For patients with refractory schizophrenia and high levels of hospital use, clozapine was somewhat more effective than haloperidol and had fewer side effects and similar overall costs.

Abstract-Elements of a renin-angiotensin system expressed along the entire nephron, including angiotensinogen secreted by proximal tubule and renin expressed in connecting tubule, may participate in the regulation of sodium reabsorption at multiple sites of the nephron. The response of this tubular renin-angiotensin system to stepwise changes in dietary sodium was investigated in 2 mouse strains, the sodium-sensitive inbred C57BL/6 and the sodium-resistant CD1 outbred. Plasma angiotensinogen was not affected by sodium regimen, whereas plasma renin increased 2-fold under low sodium. In both strains, the variation in urinary parameters did not parallel the changes observed in plasma. Angiotensinogen and renin excretion were significantly higher under high sodium than under low sodium. Water deprivation, by contrast, induced significant activation in the tubular expression of angiotensinogen and renin. C57BL/6 exhibited significantly higher urinary excretion of angiotensinogen than did CD1 animals under both conditions of sodium intake. The extent to which these urinary parameters reflect systemic or tubular responses to challenges of sodium homeostasis may depend on the relative contribution of sodium restriction and volume depletion. Key Words: angiotensinogen Ⅲ renin Ⅲ sodium Ⅲ mouse Ⅲ genetics Ⅲ urine W e have advanced the hypothesis that a paracrine tubular renin-angiotensin system operates along the entire nephron. 1 Although angiotensinogen (AGT) is not filtered across the glomerular membrane, the protein 2 and its mRNA 3,4 have been detected in proximal tubule (PT), the protein is secreted to the apical side of PT cell monolayers, 1 has been detected in final urine under normal physiological conditions, 5 and was detected in luminal fluid of PT epithelium collected by micropuncture. 6 Systemic renin is filtered and reabsorbed in the PT. 7 Although not detected in situ, it may be expressed at low level in the PT. 8,9 We have found that renin was also synthesized and secreted in connecting tubule (CNT). 1 ACE and angiotensin (Ang) II receptors are expressed along the nephron. 10,11 High luminal Ang II has been observed in the PT, 12,13 where it stimulates sodium reabsorption. 14 Some observations support a similar role in terminal segments of the nephron. 15 The potential significance of this tubular renin-angiotensin system in blood pressure regulation is underlined by the observation that double transgenic animals overexpressing human renin systemically and human AGT in the PT develop hypertension. 16 The impact of dietary sodium on the expression of renin and tubular AGT and the significance of their urinary excretion as indicators of the activity of this tissue system were tested in the mouse. Two strains were investigated, C57BL/6 and CD1. The C57BL/6 inbred differs from other inbred lines in its response to dietary sodium 17 ; its sodium sensitivity has been demonstrated 18,19 and exploited in an attempt to map genetic determinants of the arterial pressure response to dietary sodium. 19 We have verified...

Health-related quality of life in schizophrenia can be assessed by direct patient response or by a rating based on a structured interview. This study compares both types of instruments using a series of five standards: (1) sensitivity to change over time, (2) sensitivity to treatment effect, (3) correlation with symptom severity, (4) correlation with global clinical ratings, and (5)

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Instrument-based scores are often used as outcome measures. However, little is known about what changes in scores mean in terms of a clinical assessment of improvement or deterioration. The purpose of this report was to determine how much change in standard instrument scores represents a clinically detectable improvement or deterioration. The Veterans Affairs (VA) Cooperative Study of Clozapine in Refractory Schizophrenia evaluated 423 patients on clozapine or haloperidol. Symptoms and quality of life scales were completed at baseline; 6 weeks; and 3, 6, and 12 months. Among patients judged as "improved" by clinicians, the average percentage changes were a 21 percent decrease in Positive and Negative Syndrome Scale (PANSS) scores and a 26 percent increase in Quality of Life Scale (QLS) scores across all followup periods. The change in mean seven-point item scores were -0.46 (PANSS) and 0.23 (QLS). A major gain in clinically assessed improvement to "much better" was associated with a 45 percent decline in PANSS scores and 50 percent increase in QLS scores (change in mean seven-point item scores -0.88 and 0.92, respectively). Thus, modest changes in psychometric scales assessing symptoms and quality of life reflect clinically detectable improvement.

This study compared the time course to clinical improvement with clozapine and with conventional antipsychotic medications. A double-blind trial compared clozapine and haloperidol in patients with schizophrenia who were refractory to conventional antipsychotic medication and were hospitalized for 30 to 364 days at 15 Veteran Affairs medical centers during the year before study entry. Patients in the original study were randomly assigned to haloperidol or clozapine and followed for 12 months, at maximum tolerable doses. Patients who completed a full year of treatment with clozapine (n = 122), or with either haloperidol or another conventional antipsychotic medication (n = 123) and who also completed the 9- or 12-month assessment were included. Response to treatment was defined as 20 percent improvement on standard scales of symptoms and quality of life at the latter of the 9- or 12-month interviews. More patients assigned to clozapine achieved 20 percent improvement in symptoms at each followup. Among patients who did not improve at 6 weeks, 3 months, or 6 months, there were no significant differences between clozapine and comparison patients in outcomes at 1 year. Among patients who did improve, maintenance of that improvement also did not differ between the groups at 1 year on symptom measures. Maintenance of improvement in quality of life at 1 year was significantly greater for clozapine patients who had improved at 6 months (p < 0.04). Significant differential symptom response to clozapine occurred exclusively during the first 6 weeks of treatment.

Background: This study examines the role of participation in psychosocial treatment as a mediator of the clinical effectiveness of clozapine.

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