Antipsychotic agents used to augment clozapine during long-term inpatient hospitalizations.

INTRODUCTION: Literature assessing effective clozapine augmentation strategies is limited. The aim of this retrospective evaluation was to examine antipsychotics used to augment clozapine and assess whether an augmentation antipsychotic would continue at discharge. METHODS: Demographic, clinical and pharmacy data were collected retrospectively if patients had received clozapine plus an antipsychotic used for augmentation. The dose of the augmentation agent, length of augmentation therapy, and concomitant medications were collected. RESULTS: Of the 49 patients (mean age 45.3±12.1 years), 27 (55%) were male. The mean clozapine dose at discharge was 406.1±121.8 mg. When a first generation antipsychotic (FGA) was selected initially to augment clozapine there was a greater likelihood it would be continued until discharge compared to a second generation antipsychotic (SGA) (78 vs. 50%, OR=3.6, 95% CI 1.03-12.6). FGAs (3.2%) compared to SGAs (35%) were less likely to be discontinued due to a documented lack of benefit when first selected to augment clozapine (OR=16.2, 95% CI 2-131.3). Electroconvulsive therapy plus clozapine was found to be beneficial in several patients (n=14) who failed at least 1 augmentation strategy. DISCUSSION: This real world data suggests that adding an antipsychotic to clozapine is a reasonable approach to those who do not fully respond to clozapine monotherapy. While comparisons of all agents could not be conducted from this small retrospective study, these data suggest FGAs should be investigated in future studies as potential agents to successfully augment clozapine therapy.

Endogenous concentrations of DHEA and DHEA-S decrease with remission of depression in older adults.

BACKGROUND: Clinical studies of endogenous concentrations of dehydroepiandrosterone (DHEA) and its sulfated conjugate DHEA-S in depression are limited. This study was designed to evaluate the influence of successful pharmacological treatment of late-life depression on concentrations of DHEA, DHEA-S and cortisol. METHODS: We determined endogenous concentrations of DHEA, DHEA-S and cortisol in elderly control subjects (n = 16) and in elderly depressed patients who remitted (n = 44) or failed to remit (n = 16) with pharmacological treatment. Depressed patients were treated for 12 weeks with either nortriptyline or paroxetine. RESULTS: In remitters, DHEA and DHEA-S concentrations were lower at week 12 than at week 0 (p =.002 and p =.0001, respectively). In the nonremitters and control subjects, neither DHEA nor DHEA-S concentrations changed. Decreases in hormone concentrations were associated with improvement in mood and functioning in depressed patients. Although cortisol concentrations decreased in remitters and nonremitters, the change was not significant. CONCLUSIONS: Our data suggest that the decrease in DHEA and DHEA-S in remitters is related to remission of depression rather than to a direct drug effect on steroids, as nonremitters had no change in hormone concentrations.

DHEA and DHEA-S: a review.

Dehydroepiandrosterone (DHEA) and its sulfated metabolite DHEA-S are endogenous hormones secreted by the adrenal cortex in response to adrenocorticotrophin (ACTH). Much has been published regarding potential effects on various systems. Despite the identification of DHEA and DHEA-S more than 50 years ago, there is still considerable controversy as to their biological significance. This article reviews the metabolism and physiology of DHEA and DHEA-S, the influence of age and gender on concentrations, and changes in endogenous concentrations associated with disease states and other factors, including diet and exercise. This article is unique in that it also summarizes the influence of drugs on DHEA and DHEA-S concentrations, as well as concentrations of DHEA and DHEA-S observed after the administration of DHEA by various routes. Sections of the article specifically address DHEA and DHEA-S concentrations as they relate to stress, central nervous system function and psychiatric disorders, insulin sensitivity, immunological function, and cardiovascular disorders.

Identification genes that are differentially expressed during aging in Caenorhabditis elegans.

We isolated cDNA clones of transcripts that undergo change in abundance over the adult life span of the nematode Caenorhabditis elegans. Replicas of a C. elegans cDNA library were probed with cDNA synthesized from poly(A) + RNA isolated from young or old nematodes. We identified clones corresponding to nine distinct transcripts that decreased in abundance with age, two distinct transcripts that increased slightly in abundance with age, and one transcript that peaked in abundance during the early to middle part of the adult life span. Six of the twelve transcripts were quantitated as a function of age by means of a dot blot assay using total RNA isolated at several ages from two strains that have wild-type life spans. All six mRNAs showed similar age-dependent abundance patterns in these two strains. Mutation of the age-1 gene, which lengthens life span, did not appear to alter these patterns. Nucleotide sequence analysis of clone inserts revealed that three of the mRNAs that decreased in abundance with age corresponded to previously identified C. elegans vitellogenin genes. One transcript that showed a small increase in abundance with age appears to encode translation factor EF1-alpha. The other five clones represent novel nematode genes.

Total RNA, rRNA and poly(A)+RNA abundances during aging in Caenorhabditis elegans.

This is the second in a series of studies in which we characterize gene expression at the level of RNA during aging in the nematode Caenorhabditis elegans. Here, we quantitatively analyzed total RNA, poly(A)+ RNA, and ribosomal RNA as a function of chronological age in two different strains (TJ1060 and TJ1061) having wild-type life spans and in a long-lived age-1 mutant strain (TJ1062). In addition, we compared the age-dependent abundance patterns of these RNAs in two different culture environments. Total RNA yield did not show a consistent pattern of age-related changes. However, total RNA yield was significantly higher in all three strains when grown on agar than when grown in liquid. In addition, total RNA yield was significantly lower from strain TJ1061 than from strain TJ1060 and TJ1062. Relative to total RNA, rRNA did not exhibit any consistent differences with age, strain or environment. Poly(A)+ RNA decreased by 23-43% in old animals from the long-lived strain and one of the wild-type strains, but was not changed in the second wild-type strain. In addition, control experiments to determine the amount of RNA contributed by E. coli bacteria (present in the nematode culture medium as a food source) suggest that the age-1 mutant strain has a lower bacterial infection rate, which may contribute to the increased life span of this strain.

Production of age-synchronous mass cultures of Caenorhabditis elegans.

Methods are described for culturing large populations of age-synchronous Caenorhabditis elegans throughout the adult life span. Contamination of adult populations by progeny was prevented by constructing double-mutant strains that produce progeny at a frequency of less than .005 per adult at the nonpermissive temperature (25.5 degrees C). Of four double-mutant strains that we have characterized, three have wild-type life spans at 25.5 degrees. The other strain contains a mutant allele, age-1(hx542), that results in an increase in life span of 60% over wild type. All four strains produced sufficient numbers of progeny at the permissive temperature (20 degrees C) to generate populations containing 1-5 x 10(6) nematodes within two weeks. Age-synchronous young adult populations were produced using these strains and have been maintained as adults both in liquid culture and on agar medium. Procedures that reduce E. coli contamination by 30-fold in harvested samples of adults are also described.