Clozapine treatment in Australia: a review of haematological monitoring.

BACKGROUND: Clozapine is an atypical antipsychotic drug indicated for patients with schizophrenia in whom traditional antipsychotic drugs (such as haloperidol or the phenothiazines) are ineffective, or in those who experience intolerable adverse effects. Clozapine treatment may be complicated by the development of life-threatening agranulocytosis, so regular haematological monitoring is required. OBJECTIVES: To determine the incidence of clozapine-induced agranulocytosis in Australia and the importance of monitoring white blood cell counts in patients treated with clozapine. DESIGN: Review of haematological monitoring for the first three years (June 1993-July 1996) of operation of the Australian Clozaril (clozapine; Novartis Australia) Patient Monitoring System (CPMS) central database. RESULTS: In the 4061 patients prospectively monitored by the CPMS, the incidence of agranulocytosis, neutropenia and leukopenia combined was 2.6% (n = 104); the incidence of agranulocytosis was 0.9% (n = 37). So far there have been no deaths in Australia from the complications of clozapine-induced agranulocytosis. CONCLUSION: The incidence of agranulocytosis and neutropenia associated with clozapine use in Australia is similar to that in the rest of the world. Monitoring the white blood cell counts of patients being treated with clozapine ensures minimal risk to patients who develop agranulocytosis.

Intensive nutritional counselling in bulimia nervosa: a role for supplementation with fluoxetine?

OBJECTIVE: The aims of the paper are to determine whether nutritional counselling is associated with an improvement in bulimic symptomatology, whether this improvement is maintained during post-treatment follow-up, and whether the addition of fluoxetine 3 x 20 mg/day confers additional benefit. METHOD: Psychological, pharmacological and combined psychopharmacological treatments of bulimia nervosa were reviewed briefly. Sixty-seven patients referred to specialist eating disorder services who fulfilled strict diagnostic criteria were treated with intensive nutritional counselling and randomly assigned to either fluoxetine 3 x 20 mg/day or placebo. After a 1-week 'wash-out', active treatment was given over 8 weeks, followed by post-treatment interviews at 12 and 20 weeks. RESULTS: Both groups of patients improved significantly during treatment. In some respects, the fluoxetine group did slightly better as demonstrated by the items 'restraint', 'weight concern' and 'shape concern' (p < 0.05 vs p < 0.0001) on the Eating Disorder Examination (EDE). Fluoxetine patients decreased their energy intake and lost a modest amount of weight. They went on to regain weight during the follow-up period, returning to levels higher than they were initially. These patients also appeared more likely to have a recurrence of symptoms, as shown by the fall in percentage of binge-free patients and by changes in the EDE. CONCLUSION: Nutritional counselling is an effective means of treating bulimia nervosa, with improvement maintained up to 3 months follow-up. The addition of fluoxetine may confer some benefit during active treatment, but its discontinuation may contribute to a higher rate of recurrence of symptoms post treatment. Of course, this study cannot be extrapolated to the efficacy of fluoxetine when used as the only form of treatment in patients for whom intensive nutritional counselling or other structured psychological programs are not available.

Pharmacokinetics of dexamethasone and its relationship to dexamethasone suppression test outcome in depressed patients and healthy control subjects.

The pharmacokinetics of dexamethasone (DEX) were studied in 9 drug-free melancholically depressed patients and 10 healthy control subjects matched by sex and age. Each subject received 1 mg of DEX administered orally and by the (i.v.) route at 11:00 PM and serial blood samples were collected over the next 17 hours until 4:00 PM. There were no significant differences between the diagnostic groups and DEX bioavailability, peak plasma level, time to maximum concentration, or in elimination half-life after oral administration. Bioavailability estimates indicated that DEX absorption was incomplete and variable mean = 61%, SD = 14) in controls as well as depressed patients. In both groups there was a wide interindividual variability in plasma DEX levels following both oral and i.v. routes of administration. This variability could not be reliably predicted by differences in age, sex, or weight between subjects. The factors that accounted for most the variability in 4:00 PM plasma DEX levels after oral administration were clearance, bioavailability, and time to reach maximum concentration. Plasma DEX levels were lower in 3 depressed nonsuppressors compared to 3 matched controls who suppressed. No single pharmacokinetic factor was shown to be responsible for the lower DEX levels in the depressed nonsuppressors. These results indicate that plasma DEX levels need to be measured in each individual during the DST procedure so that this information may be taken into consideration when interpreting DST results.

Moclobemide for depression: an Australian psychiatric practice study.

Seven hundred twelve patients meeting DSM-III-R criteria for major depression and recommended for antidepressant treatment were treated with moclobemide as outpatients (88%) or inpatients in ordinary psychiatric practices. These differ from the highly selected patients usually studied in antidepressant research, without comorbidity, or coprescription and treated in special clinics. Sixty-five percent were women, with a mean age of 45 (+/- 13.6) years, and 88% were outpatients. Eighty-eight percent had preexisting depression. Eight percent had prior manic episodes. Previous antidepressant treatment for this episode had been received by 69%, with the most common reasons for change to moclobemide being inadequate response (66%) and poor tolerability (20%). The modal final dose was 450 mg. Regarding tolerability, 52% did not report adverse events. The most common adverse events were insomnia or stimulation (13%), nausea (11%), headache or migraine (11%), dizziness or disorientation (6%), sedation or drowsiness (5%), agitation or nervousness (3%), and diarrhea (3%). Only 10% of adverse events were severe, and 83% lasted less than 2 weeks. There was no difference when moclobemide followed fluoxetine use. Most adverse events did not significantly differ from the frequencies reported in double-blind placebo-controlled studies. Concomitant medications from all major drug groups were taken by 520 patients (73%), with no adverse interactions. Moclobemide overdose resulted in an uneventful recovery, whereas mixed overdoses caused no problems other than those attributable to coprescribed medication. On physician clinical global impression, 65% were moderately improved or better after 8 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

The reliability of manufacturer-determined, instrument-specific international sensitivity index values for calculating the international normalized ratio.

Some thromboplastin manufacturers are currently supplying the instrument-specific international sensitivity index (ISI) values of their reagents, allowing clinical laboratories to calculate instrument-specific international normalized ratio (INR) values on plasma samples from patients receiving coumarin therapy. However, the assumption that systematic interinstrument variability in the INR would be eliminated if manufacturer-determined ISI values were used remains unsubstantiated. This assumption was evaluated by comparing INR values obtained on one instrument that measures a mechanical endpoint (fibrometer) with one that measures a photo-optical endpoint (MLA-700). Three thromboplastin reagents with instrument-specific ISI values supplied by the manufacturer (ISI range, 1.23-2.79) were used. For two of three reagents, the fibrometer INR values were significantly higher than the MLA-700 INR values (P < .01). Analysis of log prothrombin time ratio plots showed that this systematic variability was caused by inaccurate manufacturer ISI values. Of clinical significance is that the inaccurate ISI values produced a high number of discordant INR values between these two instruments (> 47% of plasma samples had one INR value within and one out of the recommended therapeutic range). The implication of these findings for laboratory monitoring of oral anticoagulation is discussed.

Continuous intravenous morphine infusion in postoperative newborn infants.

The efficacy and safety of morphine sulfate was evaluated in 20 neonates requiring surgery. Following surgery, each subject received an intravenous morphine loading dose (50 micrograms/kg) followed by a continuous infusion (15 micrograms/kg/hr) for a minimum of 24 hours. Heart rate, respiratory rate, and blood pressure were frequently monitored during therapy. Blood samples were obtained following surgery and during and after morphine therapy for analysis of serum morphine and beta-endorphin content. A 12-hour urine collection was obtained 12 hours following the start of the constant morphine infusion for analysis of morphine content. The mean (+/- SD) duration of morphine infusion was 34 +/- 15 hours and a steady-rate serum morphine concentration was 39 +/- 23 ng/ml. The respective serum morphine half-life, elimination rate, and volume of distribution were 6.6 +/- 2.9 hr, 0.126 +/- 0.056 hr-1, and 5.0 +/- 6.8 liters/kg. The mean percentage of unchanged morphine recovered in the urine was 39 +/- 19 of the dose administered over 12 hours. A significant reduction in serum beta-endorphin content was observed following the onset of morphine therapy. No adverse reports were noted that could be attributed to morphine therapy. Continuous morphine therapy appears to be effective in controlling neonatal postoperative pain, as suggested by subjective nursing observations and decreased serum beta-endorphin content.

Cat gastrinoma and the sequence of cat gastrins.

Following the curative resection of a pancreatic gastrinoma in a cat, gastrin peptides were purified from the tissue and sequenced. The sequence of cat gastrinoma G17 (18-34) confirms the previously published sequence. The sequence of cat G34 (1-34) is reported for the first time. The NH2-terminal portion of cat G34 differs from that of dog by having a Q (Gln) for L (Leu) at position 10 from the NH2-terminus.

Effect of high plasma dexamethasone levels on DST sensitivity: dose-response study in depressed patients and controls.

The aim of this study was to examine cortisol dynamics over a range of plasma dexamethasone (DEX) levels using a two-dose dexamethasone suppression test (DST). Two doses of DEX (0.5 and 1.5 mg) were administered in a randomized crossover design to 29 inpatients with major depression and 26 controls to identify the upper range of plasma DEX levels that would allow reliable interpretation of DST results. It was hypothesized that due to inappropriately high plasma DEX levels following 1.5 mg, several depressed patients would switch from suppressors after the 1.5 mg dose to nonsuppressors after 0.5 mg. In contrast, the nondepressed controls with high DEX levels following 1.5 mg would remain suppressors after the lower dose. Fourteen patients were identified as having high 4 p.m. DEX levels (greater than 4 nmol/l) after the 1.5 mg DST. Cortisol was suppressed in all of the subjects with high DEX levels. After 0.5 mg, five of the eight depressed patients with high DEX levels switched to nonsuppressors. In contrast, all six controls with high DEX levels remained suppressors. These results indicate that patients with high DEX levels after a 1 mg DST should be retested with a lower dose. This strategy enhances the sensitivity of the DST without loss of specificity.

Kinetic measurement of bicarbonate in serum by thiocyanate inhibition of wheat germ phosphoenolpyruvate carboxylase.

We describe a kinetic enzymic method for serum bicarbonate analysis, using wheat germ phosphoenolpyruvate carboxylase (EC 4.1.1.31) coupled through oxaloacetate reduction with NADH in the presence of malate dehydrogenase (EC 1.1.1.37). Inhibition with potassium thiocyanate yielded first-order kinetics with respect to bicarbonate over the concentration range of 0-45 mmol/L. The inhibitor was chosen by evaluating reaction data in the presence of different anions, with use of a monoexponential model. Criteria for first-order kinetics included a constant reaction half-life over the concentration range and SDest for the model comparable with the magnitude of spectrophotometric noise. We compared our kinetic method (y) with an automated ion-selective electrode method (x), obtaining the regression relationship y = 0.97x + 1.2 mmol/L (r = 0.991; n = 77; mean = 25.5 mmol/L; y = 25.3 mmol/L). Within-run precision from duplicates was 3.1% (mean = 25.2 mmol/L; n = 72). Total analytical precision (n = 12) was 9.4% (mean = 15 mmol/L) for the low control and 4.3% (mean = 32 mmol/L) for the high control. We conclude that the kinetic assay allows use of large serum-to-reagent ratios (1:100) and smaller amounts of NADH than an equilibrium assay. The assay is suitable for automated kinetic analysis.

Digoxin elimination in a functionally anephric patient after digoxin-specific Fab fragment therapy.

The elimination of total digoxin after digoxin-specific Fab fragment therapy in a patient in end-stage renal disease is described. Two-component, nonlinear exponential regression of the patient's total digoxin concentration data revealed biphasic elimination: a fast phase with a half-life of 43 h and a slow phase with a half-life of 330 h. Serum total digoxin concentration decreased 20% 12 h after the initiation of Fab fragment therapy. The mean serum concentrations of total digoxin and apparent total digoxin as measured by fluorescence polarization immunoassay during a 520-h period after the initiation of therapy were 18.42 and 14.77 ng/ml, respectively (n = 15). The correlation between the two measurements was good (r = 0.987). The time course of free digoxin concentration obtained after ultrafiltration at 2, 20, or 37 degrees C is also described. The free digoxin concentrations (n = 10) at these temperatures averaged over a 282-h period were 0.35, 0.53, and 0.82 ng/ml, respectively (p less than 0.001, 2 degrees C vs. 37 degrees C).

The effect of age on cortisol and plasma dexamethasone concentrations in depressed patients and controls.

The aim of this study was to identify any relationships between various patient factors such as age, gender and concurrent medication that may affect plasma cortisol or dexamethasone (DEX) concentrations. Multiple regression analysis was used to formulate an equation to predict plasma DEX levels to identify factors that may influence DEX bioavailability. Pre- and post-DST cortisol levels did not increase with age, but DEX levels were higher in elderly depressed patients. Neither gender nor psychotropic medication affected plasma cortisol or DEX levels. There was no indication that pre-DST cortisol levels influenced plasma DEX levels to account for the lower DEX values in non-suppressors. Age was the only significant factor found in this study to influence DEX levels and it could be argued that the dose of DEX should be lowered when administering the DST to elderly patients to reduce plasma DEX variability.

Multipoint kinetic method for simultaneously measuring the combined concentrations of acetoacetate-beta-hydroxybutyrate and lactate-pyruvate.

This is a multipoint kinetic method for simultaneously determining acetoacetate (AcAc) plus beta-hydroxybutyrate and lactate plus pyruvate in a single cuvette of the Multistat III centrifugal analyzer. In the first step, AcAc and pyruvate are completely reduced, using 3-hydroxybutyrate dehydrogenase (EC 1.1.1.30) and lactate dehydrogenase (EC 1.1.1.27) in the presence of excess NADH at pH 7.5, to beta-hydroxybutyrate and lactate, respectively. After dilution, the endogenous beta-hydroxybutyrate and lactate and that resulting from reduction are simultaneously oxidized by their respective dehydrogenases in the presence of excess NAD+ at pH 9.0. Adjustment of the relative enzyme concentrations allows simultaneous estimation of AcAc plus beta-hydroxybutyrate and lactate plus pyruvate by analyzing multipoint absorbance data, collected during the oxidation reaction, with use of a two-component linear-regression model. Total run-to-run CVs were 6.4% and 6.1% at 5 mmol/L beta-hydroxybutyrate and 5 mmol/L lactate, respectively. The method was designed to be useful for identifying the cause of an increased anion gap in serum.

The plasma dexamethasone window: evidence supporting its usefulness to validate dexamethasone suppression test results.

Two doses of dexamethasone (DEX) (0.5 and 1.0 mg) were administered in a randomized crossover design to 31 patients with major depression, 9 healthy controls, and 14 nondepressed psychiatric patients. Using this modified Dexamethasone Suppression Test (DST), minimum DEX levels of 6 nmol/liter at 8:00 AM and 2.0 nmol/liter at 4:00 PM were required to achieve reliable suppression of cortisol in healthy controls and nondepressed psychiatric patients. Failure to achieve these minimum plasma DEX levels was associated with similar rates of nonsuppression in both depressed and nondepressed patients, thereby reducing the specificity of the DST. Conversely, high DEX levels greater than 13 nmol/liter at 8:00 AM or 4.0 nmol/liter at 4:00 PM were associated with abnormal "suppressibility" in depressed patients, thereby reducing the sensitivity of the test. Controlling for plasma DEX concentrations by selecting a test result that fell within a plasma DEX window at 8:00 AM and 4:00 PM increased the sensitivity and specificity of the DST. Significant differences in plasma DEX between suppressors and nonsuppressors were no longer evident when comparing patients with adequate DEX levels, thus ensuring that cortisol escape reflected HPA axis changes associated with depression and not peripheral mechanisms responsible for the availability of DEX. These results suggest that the clinical utility of the DST would be significantly enhanced by extending the standard 1.0-mg DST and retesting those patients with levels outside the DEX window with a higher or lower dose. The data also indicate that the measurement of plasma DEX is essential to validly interpret DST status and highlight the need to standardize DEX assays to compare DST results between research centers.

Kinetic measurement of the combined concentrations of acetoacetate and beta-hydroxybutyrate in serum.

This is an automated method for the kinetic measurement of the combined concentrations of acetoacetate and beta-hydroxybutyrate in a single channel of the "Multistat III" centrifugal analyzer. Acetoacetate is first reduced with high concentrations of NADH by catalysis with 3-hydroxybutyrate dehydrogenase (EC 1.1.1.30). This reaction mixture is diluted with excess NAD+. The endogenous beta-hydroxybutyrate and that resulting from acetoacetate are then measured kinetically. Comparing the combined concentration of acetoacetate and beta-hydroxybutyrate (y) with the sum of acetoacetate and beta-hydroxybutyrate measured as described by Hansen and Freier (Clin Chem 1978;24:475) (x) yielded the relationship: y = 0.99x - 0.57 (r = 0.93, n = 25). The run-to-run CVs for low (5 mmol/L) and high (15 mmol/L) acetoacetate controls were 12% and 6%, respectively. The method is useful for determining the concentration of ketone bodies in 2-microL samples of serum of patients with diabetic ketoacidosis. The sensitivity can be increased to determine ketone body concentration in nonketotic individuals by increasing sample volume to 10 microL.

Plasma dexamethasone and the dexamethasone suppression test. Initial and follow-up tests in depressed patients.

Plasma dexamethasone concentrations following oral dexamethasone administration were examined in 78 patients with major depression prior to and during treatment. The test-retest stability of plasma dexamethasone levels within patients was satisfactory with an overall significant positive correlation between tests for each patient. However, significant variability was noted in individual patients. Change in pre-DST cortisol and plasma dexamethasone levels were the two variables, in that order of importance, contributing to change in DST status. In studies examining the clinical utility of serial dexamethasone suppression tests as a guide to recovery from depression, the effect of variability in plasma dexamethasone concentrations should be taken into account.

The Weismann-Netter syndrome.

The Weismann-Netter syndrome is a rare, heritable dysplasia of anterior bowing of tibiae and fibulae, often with lateral bowing of femora, short stature, and mild mental retardation. The condition is probably due to a primary metabolic abnormality of bone. The disease process is inactive in the adult. The pathogenesis is unknown. The patient reported here is the only child described in the Anglo-American literature.

Craniofacial pattern similarities and additional orofacial findings in siblings with the Robinow syndrome.

This study elucidates a craniofacial profile pattern similarity among four family members with the Robinow syndrome. Using eight angular measurements, these profiles (created from standard scores and correlation coefficients (rz) among siblings) exceed 0.80. Dental examination of these same children demonstrates an unusual incisal edge morphology that could comprise one additional identifying feature in this disorder. The accumulation of findings in this study, along with those previously reported, emphasizes midline craniofacial involvement in the Robinow syndrome.