Double-blind study of clozapine dose response in chronic schizophrenia.

OBJECTIVE: This study explored the relative efficacy of three different doses of clozapine. METHOD: Fifty patients who met Kane et al.'s criteria for treatment-refractory schizophrenia or schizoaffective disorder were studied. All subjects were randomly assigned to 100, 300, or 600 mg/day of clozapine for 16 weeks of double-blind treatment. Forty-eight patients completed this first 16 weeks. Of the 50 patients, 36 went on to second and third 16-week trials of double-blind treatment at the remaining doses. RESULTS: Four subjects (8%) responded to the first 16-week condition, and one subject (2%) responded to the next 16-week crossover condition. A chi-square comparison of the response rates from the three dose groups failed to show a significant effect. An analysis of variance (ANOVA) comparison of Brief Psychiatric Rating Scale-Anchored (BPRS-A) total change scores from baseline to last observation carried forward showed a significant dose effect (600>300>100 mg/day) at 16 weeks of treatment. A crossover ANOVA of the BPRS-A total scores from the 48-week study also showed that the main effect for dose was highly significant; the 100-mg/day dose gave the higher (poorer) values, and the 300- and 600-mg/ day doses gave equal (better) values. Gender played a role in clinical response to treatment at 100 mg/day. CONCLUSIONS: Clozapine treatment at 100 mg/day was less effective than at 300 or 600 mg/day. At 100 mg/day, women responded better than did men. The 600 mg/day group had the best results, but an occasional patient required up to 900 mg/day. Overall response rates were lower than expected.

Does akathisia influence psychopathology in psychotic patients treated with clozapine?

BACKGROUND: Akathisia has been reported to predict more severe symptoms and poorer treatment response to typical neuroleptics among patients with schizophrenia. Akathisia has also been associated with symptom exacerbation. This study addressed four questions: 1) Does akathisia predict greater severity in global psychopathology? 2) Is this effect global or specific? 3) Does clozapine treatment alter this relationship? 4) Does severity of psychopathology covary with the level of akathisia? METHODS: Akathisia and clinical symptoms were examined in 33 "treatment refractory" schizophrenic patients treated with clozapine across 16 weeks. Weekly ratings were Barnes Akathisia Rating Scale, Abbreviated Dyskinesia Rating Scale, and Brief Psychiatric Rating Scale (BPRS). Patients were classified as "with" (n = 15) or "without" (n = 18) akathisia. Data analyses involved independent t-test comparisons of selected variables, between-group multivariate analyses of variance across time for BPRS Total scores and Guy's five factors, and partial correlations to assess covariation between BPRS scores and level of akathisia. RESULTS: Akathisia predicted more severe global psychopathology, specific to the Activation (AC) and Thought Disturbance (TH) factors. These relationships did not change with clozapine treatment even when akathisia declined. Interestingly, level of akathisia did not covary with severity of psychopathology. CONCLUSIONS: In this sample, akathisia predicted more severe psychopathology, specific to AC and TH BPRS factor scores. Clozapine treatment did not alter this relationship. Although the presence of akathisia predicted more severe symptoms, the level of akathisia did not covary across time with severity of psychopathology, suggesting an "uncoupling" of these symptom domains.

Diurnal variability of orofacial dyskinetic movements.

OBJECTIVE: Instrumental methods to measure tardive dyskinesia (TD) have been introduced in the last few years to try to eliminate the differences in inter-rater reliability. After eliminating variations attributed to the use of different raters, it is clear that TD frequently shows fluctuations in severity contributing to a low test-retest reliability. In the present study the diurnal variability of dyskinetic movements was explored by a computerized technique using digital imaging processing to measure orofacial movements. METHOD: Ten patients with persistent tardive dyskinesia were assessed three times a day once a week for four consecutive weeks. RESULTS: Four patients had significant diurnal variations in the severity of dyskinetic movements and six did not have significant variations. The period of time between waking and the assessment, the severity of dyskinetic movements, and smoking were significantly different between these two groups. CONCLUSION: Diurnal variations, particularly in relation to sleeping and smoking patterns, may need to be taken into account during longitudinal studies of tardive dyskinesia.

Absence of changes in antidiuretic hormone, angiotensin II, and atrial natriuretic peptide with clozapine treatment of polydipsia-hyponatremia: 2 case reports.

BACKGROUND: Polydipsia-hyponatremia is a poorly understood disorder that causes considerable mortality and morbidity. Hyponatremia in polydipsia-hyponatremia has been attributed to disturbances in antidiuretic hormone (ADH) function. Improvements in polydipsia-hyponatremia during clozapine treatment offered the chance to see if levels of ADH and other hormones associated with osmoregulation changed with improvement in biochemical and clinical measures of polydipsia-hyponatremia. METHOD: In this preliminary, longitudinal study, we studied 2 male schizophrenic patients (DSM-III-R) who had polydipsia-hyponatremia. Measures were (1) biochemical and clinical: serum sodium and osmolality, urine osmolality and specific gravity, normalized diurnal weight gain, and estimated urine volume and (2) endocrine: ADH, angiotensin II, atrial natriuretic peptide, and prolactin. Measures were collected during 2 months of baseline (typical neuroleptic) and 6 months of clozapine treatment. RESULTS: Single-case statistical procedures showed significant changes in sodium levels (a.m. and p.m.), estimated urine volume, and a.m. urine specific gravity in both patients and significantly decreased diurnal weight gain in 1 patient. Both serum and urine osmolality showed improvement, but values did not reach statistical significance. Low baseline ADH levels persisted through 6 months of clozapine treatment and showed no changes in the context of improvements in serum sodium and osmolality. No significant changes were seen in levels of angiotensin II and atrial natriuretic peptide. CONCLUSION: Given the limitations of this study, there is some evidence to suggest that the improvements in serum sodium and osmolality during clozapine treatment of polydipsia-hyponatremia may not be related to serum levels of ADH, although altered ADH receptor function cannot be ruled out. These data need to be extended in larger samples.

Clozapine withdrawal resulting in delirium with psychosis: a report of three cases.

BACKGROUND: Withdrawal symptoms for typical antipsychotics are generally mild, self-limited and do not include development of psychotic symptoms. In contrast, withdrawal symptoms for clozapine can be severe with rapid onset of agitation, abnormal movements, and psychotic symptoms. Different pathophysiologic etiologies have been suggested for these severe symptoms, including dopaminergic supersensitivity and rebound. METHOD: Three case reports of clozapine withdrawal symptoms are presented. A review of previous case reports and discussion of the etiology of withdrawal symptoms of typical antipsychotics and clozapine are provided. RESULTS: These three patients developed delirium with psychotic symptoms that resolved rapidly and completely upon resumption of low doses of clozapine. CONCLUSION: The severe agitation and psychotic symptoms after clozapine withdrawal in these three patients were due to delirium, perhaps the result of central cholinergic rebound. The withdrawal symptoms and delirium resolved rapidly with resumption of low doses of clozapine. Severe withdrawal symptoms can probably be avoided by slowly tapering clozapine and/or simultaneously substituting another psychotropic with high anticholinergic activity, such as thioridazine.

Polydipsia and water intoxication in a long-term psychiatric hospital.

This cross-sectional survey attempts to establish the prevalence of polydipsia and water intoxication at a state hospital (N = 360) using staff diagnosis, specific gravity of the urine (SPGU), weight changes, and chart review. There were 150 [42%, 95% confidence interval (CI) 37-47%] patients diagnosed as polydipsic by the staff or by SPGU. At least 93 (26%, CI 21-30%) had primary polydipsia not explained by other causes. Chart review identified 17 (5%, CI 3-7%) patients with a history of water intoxication. Using a case-control study design, schizophrenia, extended duration of hospitalization, and heavy smoking were associated with primary polydipsia in a logistic regression analysis (respective odds ratios were 1.6, 1.8, and 3.6). All patients with a history of water intoxication were Caucasian (versus 83% in those without a history) and had significantly more extended hospitalizations (94 vs. 49%). Future case-control studies should combine longitudinal identification of true cases and controls and exhaustive collections of clinical information in a standardized way.

Diurnal and weekly variation of tardive dyskinesia measured by digital image processing.

The diurnal and weekly variability of tardive dyskinesia (TD) was assessed instrumentally by digital image processing. Weekly assessments were obtained in ten patients over a 6-week period. In six of the ten patients, assessments were obtained four times over a single 12-h period. Results indicate that TD movements measured by instrumental assessment vary from week to week and throughout the day. Factors that appear to have affected the variability were changes in medications and the time of day when the assessments were conducted.

Treatment of polydipsia and hyponatremia in psychiatric patients. Can clozapine be a new option?

Polydipsia occurs frequently in chronic schizophrenic patients, some of whom develop intermittent hyponatremia. Most therapeutic efforts have tried to control the hyponatremia. Four schizophrenic patients, followed for more than one year, showed improvement on clozapine. Case 1 was an outpatient without history of hyponatremia who improved from polydipsia and psychosis. The last three were inpatients with polydipsia, intermittent hyponatremia, and psychosis who showed minimal improvement of psychosis but significant decrease in polydipsia and water intoxication. Case 2 relapsed to polydipsia when clozapine was discontinued on two occasions. Case 3 demonstrated polyuria during 39% of days before clozapine and in 0% of days after two weeks of clozapine. In case 4, most baseline sodium levels were abnormal, but all became normal after clozapine. A time-series analysis for intervention effects showed a significant effect of clozapine (p = .017). The limited information provided by these case reports suggest the need for controlled studies of the clozapine effect on polydipsic patients.

Schizophrenia and smoking: an epidemiological survey in a state hospital.

OBJECTIVE: The authors sought to determine whether smoking is related to schizophrenia or neuroleptic treatment. METHOD: Cigarette smoking was measured in all patients hospitalized at a state hospital (N = 360) and compared in relation to gender and diagnosis (schizophrenic versus nonschizophrenic). RESULTS: The overall frequency of smoking was 79% (N = 284). Male schizophrenic patients had the highest frequency of smoking, followed by male nonschizophrenic patients, female schizophrenic patients, and female nonschizophrenic patients, respectively. Schizophrenia and polydipsia were associated with both smoking and heavy smoking. CONCLUSIONS: After correction for other variables, schizophrenia appears to increase the risk of being both a smoker and a heavy smoker. There was a possible association between high doses of neuroleptics and smoking but only for nonschizophrenic patients.

Misidentification syndromes in schizophrenia: case reviews with implications for classification and prevalence.

Misidentification syndromes represent false, delusionally-based identification of self and/or others. These are variants of the Capgras Syndrome. Although the frequency of misidentification syndromes in schizophrenic populations has not yet been established, the authors believe this syndrome is more prevalent than previously described. Seven of twenty-five (28%) consecutive patients admitted to a chronic clozapine unit with a variant of misidentification syndrome will be described. Their symptoms are categorised according to traditional classification, and Silva's proposed nomenclature. Problems inherent in these classifications are discussed. The need for a more systematic classification of misidentification syndromes is emphasised. Longitudinal studies of misidentification syndrome, and the development of a standardised assessment tool for clinicians who treat chronically psychotic patients, are encouraged.