Neuroleptic-resistant Schizophrenia Research Articles

Interferon Status during the Treatment of Drug Resistant Patients with Paranoid Schizophrenia

A total of 73 patients with neuroleptic-resistant paranoid schizophrenia were studied. Patients were divided into two groups: a study group (37 patients) and a reference group (36 patients). Both groups of patients received standard psychopharmacotherapy. Patients of the study group also received a combination of Reamberin and Cycloferon. Before treatment, both groups of patients showed significant impairments to interferon status, characterized by decreases in serum interferon (sIFN) activity and blood α- and γ-interferon (IFN) levels. This combination of agents was found to have positive effects on both the clinical picture of the disease and on measures of interferon status, with normalization of sIFN activity and increases in blood α- and γ-IFN levels.

Decreased plasma tryptophan and tryptophan/large neutral amino acid ratio in patients with neuroleptic-resistant schizophrenia: Relationship to plasma cortisol concentration

Tryptophan is the precursor of kynurenine and kynurenic acid, an α-7 nicotinic acetylcholine receptor antagonist and a N-methyl- d-aspartate (NMDA) receptor antagonist, both of which have been implicated in schizophrenia (SCH), as well as of serotonin. Glucocorticoids can activate the tryptophan–kynurenine pathway and lower plasma tryptophan concentrations. Some previous studies have reported decreases in the plasma tryptophan concentration and the tryptophan/large neutral amino acid (LNAA) ratio, a measure reflecting the brain tryptophan concentration, in patients with SCH. However, the influence of plasma cortisol, which has been reported to be increased in patients with SCH, on plasma tryptophan levels has not been examined in prior studies. Thus, we examined plasma tryptophan concentrations, tryptophan/LNAA ratios, and their relationships with plasma cortisol concentrations in treatment-resistant SCH (TR-SCH) patients, in non-treatment-resistant SCH (NTR-SCH) patients, and in normal controls (NC). Plasma tryptophan concentrations were significantly lower in TR-SCH patients ( n = 74) than in NTR-SCH patients ( n = 85) and NC subjects ( n = 55). In addition, tryptophan/LNAA ratios were significantly lower in TR-SCH patients than in NC subjects. No difference was observed in either measure between NTR-SCH patients and NC subjects. Tryptophan/LNAA ratios and plasma tryptophan concentrations showed a significant negative correlation and a trend-level correlation, respectively, with plasma cortisol concentrations in TR-SCH patients, but not in NTR-SCH patients or in NC subjects. These results suggest the tryptophan–kynurenine pathway may be particularly relevant to TR-SCH and that this may be influenced by the activity of the hypothalamic–pituitary–adrenal axis.

Determinants of work outcome in neuroleptic-resistant schizophrenia and schizoaffective disorder: Cognitive impairment and clozapine treatment

There is considerable evidence that cognitive impairment is a better predictor of work and social function in schizophrenia than are positive and negative symptoms. Atypical antipsychotic drugs have been shown to improve cognitive function in schizophrenia patients, but it is unclear whether this improves patients' ability to gain employment. Data from a prospective longitudinal study was used to test the hypotheses that (1) clozapine treatment would improve employment outcome in treatment-resistant schizophrenia or schizoaffective disorder patients, and (2) specific cognitive functioning at baseline and after treatment would predict work status at baseline and change in work status. Employment status and cognitive assessment data were collected in 59 treatment-resistant schizophrenia or schizoaffective disorder patients. Forty-seven of 59 (79.7%) patients were unemployed at baseline. Over a 12-month period, 23 (48.9%) additional patients were able to gain paid or volunteer jobs, or attend school. As predicted, neurocognitive performance was a better predictor of employment status and ability to gain of employment than clinical symptoms. Improvement in verbal working memory was found to be a better predictor of employment outcome than other cognitive functions. Treatment that enhances cognitive function, especially verbal working memory, may lead to better employment outcomes in treatment-resistant schizophrenia or schizoaffective disorder patients.

Déficit atencionales y respuesta al tratamiento farmacológico en pacientes con esquizofrenia resistente al tratamiento: Resultados mediante análisis factorial confirmatorio

There are no experimental data that demonstrate whether patients with neuroleptic-resistant schizophrenia differ or not in their pattern of neuropsychological functioning from patients with adequate drug response.Fifty-two patients with drug-resistant psychosis (DRP) and 42 patients with schizophrenia not resistant to treatment (NDRP) were recruited following the criteria of Kane et al (1988). A sample of 45 healthy controls matched by age, sex and educational level was also recruited. The clinical evaluations used were the Positive and Negative Symptom Scale (PANSS), functional disability (WHO-DAS) and the Clinical Global Impression (CGI) scale.Through the use of confirmatory factor analysis, we obtained a latent cognitive structure of six cognitive factors: attention, processing speed, verbal memory, working memory, verbal fluency and executive functions. As expected, the control group performed better than the two patient groups (both DRP and NDRP) in all neuropsychological domains. Additionally, the DRP group scored significantly worse in attention than the NDRP group even though no differences between these two groups were found in age of disease onset, number of hospitalizations or length of hospitalization. From a clinical point of view, the DRP group showed greater severity of positive symptoms (p<0.01) and higher global deterioration (p<0.01), which did not translate into greater functional disability.The results obtained do not allow us to conclude that there is a specific neuropsychological profile in neuroleptic-resistant patients. The only differential parameter was performance in the attentional domain. Our findings better fit the hypothesis of a «clinical continuum» and differ from the categoric classification of this mental disorder.

Attention Deficits and Response to Drug Therapy in Patients With Treatment-Resistant Schizophrenia: Results Through Confirmatory Factorial Analysis

IntroductionThere are no experimental data that demonstrate whether patients with neuroleptic-resistant schizophrenia differ or not in their pattern of neuropsychological functioning from patients with adequate drug response. MethodFifty-two patients with drug-resistant psychosis (DRS) and 42 patients with schizophrenia not resistant to treatment (NDRS) were recruited following the criteria of Kane et al (1988). A sample of 45 healthy controls matched by age, sex and educational level was also recruited. The clinical evaluations used were the Positive and Negative Symptom (PANSS), functional disability (WHO-DAS) and Clinical Global Impression (CGI) scales. ResultsThrough the use of confirmatory factorial analysis, we obtained a latent cognitive structure of six cognitive factors: attention, processing speed, verbal memory, working memory, verbal fluency and executive functions. As expected, the control group performed better than the two patient groups (both DRS and NDRS) in all neuropsychological domains. Additionally, the DRS group scored significantly worse in attention than the NDRS group even though no differences between these two groups were found in age of disease onset, number of hospitalisations or length of hospitalisation. From a clinical point of view, the DRS group showed greater severity of positive symptoms (P<0.01) and higher global deterioration (P<0.01), which did not translate into greater functional disability. ConclusionsThe results obtained do not allow us to conclude that there is a specific neuropsychological profile in neuroleptic-resistant patients. The only differential parameter was performance in the attention domain. Our findings better fit the hypothesis of a “clinical continuum” and differ from the categoric classification of this mental disorder.

Sertindole

Oral sertindole (Serdolect) is an atypical antipsychotic approved in the EU for once-daily use in patients with schizophrenia who are intolerant to at least one other antipsychotic agent. Extensive data from post-marketing studies do not indicate an excess of overall mortality with sertindole. Sertindole is at least as effective as haloperidol and risperidone in the treatment of neuroleptic-responsive schizophrenia. Sertindole improves negative symptoms, and is also effective for the treatment of neuroleptic-resistant schizophrenia. Sertindole is generally well tolerated and is associated with a low rate of extrapyramidal symptoms (EPS). Thus, sertindole is a useful option in the treatment of patients with schizophrenia.

P.2.052 Electroencephalographic changes in chronic neuroleptic-resistant schizophrenia patients during clozapine treatment

P.2.052 Electroencephalographic changes in chronic neuroleptic-resistant schizophrenia patients during clozapine treatment

The effect of melperone, an atypical antipsychotic drug, on cognitive function in schizophrenia

Melperone, a butyrophenone, has been shown to possess atypical antipsychotic properties, i.e. ability to produce an antipsychotic effect in man at doses that cause minimal extrapyramidal side effects. In addition, melperone shares the following with other atypical antipsychotic drugs: (1) effectiveness for ameliorating negative symptoms; (2) no prolactin elevation; and (3) effectiveness in the treatment of some patients with neuroleptic-resistant schizophrenia. Other atypical antipsychotic drugs have been reported to improve cognitive function. This study was performed to investigate the effect of melperone on cognitive function. Nineteen patients with schizophrenia or schizoaffective disorder, including 11 neuroleptic-resistant patients, were treated with melperone for 6 weeks. A comprehensive neurocognitive test battery and psychopathological ratings (Brief Psychiatric Rating Scale, BPRS) were administered at baseline and after 6 weeks of melperone treatment. Treatment with melperone was associated with improvement in executive function, as measured by the Wisconsin Card Sorting Test (WCST)-Categories and WCST-Percent Perseveration. On the other hand, visuospatial manipulation, as measured by the Wechsler Intelligent Scale for Children-Revised (WISC-R) Maze, worsened during melperone treatment. There were no significant changes in other domains of cognition, i.e. verbal learning and memory, verbal working memory, verbal fluency and sustained attention. Scores of WCST-Categories and Perseveration at 6 weeks were predicted from the relevant cognitive test scores at baseline and the change in BPRS Total and Positive scores. These results suggest the usefulness of melperone for facilitating work and social function in patients with schizophrenia. The differences in the cognition-enhancing abilities between melperone and clozapine are discussed.

Melperone in the treatment of neuroleptic-resistant schizophrenia

Melperone is an effective antipsychotic drug that has been reported to have atypical properties, i.e. low extrapyramidal side effect liability at clinically effective doses. It also does not increase serum prolactin levels. Its effectiveness for patients with neuroleptic (treatment)-resistant schizophrenia has not been evaluated. In this study, melperone was administered, in an open trial design of 6 weeks’ duration, to 44 patients with chronic neuroleptic-resistant schizophrenia. The Global Assessment Scale (GAS), Brief Psychiatric Rating Scale (BPRS) and measures of extrapyramidal symptoms and other clinical variables were assessed at baseline and 6 weeks. Thirty-seven patients completed the 6-week trial. Melperone significantly improved overall psychiatric status as measured by GAS score for all evaluable subjects [last value carried forward (LVCF) and a completers analysis]. No significant effects on BPRS measures of psychopathology scores were found in the LVCF or completers analysis. Patients who showed ≥20% decrease in the BPRS Total score ( N=7) were more likely to have high baseline psychopathology, as measured by BPRS Total and Anxiety–Depression subscales, than those who showed ≥20% increase in the BPRS Total score ( N=8). Non-responders to melperone generally did not respond to subsequent treatment with clozapine, indicating that this group of patients was very treatment resistant. Melperone was not associated with worsening of extrapyramidal symptoms, elevation in plasma prolactin levels, or an increase in body mass index (BMI). The results suggest that a proportion of neuroleptic-resistant patients with schizophrenia respond to melperone, which requires further controlled study.

Clozapine-induced decrease in the production of reactive oxygen metabolites by monocytesin vitro may predict clinical response to clozapine in treatment-resistant schizophrenia

Reactive oxygen metabolites (ROM), produced by mononuclear phagocytes may participate in brain pathology. Clozapine (CLO) may modulate cell immunity, and it is also superior to conventional neuroleptics in conditions with a putative impact of oxidative damage by ROM, i.e. negative symptoms and neuroleptic-resistance in schizophrenia, and tardive dyskinesia. In line with a hypothesis of a possible impact of the phagocyte-produced ROM in schizophrenia, we measured the ROM production by in vitro CLO-incubated blood phagocytes from eight patients with neuroleptic-resistant schizophrenia at weeks 0, 3, and 10 of a clinical CLO trial. The ROM production by non-stimulated monocytes (MOn) decreased after incubation in vitro with CLO at weeks 0 (baseline) and 3, with a similar trend seen also at week 10 of the trial. The magnitude of this decrease at week 0 correlated positively with subsequent improvement in clinical symptomatology (R2=0·789, p=0·003 for negative symptoms at week 3 of the trial). We conclude that the sensitivity of MOn to the in vitro effect of CLO on their ROM production may be predictable for the clinical response to CLO in neuroleptic-resistant schizophrenia. Copyright © 1999 John Wiley & Sons, Ltd.

A comparison of the effect of clozapine with typical neuroleptics on cognitive function in neuroleptic-responsive schizophrenia

Clozapine has been reported to improve selected aspects of cognitive function in neuroleptic-resistant schizophrenia. In this study, we report the first direct comparison of the effect of clozapine and typical neuroleptic drugs on cognitive function in neuroleptic-responsive schizophrenia. Sixty-four patients with recent onset, neuroleptic-responsive schizophrenia or schizoaffective disorder were randomly assigned to either clozapine ( n=35) or typical neuroleptics ( n=29) and followed for 12 months. They were administered a comprehensive cognitive test battery at baseline and at 6 weeks, 6 months and 12 months after initiating drug treatment. Treatment with clozapine improved psychomotor speed and attention [Digit Symbol Substitution Test (DSST)] and verbal fluency [Category Instance Generation and Controlled Word Association Test (CWAT)] at 6 weeks. The improvement in these measures was maintained throughout the 12-month period. Treatment with typical neuroleptics produced no sustained improvement in any cognitive measure, except for a tendency to improve delayed recall memory (Verbal List Learning Test). The improvement in the DSST and CWAT was significantly greater with clozapine treatment compared to that with typical neuroleptics. These improvements were not related to improvement in psychopathology. These results suggest that clozapine is superior to typical neuroleptics in improving specific types of cognitive function in recent onset, neuroleptic-responsive schizophrenia.

Is there an association between the effects of clozapine on the production of reactive oxygen metabolites by blood monocytes and clinical outcome in neuroleptic-resistant schizophrenia?

The production of reactive oxygen metabolites (ROM) by monocytes (MO) and polymorphonuclear leukocytes (PMNL) from eight patients with neuroleptic-resistant schizophrenia was measured before and after 3 and 10 weeks of clozapine (CLO) treatment. Although ROM production did not show significant longitudinal trends during the trial, the changes in ROM production by non-stimulated (Mon) and phorbol myristate acetate (PMA)-stimulated MO (MOs) at week 3 (values at base-line minus those at week 3) correlated positively (r=0·743, p=0·035, and r=0·838, p=0·009, respectively) with the changes on the total Positive and Negative Syndrome Scale (PANSS) scores, i.e. a decrease or relatively small increase in the ROM production by MOn and MOs was associated with more favourable clinical outcome than a clear-cut increase in their ROM production. The serum concentrations of CLO at week 3 also correlated positively with the changes in ROM production by MOs at week 3 (r=0·761, p=0·047) and at week 10 (r=0·985, p<0·001). A possible causal relationship between these observations and the mechanism of action of CLO is discussed. © 1998 John Wiley & Sons, Ltd.

Is there an association between the effects of clozapine on the production of reactive oxygen metabolites by blood monocytes and clinical outcome in neuroleptic-resistant schizophrenia?

Is there an association between the effects of clozapine on the production of reactive oxygen metabolites by blood monocytes and clinical outcome in neuroleptic-resistant schizophrenia?

Olanzapine in Treatment-Refractory Schizophrenia

Clozapine is currently the treatment of choice for neuroleptic-resistant schizophrenia. Olanzapine is a new antipsychotic drug that has shown efficacy against positive and negative symptoms of schizophrenia, with minimal extrapyramidal side effects. However, the effectiveness of olanzapine has not yet been reported among treatment-refractory schizophrenic patients. A total of 25 schizophrenic patients (DSM-IV criteria) with documented lack of response to two conventional antipsychotic drugs entered this 6-week prospective, open-label treatment trial with olanzapine 15 to 25 mg/day. An optional extension up to 6 months was provided. As a group, the olanzapine-treated patients showed statistically significant improvement (p < .05) in both positive and negative symptoms by the end of 6 weeks of therapy. Overall, 9 of the patients (36%) met the a priori criteria for treatment-response (> or = 35% decrease in Brief Psychiatric Rating Scale [BPRS] total score, plus posttreatment Clinical Global Impression-Severity < or = 3 or BPRS total < 18). Only one patient discontinued treatment because of an adverse event during the study. Despite the relatively high dosages of olanzapine used, there were no reports of parkinsonism, akathisia, or dystonia, and no patients required anticholinergic medication. This open study suggests that olanzapine may be effective and well tolerated for a substantial number of neuroleptic-resistant schizophrenic patients. Further blinded, controlled trials are needed to confirm our results.

An open trial of clozapine in neuroleptic-resistant childhood-onset schizophrenia.

Studies performed with schizophrenic adults who were resistant to classical neuroleptics showed improvement in 30% of the patients when treated with clozapine. Very early onset schizophrenic patients benefit only partially from conventional antipsychotics and are at increased risk of developing extrapyramidal symptoms; clozapine may offer an alternative treatment for these patients. Eleven neuroleptic-resistant children (< 13 years) with schizophrenia were treated with clozapine. Improvement was monitored during the first 16 weeks using the Brief Psychiatric Rating Scale, Positive and Negative Syndrome Scale and Clinical Global Impression. The mean clozapine dosage was 227.3 (s.d. 34.4 mg/day at the end of the 16 weeks. There was an overall statistically significant reduction in all parameters, especially positive symptoms, implying a favourable outcome. Most of the improvement occurred during the first 6 to 8 weeks. The major side-effects were somnolence and drooling (no agranulocytosis). Clozapine may be a promising drug for the treatment of resistant childhood-onset schizophrenia.

Pre-morbid asociality in neuroleptic-resistant and neuroleptic-responsive schizophrenia.

The purpose of this study was to evaluate whether childhood and adolescent pre-morbid asociality differed in neuroleptic-responsive and neuroleptic-resistant schizophrenia. Pre-morbid asociality was assessed with the Pre-morbid Asociality Adjustment Scale in 411 patients meeting DSM-III-R criteria for chronic schizophrenia or schizoaffective disorder categorized as being either neuroleptic-responsive or neuroleptic-resistant. Patterns of childhood and adolescent asociality were found to be different in neuroleptic-resistant and neuroleptic-responsive patients. Pre-morbid asociality during the pre-adult years was not consistently worse in patients with poor response to neuroleptic treatment. Greater impairment in late adolescent psychosexual functioning was predictive of poor outcome with regard to neuroleptic treatment.

Neuropsychologic deficits in schizophrenia: relation to social function and effect of antipsychotic drug treatment.

Cognitive impairment is present in the majority of schizophrenic patients, even at the onset of psychosis. It is a relatively stable characteristic in most patients, usually with little progression over the course of illness, but sometimes progresses to severe dementia. The results of studies of the effects of typical neuroleptic drugs on cognitive functioning in schizophrenia are conflicting. Clozapine, which has superior antipsychotic effects compared to typical neuroleptic drugs, has been reported to improve executive function, verbal fluency, attention, and recall memory in two of three studies. Cognitive measures predict work function and overall outcome on clozapine as assessed by the Global Assessment Scale and Quality-of-Life Scale in neuroleptic--resistant schizophrenia. Improvement in cognitive function by clozapine may be a major reason for expanding its currently limited utilization.

The use of clozapine plasma levels in optimising therapy

Clozapine is well known to be an effective treatment for neuroleptic-resistant schizophrenia. However, its use is complicated by a variable and delayed response and by a range of troublesome adverse effects. Current practice is usually to increase the dose initially to around 450 mg/day and then by small increments to a maximum of 900 mg/day according to response and tolerability. While this method is often successful, it has been suggested that a better way of optimising the dose of clozapine might be to monitor plasma concentrations of the drug.

Effectiveness of clozapine in hospitalised people with chronic neuroleptic-resistant schizophrenia.

Clozapine's effectiveness in reducing symptoms and facilitating discharge among patients with chronic schizophrenia who were resistant to neuroleptics was studied. All 169 such patients in a public psychiatric hospital were given clozapine. BPRS ratings (0-5 scale) were completed before treatment and 21 months later. Patients were followed for about 2.5 years. Clozapine was discontinued in 37.8% of cases due to non-compliance, non-response, or side-effects. At follow-up 41% of clozapine recipients and 25.9% of the drop-outs were discharged and remained so, and 33% of recipients and 24.1% of drop-outs were being prepared for discharge. Longer treatment was associated with more improvement. Decline in average BPRS total scores of recipients was significantly more than drop-outs (32.7, s.d. 16.8 v. 12.1, s.d. 14.1, d.f. = 155, t = 7.5, P = 0.000). Clozapine appears to be effective for treating some chronic neuroleptic nonresponding schizophrenic patients.

Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit assessment.

Suicide has been reported to occur in 9%-13% of schizophrenic patients. It has been suggested that neuroleptic-resistant or neuroleptic-intolerant schizophrenic patients are at higher risk for suicide than neuroleptic-responsive patients. Clozapine is the treatment of choice for neuroleptic-resistant patients, but its use has been greatly limited because of its ability to cause potentially fatal agranulocytosis. The purpose of this study was to compare the suicidality of neuroleptic-resistant and neuroleptic-responsive patients and to determine if clozapine treatment decreased suicidality in the former group. Prior episodes of suicidality were assessed in a total of 237 neuroleptic-responsive and 184 neuroleptic-resistant patients with schizophrenia or schizoaffective disorder. Eighty-eight of the neuroleptic-resistant patients were treated with clozapine and prospectively evaluated for suicidality for periods of 6 months to 7 years. There was no significant difference in prior suicidal episodes between neuroleptic-responsive and neuroleptic-resistant patients. Clozapine treatment of the neuroleptic-resistant patients during the follow-up period resulted in markedly less suicidality. The number of suicide attempts with a high-probability of success decreased from five to zero. This decrease in suicidality was associated with improvement in depression and hopelessness. These results suggest a basis for reevaluation of the risk-benefit assessment of clozapine, i.e., that the overall morbidity and mortality of patients with neuroleptic-resistant schizophrenia are less with clozapine treatment than with typical neuroleptic drugs because of less suicidality. This conclusion also has implications for increasing the use of clozapine with neuroleptic-responsive patients.