Discontinuation of clozapine: a 15-year naturalistic retrospective study of 320 patients.

OBJECTIVE: Clozapine is underutilized in the management of treatment-resistant schizophrenia. To understand contributing factors, we analyzed the frequency and causes of clozapine discontinuations that occurred over a 15-year period in a clinical setting. METHOD: Data were extracted from computerized records and from mandatory termination reports for discontinuation events 1993-2007. The reasons for termination were analyzed. RESULTS: Over half of the patients (n = 183/320; 57%) had at least one discontinuation (median time 609 days). The two most common causes for discontinuation were non-adherence (35%) and side-effects (28%). Hematological side-effects accounted for 45% of all side-effect associated discontinuations; most such patients remained eligible for clozapine treatment, and a significant fraction remained on clozapine after rechallenge. Central nervous system side-effects accounted for 35% of side-effect induced discontinuations. General factors significantly associated with discontinuation were African American race, older age at initiation of clozapine and less improvement in psychiatric symptoms. CONCLUSION: In addition to anticipating and addressing causes of non-adherence, psychiatrists should consider clozapine rechallenge in eligible patients and implement measures to mitigate clozapine-associated sedation, seizures, and other side-effects. Future studies should particularly address why African American and older patients may be more likely to discontinue clozapine.

Clozapine and associated diabetes mellitus.

BACKGROUND: Clozapine is an effective therapy for the treatment of refractory psychosis. Clozapine-associated adverse effects include sedation, weight gain, sialorrhea, palpitations, seizures, and hematologic changes such as agranulocytosis. METHOD: We present a four-case series in which clozapine use was associated with either a de novo onset or severe exacerbation of preexisting diabetes mellitus. RESULTS: The change in glycemic control was not significantly related to weight gain. Three of the patients have been able to continue on clozapine therapy and have experienced a reduction in psychotic symptoms. CONCLUSION: Patients with a family history of diabetes mellitus or with preexisting diabetes mellitus may need to have blood sugar monitored closely during initiation of clozapine treatment.

Clozapine-induced urinary incontinence: incidence and treatment with ephedrine.

BACKGROUND: Treatment with the atypical antipsychotic drug clozapine appears to be associated with an increased incidence of urinary incontinence (UI). We posited that the potent anti-alpha-adrenergic effects of clozapine were involved, and hence that an alpha-adrenergic agonist would reduce UI. We tested this hypothesis by using ephedrine, an approved alpha-adrenergic agonist. METHOD: Fifty-seven inpatients with schizophrenia or schizoaffective disorder (DSM-IV) who met the Kane criteria for being treatment refractory were treated with clozapine (75-900 mg/day). Patients who developed UI were then openly treated with ephedrine in increasing doses until UI was attenuated or a dose of 150 mg/day was attained. RESULTS: Seventeen patients developed UI as evidenced by either urine-stained sheets/clothing or direct patient reports. In 2 cases, the UI was sufficiently severe that adult diapers had to be used. Comparison of patients who developed UI and those who did not showed that UI was associated with female gender and with concomitant treatment with typical antipsychotic drugs. One patient was treated with a behavioral program, but the remaining 16 patients were treated with ephedrine. Ephedrine treatment was very effective, with 15/16 patients showing improvement within 24 hours after reaching maximum ephedrine dosage. Twelve of 16 (including the 2 most severe) eventually had a complete remission of their UI. In the remaining 4 patients, 3 had a reduction in the frequency of UI and 1 showed no response. These benefits have been maintained over the course of 12 months of subsequent treatment for several patients. There were no side effects associated with the use of ephedrine nor were there any changes in neuropsychiatric status. CONCLUSION: Ephedrine appears to be a safe and effective treatment clozapine-associated UI. By inference, it is likely that clozapine may cause UI via its anti-alpha-adrenergic properties.

Searching for an enhanced predictive tool for mutagenicity.

The Multiple Computer Automated Structure Evaluation (MCASE) program was used to evaluate the mutagenic potential of organic compounds. The experimental Ames test mutagenic activities for 2513 chemicals were collected from various literature sources. All chemicals have experimental results in one or more Salmonella tester strains. A general mutagenicity data set and fifteen individual Salmonella test strain data sets were compiled. Analysis of the learning sets by the MCASE program resulted in the derivation of good correlations between chemical structure and mutagenic activity. Significant improvement was obtained as more data was added to the learning databases when compared with the results of our previous reports. Several biophores were identified as being responsible for the mutagenic activity of the majority of active chemicals in each individual mutagenicity module. It was shown that the multiple-database mutagenicity model showed a clear advantage over normally used single-database models. The expertise produced by this analysis can be used to predict the mutagenic potential of new compounds.

A practical alternative to conventional aminoglycoside dosing methods.

OBJECTIVE: One-compartment pharmacokinetic equations are adequate to perform clinical dosing adjustments for aminoglycoside monitoring. This article describes the Fuller-Goldman (FG) method, an alternative method of aminoglycoside dosage adjustment after serum concentrations have been obtained. The FG method uses pharmacokinetic principles, but does not use standard pharmacokinetic equations (SPE) for aminoglycoside dosage adjustment. A comparison of the FG method to SPE is also presented. DATA SOURCES: Information was obtained from pharmacokinetic textbooks and references using basic pharmacokinetic concepts. Forty sets of peak and trough serum drug concentrations were randomly chosen, retrospectively, from routine pharmacokinetic service data. All of the patients were men with a variety of infectious diseases and cared for on general surgical and medical floors, intensive care units, and a spinal cord injury unit. STUDY SELECTION: No studies have previously been published using this dosing method. DATA EXTRACTION: Peak and trough data were extracted from routine pharmacokinetic monitoring forms kept by the coordinator of the Pharmacokinetic Monitoring Service at the Department of Veterans Affairs Medical Center. DATA SYNTHESIS: The FG method is characterized by assumptions and limitations similar to those of standard pharmacokinetic dosing methods. Forty sets of data were evaluated using both the FG method and SPE. These data were analyzed using mean percent differences of projected dosages and projected half-lives (t1/2S) as measures of the average magnitude of the discrepancy between the two methods. Ninety-five percent confidence intervals for mean percent differences also are provided. CONCLUSIONS: The FG method overestimated by 10.18 percent the dosage recommendations of the SPE method. This method also underestimated t1/2 by 2.96 percent, compared with SPE. The FG method is a viable alternative aminoglycoside dosing technique that requires one to use learned pharmacokinetic concepts.

Selegiline: initial or adjunctive therapy of Parkinson's disease?

Parkinson's disease (PD) is a progressive neurologic motor disorder. Currently, levodopa/carbidopa is the standard mode of therapy for PD; however, it does not prevent progression of the disease. Selegiline (also known as deprenyl), is a selective irreversible monoamine oxidase type B inhibitor virtually devoid of the tyramine reaction at the recommended dosage of 10 mg/d. It is approved by the Food and Drug Administration for the adjunctive use in the management of patients with PD who are receiving levodopa/carbidopa and exhibit a "wearing off" effect of levodopa. Numerous clinical trials have been conducted evaluating selegiline's role in the treatment of PD. Preliminary evidence from the DATATOP trial suggests that selegiline may slow the progression of PD when used as initial therapy. However, final results of this trial and additional long-term controlled trials comparing selegiline to levodopa and placebo groups are necessary to further clarify selegiline's role in the treatment of PD.

Selegiline in treatment of behavioral and cognitive symptoms of Alzheimer disease.

OBJECTIVE: To evaluate the effects of selegiline on behavioral and cognitive symptoms of patients with Alzheimer disease. DATA SOURCES: An English-language MEDLINE search (1982-1995) was used to identify the review articles and human clinical trials discussed in this article. STUDY SELECTION: Double- and single-blind and open-label trials were reviewed. Studies were also reviewed if selegiline was evaluated comparatively with other agents. Review articles were used for background information. DATA EXTRACTION: Data were evaluated from human studies. Studies were critiqued on the basis of design, methodology, duration, sample size, and the degree to which neuropsychological tests used in each study were compared. DATA SYNTHESIS: Selegiline is a selective, irreversible inhibitor of monoamine oxidase type B. Eight of 11 controlled trials showed selegiline had a positive effect on cognition (e.g., word fluency, delayed recall, total recall). Two of 5 controlled trials evaluating selegiline's effect on behavior (e.g., anxiety, tension, excitement, depression) showed a positive effect. CONCLUSIONS: The role of selegiline remains to be determined by large well-controlled long-term clinical trials. Selegiline may be a useful agent in managing behavioral and cognitive symptomatology associated with Alzheimer disease. Given that the management of Alzheimer disease is symptomatic and no standard treatment exists, selegiline should be considered among the various options.

Isoniazid-associated psychosis: case report and review of the literature.

OBJECTIVE: To describe a case of isoniazid-associated psychosis and review the incidence of this adverse effect. DATA SOURCES: Information about the patient was obtained from the medical chart. A MEDLINE search of the English-language literature published from 1950 to 1992 was conducted and Index Medicus was manually searched for current information. STUDY SELECTION: All case reports describing isoniazid-associated psychosis were reviewed. DATA EXTRACTION: Studies were evaluated for the use of isoniazid, symptoms of psychosis, onset of symptoms, and dosage of isoniazid. DATA SYNTHESIS: The case report is compared with others reported in the literature. The incidence of isoniazid-associated psychosis is rare. CONCLUSIONS: The mechanism of isoniazid-associated psychosis is uncertain. It appears that isoniazid was associated with the psychosis evident in our patient and in the cases reviewed.

Sertraline and psychotic symptoms: a case series.

Sertraline and other SSRIs have a relatively favorable side-effect profile and are widely prescribed. We report the emergence of psychotic symptoms during treatment with sertraline in four patients. Three of these patients had a history of psychotic illness and were on antipsychotic medication, when sertraline was added. The psychotic symptoms emerged within 3 days-7 weeks of starting sertraline and resolved on its discontinuation. We wish to alert clinicians to the possibility that sertraline may provoke or exacerbate positive psychotic symptoms, particularly in patients on neuroleptics, with a previous history of psychosis.

Clozapine reduces water-drinking behavior in schizophrenic patients with polydipsia.

Disordered water balance, or polydipsia, is an underassessed and underreported phenomenon present in the severely psychiatrically disabled population. Prevalence rates for polydipsia range from 6.2 to 20%. We followed up five male patients (mean age 43) with chronic schizophrenia who met the Kane criteria for being treatment nonresponders and who, in addition, had marked polydipsia. Three patients had previously received medical care for hyponatremia and had to be placed on fluid restriction when admitted to the hospital. All patients exhibited polydipsia despite high doses of typical antipsychotic drugs. Each patient was treated openly with clozapine (range 450-800 mg/day) for at least 6 months. In each case, there was a decline in the Brief Psychiatric Rating Scale score (preclozapine mean, 63; postclozapine mean, 46), and a marked reduction in fluid-seeking behavior. All fluid restrictions could be lifted, and the patients were discharged from the hospital. During a mean follow-up period of 17 months, during which patients were evaluated weekly, polydipsic behavior that required intervention had not been noted. We conclude that clozapine may be a highly effective treatment for polydipsia in patients with treatment-refractory schizophrenia. Future studies may aim to delineate neurobiologic mechanisms.

Activity of soybean lipoxygenase isoforms against esterified fatty acids indicates functional specificity.

In soybean (Glycine max L.) vegetative tissue at least five lipoxygenase isozymes are present. Four of these proteins have been localized to the paraveinal mesophyll, a layer of cells that is thought to function in assimilate partitioning. In order to determine the role of the lipoxygenase isozymes within the soybean plant, the leaf lipoxygenases were cloned into bacterial expression vectors and expressed in Escherichia coil. The recombinant lipoxygenases were then characterized as to substrate preference, pH profiles for the most common plant lipoxygenase substrates, linoleic acid, and alpha-linolenic acid, and the reaction products with the substrates linoleic acid, alpha-linolenic acid, arachidonic acid, gamma-linolenic acid, and the triacylglycerol trilinolein. All five enzymes were shown to be (13S)-lipoxygenases against linoleic acid. The results of these assays also indicate that two of these isozymes are highly active against esterified fatty acid groups, such as those found in triacylglycerols. Lipid analysis of leaves from plants subjected to sink limitation conditions indicates that the soybean leaf lipoxygenases are active in vivo against both free fatty acids and esterified lipids, and that the quantities of lipoxygenase products found in leaf tissue show a positive correlation with the level of lipoxygenase in the leaf. Implications for the putative role of these enzymes in the paraveinal mesophyll are discussed.

Protein dynamics, activity and cellular localization of soybean lipoxygenases indicate distinct functional roles for individual isoforms.

Vegetative lipoxygenases (VLXs) in soybean are hypothesized to function in nitrogen storage and partitioning. Isoform-specific antibodies for four of the five known VLX isoenzymes were used to investigate the influence of source-sink status on protein levels, as well as to analyze the tissue and subcellular localization of the different isoforms. VLXD responded most strongly to sink limitation, although the levels of VLXA, B and C increased as well. After sink limitation, VLXD and the vegetative storage protein, VSPalpha, accumulated in the vacuoles of bundle sheath and paraveinal mesophyll cells, while VLXA, B and C localized to the cytosol of these cells. All five known VLX isoenzymes were active with both linoleic and linolenic acid substrates after expression in Escherichia coli. The strong upregulation of VLXD levels after sink limitation as well as the localization of this isoform to the vacuoles of paraveinal mesophyll and bundle sheath cells (where VSPs are found) strongly suggest that VLXD should be considered as a major storage protein in soybean leaves. Furthermore, since VLXA, B and C also accumulate in sink-limited soybean leaves, are located in the cytosol of paraveinal mesophyll cells and are active at pH values typically found in this compartment, their activities may well contribute to lipid metabolism in this tissue. This multi-gene family is thus ideally poised to play a pivotal role in the balance of N deposition relative to lipid-based storage, defense or signaling, by modulating contributions to these processes in the transient storage cells of the paraveinal mesophyll.