical antipsychotics in treatment-refractory schizophrenic patients, and some evidence suggests that it may be particularly useful in treating the negative symptoms of schizophrenia. However, it is unclear whether this observation reflects improvement in “primary” or “secondary” negative symptoms. We hypothesized that a portion of clozapine's effect on negative symptoms would be related to an improvement in positive (psychotic and disorganization) symptoms, a decrease in extrapyramidal side effects (EPSE), and/or a decrease in depressive symptoms. The remainder of its effect would be related to a direct effect on the neural circuits or pathologic processes responsible for the negative symptoms. Twenty-nine treatment-refractory schizophrenics treated with clozapine for 6 weeks were studied. The core negative symptoms measured by the Scale for the Assessment of Negative Symptoms ([SANS] affective flattening, anhedonia/asociality, avolition/apathy, and alogia) all improved with clozapine treatment. Overall, there was a 31% improvement in negative symptoms, a 32% improvement in psychotic symptoms, and a 35% improvement in disorganization. The improvement in negative symptoms was correlated with improvement in disorganization, but not with improvement in psychotic symptoms, depression, or drug-induced EPSE. Although there was a correlation between improvement in negative symptoms and improvement in disorganization, there was a suggestion that the two are changing in parallel, but are independent of each other. It appears that at least a portion of clozapine's effect on core negative symptoms is mediated through a direct effect on the underlying pathophysiology of schizophrenia associated with negative symptoms.

Neuropharmacologic Basis for Clozapine's Unique Profile

<h3>To the Editor.—</h3> In comparison with standard neuroleptics, clozapine is more effective in decreasing positive and negative symptoms in treatmentrefractory schizophrenic patients, and causes significantly fewer parkinsonian side effects and less tardive dyskinesia.¹In recent months, three distinct neurochemical hypotheses to explain clozapine's unique profile have been discussed in theArchives.^2-4Farde et al²propose that clozapine's lower D₂dopamine receptor binding may explain the infrequent extrapyramidal syndromes (EPSs), and its higher D₁dopamine receptor binding may explain its superior efficacy. Meltzer and Stockmeier³suggest that clozapine's significant serotonin (5-HT₂) antagonist activity may explain both its unique properties. Pickar et al⁴propose that clozapine's potent α₂-noradrenergic antagonist activity (in addition to its anti-5-HT₂activity) may be relevant to its unique profile. Clozapine's greater affinity for the D₄dopamine receptor site⁵has been implicated as well. Recent data

Treatment with clozapine and its effect on plasma homovanillic acid and norepinephrine concentrations in schizophrenia

Measurement of plasma concentrations of the dopamine metabolite, homovanillic acid (pHVA), is an indirect tool to assess changes in dopamine turnover. Levels of pHVA have been reported to decrease during treatment with conventional antidopaminergic, neuroleptics, with the decrement correlating with symptomatic improvement in schizophrenic symptoms. Clozapine, an atypical neuroleptic, is the only drug proved to be effective in treatment-refractory patients. However, the mechanism mediating this unique efficacy has not been fully elucidated. This study examined the effect of clozapine on pHVA concentrations in schizophrenic patients. Since clozapine potently binds to α 2-adrenergic receptors, plasma norepinephrine (pNE) concentrations were also measured. Twenty-eight treatment-refractory schizophrenic patients (24 men, 4 women) were treated with clozapine (up to 600 mg/day) for 5 weeks, after a minimum 1-week drug-free period. Symptomatology and pHVA and pNE concentrations were measured at the last drug-free day and weekly for 5 weeks. Fourteen patients responded to clozapine treatment, while an equal number did not. Mean pHVA concentrations did not significantly change during treatment with clozapine. Although clozapine tended to lower pHVA concentrations in treatment responders, the effect was small and not significant. Clozapine treatment significantly raised pNE concentrations, but this did not differentiate responders from nonresponders to clozapine. These findings suggest that clozapine's effect on DA turnover is small and that clozapine may be effective in treatment-refractory schizophrenia by mechanisms other than, or in addition to, dopamine receptor blockade. However, since about one-third of NE is metabolized into HVA, the clozapine-induced increase in pNE may have overshadowed a possible lowering effect of clozapine on pHVA.