The effectiveness of olanzapine in treatment-refractory schizophrenia when patients are nonresponsive to or unable to tolerate clozapine.

OBJECTIVE: This multicenter, open-label study was designed to assess the efficacy and tolerability of olanzapine in patients with chronic schizophrenia who are resistant to therapy with classic neuroleptic agents and are either not responsive to or unable to tolerate clozapine. METHODS: Patients received olanzapine orally once daily for 18 weeks at doses ranging from 5 to 25 mg. The primary efficacy measure was change in the total score on the Positive and Negative Syndrome Scale (PANSS) from baseline to end point. Secondary efficacy measures were the total score on the Brief Psychiatric Rating Scale (BPRS); the PANSS positive, negative, general psychopathology, and mood subscores; and the Clinical Global Impression improvement score. Also recorded were spontaneously reported adverse events; extrapyramidal symptoms (assessed by the Abnormal Involuntary Movement Scale, Simpson-Angus Scale, and Barnes Akathisia Scale); vital signs; and clinical laboratory test results. RESULTS: Forty-eight patients were treated with olanzapine; of these, 45 were assessable over the full 18-week study period. Total scores on the PANSS and BPRS were reduced from baseline by an average of 17.7 (14.2%) and 9.8 points (20.2%), respectively. Eighteen patients (40.0%) experienced a treatment response, defined as a reduction in PANSS total score of > or = 20%. A total of 25 patients (55.6%) achieved a similar reduction in BPRS total score. Significant reductions were seen in both the positive and negative symptom scores on the PANSS (P < 0.001). Olanzapine was well tolerated, with minimal treatment-emergent adverse events or clinically relevant changes in vital signs or clinical laboratory test results. No clinically significant blood dyscrasias were observed in olanzapine-treated patients, including those who had discontinued clozapine because of treatment-associated leukopenia or neutropenia. CONCLUSION: The results of this study suggest that olanzapine may be of benefit in patients who are refractory to or unable to tolerate clozapine.

Schizophrenia, chronic hospitalization and the 5-HT2C receptor gene.

Frequency of a polymorphism in the coding region of the 5-hydroxytryptamine2C (5-HT2C) receptor gene (HTR2C Xq24) was not significantly different in 122 unrelated Israeli schizophrenia patients compared with 180 control subjects matched for gender and ethnicity. However, proportion of time spent in hospital since the first admission was significantly greater in patients hemi- of homozygous for the 5-HT2Cser allele than in patients carrying other genotypes (p = 0.006). The 5-HT2Cser genotype conferred a 3.3-fold increased risk for lifetime hospitalization exceeding 10 years. Genetically determined variation in the 5-HT2C receptor may influence the clinical course and phenotypic expression of schizophrenia.

Cerebral bioimpedance pattern as a function of psychiatric signs and symptoms.

A new way of inferring and presenting psychiatric signs and symptoms as a correlate of cerebral bioimpedance pattern is proposed. The basal principles of bioimpedance have been applied through promising techniques already developed and used. The biophysical electrical shunt model meets the fundamental criteria for static and dynamic regional extracellular fluid volume alterations and ionic density, velocity and compositional changes in the same spatial and temporal units. Bioimpedance technology applied by a suitable method can potentially utilize bioimpedance essentials to display high sensitivity and specificity resolution revealing regional extracellular iono-liquid disturbances in the brain. We suggest that the theoretical model for utilizing bioimpedance as a function for estimating psychiatric signs and symptoms may open new horizons in the neuroscience of biotyping mental disorders.

Dopamine D4 receptor gene polymorphisms: relation to ethnicity, no association with schizophrenia and response to clozapine in Israeli subjects.

The dopamine D4 receptor (DRD4) is a candidate gene in the search for a genetic etiology of schizophrenia and for pharmacogenetic factors in the response to antipsychotic treatment. Previous work has not found linkage or association of a polymorphism in exon 3 of this gene with diagnosis of schizophrenia or response to clozapine. In this study we examined this association in Israeli schizophrenic subjects treated with clozapine, compared to ethnically matched controls. Another polymorphism of this gene, in exon 1, was also studied. Both polymorphisms showed no association with schizophrenia or treatment response. A significant difference in allelic distribution of DRD/ exon 3 polymorphism was found between Ashkenazi and non-Ashkenazi control subjects.

Evidence for an association between the dopamine D3 receptor gene DRD3 and schizophrenia.

Association of the dopamine D3 receptor gene (DRD3) and schizophrenia was examined in unrelated Israeli and Italian schizophrenic patients and ethnically matched normal control subjects. In the combined sample, there was a significant excess of DRD3 allele 2 among the schizophrenic patients (chi2 = 4.70, d.f. 1, p = 0.03). Comparison of genotype frequencies revealed an excess of the 2-2 genotype in the combined schizophrenic sample (chi2 = 8.30, d.f. 1, p = 0.01) and in the non-Ashkenazi Israeli schizophrenics alone (chi2 = 5.70, d.f. 2, p = 0.05). DRD3 2-2 genotype conferred a significantly increased risk of schizophrenia (chi2 = 8.21, d.f. 1, p = 0.004; OR = 2.87, CI 95% = 1.36-5.76) in the combined sample and in the non-Ashkenazi Israeli schizophrenics (chi2 = 7.22, d.f. 1, p = 0.04; OR = 7.22, CI 95% = 1.04-24.83). In the combined and Italian samples, allele 2 was associated with early age of onset as was the 2-2 genotype in the combined sample and non-Ashkenazi group. The 2-2 genotype was associated with poor response to neuroleptics, particularly in the non-Ashkenazi, Israeli schizophrenics. The possibility that DRD3 or a locus in linkage disequilibrium with it may play a role in the transmission of schizophrenia, is considered in relation to previous positive and negative reports.

Length of hospitalization and disposition of elderly vs younger delirium patients in psychiatric hospitals.

Although it is commonly accepted that delirium patients require the full facilities of general hospitals, practical experience has shown that delirium patients of all ages continue to be admitted to psychiatric institutions. The present study was designed to detect any differences in the length of hospitalization and disposition (discharge back to the community, transfer to a general hospital, death during the index hospitalization, transfer to another psychiatric hospital) between elderly (> 65 years) and younger delirium patients admitted to psychiatric hospitalization. Our hypothesis was that the prognosis (represented in this study by the above-mentioned measures) of elderly delirium patients in a psychiatric hospital would be poorer compared with younger delirium patients. We studied psychiatric case register data of 805 patients with delirium admitted to psychiatric hospitals during the period 1984-1993. Our sample was divided into four ICD-9-CM categories: delirium in dementia, delirium tremens (DT), drug-induced delirium, and acute and subacute delirium. No significant differences in the length of hospitalization were found between < 65- and > 65-year-old patients in the categories studied. There were disposal differences between the two age groups in the acute and subacute delirium parameters, but findings in the other categories were similar. Practical implementation of the results in terms of appropriate place of management of delirium patients in a psychiatric hospital is discussed.

Involuntary hospitalization of delirium patients in Israel: a psychiatric case register study.

This paper compares the national Psychiatric Case Register (PCR) data of two groups of delirium patients who were admitted to psychiatric hospitals. One group consists of patients who underwent involuntary civil commitment following a hospitalization order by a district psychiatrist. The second group consists of delirium patients who were voluntarily admitted. During the period 1984-1993, 805 patients with a diagnosis of delirium were admitted to psychiatric hospitals: 710 (88%) were admitted on a voluntary basis, 88 (10.9% were admitted through civil commitment, 7 (0.8%) were admitted in other ways. The two major groups are further analysed regarding demographic, clinical and administrative variables. No statistically significant differences were found between the groups concerning the clinical and administrative variables studied (type of admission, suicide attempt prior to admission, length of hospitalization, type of discharge). Given the prevailing tendency to treat delirium patients in general hospitals, the small number of those involuntarily admitted and the lack of clinical and administrative differences between the groups, the appropriateness of civil commitment procedures regarding delirium patients is questioned.

Effect of clozapine on physical and verbal aggression.

OBJECTIVE: The hypothesis that clozapine reduced serious physically and verbally aggressive behavior of persons with schizophrenia whose symptoms did not respond to typical neuroleptic treatment was tested. METHOD: Incident reports of aggression and restraint of 75 such inpatients were reviewed for 3 months before clozapine treatment and for 6 months of clozapine treatment. BPRS scores were also examined. Twenty-eight patients with no incidents were removed from study. RESULTS: There were significantly fewer incidents of physical aggression per month per patient on clozapine than before clozapine (mean +/- S.D. = 0.13 +/- 0.25 vs. 0.54 +/- 0.93; t = 3.4, df = 46, p < 0.002) and a similar decline in verbal aggression (0.21 +/- 0.31 vs. 0.73 +/- 0.83; t = 4.3, df = 46, p < 0.000). On clozapine, 49% (n = 23) of patients had fewer incidents of physical aggression, 36% (n = 17) showed no change and 15% (n = 7) showed more. Seventy percent (n = 33) of patients had fewer incidents of verbal aggression, 4% (n = 2) showed no change and 25% (n = 12) had more. During the 3 months before clozapine, 14 patients (30%) were restrained a total of 40 times. During the first 6 months of clozapine treatment, three patients (6%) were restrained a total of six times. There were significant decreases in BPRS hostility, positive, negative and psychosis scores. CONCLUSION: Clozapine appears to reduce serious aggression among some patients.

Biophysical shunt theory for neuropsychopathology. Part II: Neuronal network miswiring.

Neuronal networks have become recognized in neuroscience as the backbone of information-processing by virtue of their dynamics and their relationship to biocommunication to defined targets. Their patterns of activity and regulation derive from the final architecture of the associated neurons, each with its distinct network and working regimen. These networks are spatially localized in the brain, adhere to temporal, fixed bonds and have a definite unit specification. This article focuses primarily on the vast amount of data concerning normal neuronal networks which can produce collateral pathways to compensate for the loss of innervation of adjacent cells. It is suggested that, under abnormal conditions such mechanisms may cause 'miswiring' leading to a fundamental bypass in neuroconduction, misguided biosignal orientation, direction and distribution, and culminating in misinformation. This re-establishment of complementary neuronal networks is manifested in recognizable neuropsychopathological states.

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

BACKGROUND: Clozapine's effectiveness in reducing symptoms and facilitating discharge among patients with chronic schizophrenia who were resistant to neuroleptics was studied. METHOD: 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. RESULTS: 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). CONCLUSIONS: Clozapine appears to be effective for treating some chronic neuroleptic nonresponding schizophrenic patients.

Biophysical shunt theory for neuropsychopathology: Part I.

We present a new model of the origin of schizophrenia based on biophysical ionic shunts in neuronal (electrical) pathways. Microstructural and molecular evidence is presented for the way in which changes in the neuronal membrane ionic channels may facilitate membrane property rearrangement, leading to a change in the density and composition of the ion channel charge which in turn causes a change in ionic flow orientation and distribution. We suggest that, under abnormal conditions, ionic flow shunts are created which redirect the biophysical collateral neuronal (electrical) pathways, resulting in psychiatric signs and symptoms. This model is complementary to the biological basis of schizophrenia.

Effects of psychosocial rehabilitation for hospitalized mentally ill homeless persons.

The effectiveness of a psychosocial rehabilitation program in preventing further hospitalization among a group of hospitalized severely mentally ill homeless persons in Israel was evaluated. The program includes inpatient and community residential phases designed to help the participants gradually become more independent. All clients (N = 98) discharged from the inpatient phases to supervised or independent community residences since 1982 were followed until December 31, 1992, to determine changes in hospitalization rates. The average follow-up time was six years. The percentage of time clients were hospitalized dropped from 64.9 percent before discharge to the community residences to 12 percent between discharge and follow-up.

Diagnosis of dementia by different specialties.

The present study was undertaken to describe, explore and compare the specific methods and services provided by physicians of different specialties (general practitioners, geriatricians, neurologists, psychiatrists and geriatric psychiatrists) in the evaluation process of patients with suspected dementia in Israel. A self-administered questionnaire--mailed to 203 physicians (response rate 37%)--included items covering medical and specialty training, numbers of patients examined, evaluation approaches, use of formal diagnostic criteria, use of mini-mental tests, use of dementia severity rating scales, use of psychiatric and behavioral rating scales, and the use of laboratory examinations. Results indicate that the majority of physicians in all specialties either provided history taking, physical and neurological examination, or referred for it elsewhere. Deficiencies were noted regarding the use of psychiatric examination by the nonpsychiatric specialties, and provision of ADL evaluation by all specialties (except geriatricians). All specialties made a minimal use of neuropsychological tests. DSM-3/DSM-3R criteria for dementia were widely used by all specialties (except general practitioners). MMSE was the most widely used brief cognitive screening test. However, only a minority of general practitioners and psychiatrists made use of it. Laboratory tests in dementia evaluation were widely used by most physicians, irrespective of specialty. Further research is needed in order to define in more specific terms the advantages contributed by each specialty separately and in collaboration to the diagnostic process of dementia.

Psychiatric hospitalization of dementia patients by commitment order in Israel.

Commitment order by a district psychiatrist is one of several modes of involuntary admission into a psychiatric hospital. Data regarding all the commitment orders by district psychiatrists in 1990 for elderly patients age 65 years or more were obtained from the national psychiatric case register. Demographic and clinical characteristics of patients diagnosed as ICD-9 senile organic psychotic conditions have been compared with the same characteristics of patients suffering from ICD-9 affective psychoses, schizophrenic disorders, paranoid states and transient organic psychotic conditions. The conclusions are: (a) Dementia patients are underrepresented in this sample of commitment orders; (b) from a demographic point of view dementia patients are no different from other psychiatric patients, age being the sole exception; and (c) from a clinical point of view dementia patients differ from other committed psychiatric patients in three ways: (i) their commitment is usually their first hospitalization; (ii) they are discharged from hospital within a two-month period; and (iii) they are referred for continuation of treatment in a non-psychiatric system. We conclude that psychiatric admissions under commitment order constitute a temporary solution for a very small group of dementia patients.

Acute phase of drug withdrawal management by clothiapine (Entumin): a pilot project.

Fifty-nine drug addicts and alcoholics were treated with clothiapine for a period up to 2 months for alleviation of their withdrawal symptoms. Most of the patients cooperated with the treatment, and this was due to the very few side effects that were experienced by them. The patients were completely withdrawn from physical dependence on drugs and we were able to discharge them without an irresistible impulse for the drug.