Transcriptomic analysis delineates preterm prelabor rupture of membranes from preterm labor in preterm fetal membranes.

BACKGROUND: Globally, preterm birth remains the leading cause of death in children younger than 5 years old. Spontaneous preterm birth is comprised of two events that may or may not occur simultaneously: preterm labor and preterm prelabor rupture of membranes (PPROM). To further explore the concept that spontaneous preterm birth can result from the initializing of two separate but overlapping pathological events, we compared fetal membrane tissue from preterm labor deliveries to fetal tissue from preterm labor with PPROM deliveries. We hypothesized that the fetal membrane tissue from preterm labor with PPROM cases will have an RNA-seq profile divergent from the fetal membrane tissue from preterm labor controls. METHODS: Chorioamnion, separated into amnion and chorion, was collected from eight gestationally age-matched cases and controls within 15 min of birth, and analyzed using RNA sequencing. Pathway enrichment analyses and functional annotations of differentially expressed genes were performed using KEGG and Gene Ontogeny Pathway enrichment analyses. RESULTS: A total of 1466 genes were differentially expressed in the amnion, and 484 genes were differentially expressed in the chorion (log2 fold change > 1, FDR < 0.05) in cases (preterm labor with PPROM), versus controls (preterm labor only). In the amnion, the most significantly enriched (FDR < 0.01) KEGG pathway among down-regulated genes was the extracellular matrix receptor interaction pathway. Seven of the most significantly enriched pathways were comprised of multiple genes from the COL family, including COL1A, COL3A1, COL4A4, and COL4A6. In the chorion, the most significantly enriched KEGG pathways in up-regulated genes were chemokine, NOD receptor, Toll-like receptor, and cytokine-cytokine receptor signaling pathways. Similarly, KEGG pathway enrichment analysis for up-regulated genes in the amnion included three inflammatory pathways: cytokine-cytokine interaction, TNF signaling and the CXCL family. Six genes were significantly up regulated in chorionic tissue discriminated between cases (preterm labor with PPROM) and controls (preterm labor only) including GBP5, CXCL9, ALPL, S100A8, CASP5 and MMP25. CONCLUSIONS: In our study, transcriptome analysis of preterm fetal membranes revealed distinct differentially expressed genes for PPROM, separate from preterm labor. This study is the first to report transcriptome data that reflects the individual pathophysiology of amnion and chorion tissue from PPROM deliveries.

VIVA (VIsualization of VAriants): A VCF File Visualization Tool.

High-throughput sequencing produces an extraordinary amount of genomic data that is organized into a number of high-dimension datasets. Accordingly, visualization of genomic data has become essential for quality control, exploration, and data interpretation. The Variant Call Format (VCF) is a text file format generated during the variant calling process that contains genomic information and locations of variants in a group of sequenced samples. The current workflow for visualization of genomic variant data from VCF files requires use of a combination of existing tools. Here, we describe VIVA (VIsualization of VAriants), a command line utility and Jupyter Notebook based tool for evaluating and sharing genomic data for variant analysis and quality control of sequencing experiments from VCF files. VIVA combines the functionality of existing tools into a single command to interactively evaluate and share genomic data, as well as create publication quality graphics.

Occurrence of myoclonus in patients treated with cyclic antidepressants.

Myoclonus associated with cyclic antidepressant therapy has been considered to be a rare phenomenon. Ninety-eight patients who were to begin receiving cyclic antidepressant therapy were prospectively evaluated for myoclonus. Thirty patients experienced clinically insignificant drug-associated myoclonus. Nine patients had clinically significant myoclonus. The myoclonus was reversible with the discontinuation of therapy but tended to persist if medication changes were not made. None of the tested clinical variables were able to predict which patients would develop myoclonus.

Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol.

BACKGROUND: Depressive signs and symptoms during the course of schizophrenia are common and have been associated with impaired recovery and a higher risk of self-harm. Novel antipsychotic agents introduce new pharmacological avenues that may differentially affect schizophrenic signs and symptoms, including depression. METHODS: This was a 17-country investigation of 1996 patients with schizophrenia or a related diagnosis randomly assigned to a blinded, comparative trial of the novel antipsychotic agent olanzapine (5-20 mg/d) or the conventional D2 antagonist haloperidol (5-20 mg/d). Patients were evaluated with the Positive and Negative Syndrome Scale, the Montgomery-Asberg Depression Rating Scale, and the Simpson-Angus Rating Scale. The trial consisted of a 6-week and a 46-week masked responder maintenance period. RESULTS: At least moderate depressive signs and symptoms (Montgomery-Asberg Depression Rating Scale score, > or =16) were seen in slightly more than half of this sample. Although both treatments were associated with short-term baseline-to-end point improvement on the Montgomery-Asberg Depression Rating Scale, olanzapine-associated improvements were significantly superior to those observed with haloperidol (P=.001). Furthermore, the response rate for the group receiving olanzapine (> or =50% improvement on the Montgomery-Asberg Depression Rating Scale after at least 3 weeks of treatment) was also significantly higher (P=.008). Analysis demonstrated that improvement in positive, negative, and/or extrapyramidal symptoms was associated with mood improvement (indirect effect); however, most of the olanzapine treatment effect on mood was a primary direct effect (57%) that alone was significantly greater than that seen with haloperidol treatment (P<.001). CONCLUSIONS: Depressive signs and symptoms in schizophrenia are responsive to treatment. The pleotrophic pharmacological features of olanzapine, through 1 or more non-D2-mediated pathways, likely contribute to its superior treatment effect. Better control of the mood disorders accompanying schizophrenia holds the possibility for improved patient outcomes.

Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. The Canadian Collaborative Group for research in schizophrenia.

BACKGROUND: The purpose of this investigation was to test the efficacy of novel antipsychotic medications in the treatment of cognitive impairment in early phase schizophrenia. METHODS: Sixty-five patients in this multicenter double-blind study were randomly assigned to olanzapine (5-20 mg), risperidone (4-10 mg), or haloperidol (5-20 mg). Standard measures of clinical and motor syndromes were administered, as well as a comprehensive battery of tests to assess (1) motor skills, (2) attention span, (3) verbal fluency and reasoning, (4) nonverbal fluency and construction, (5) executive skills, and (6) immediate recall at baseline and after 6, 30, and 54 weeks of treatment. RESULTS: The general cognitive index derived from the 6 domain scores revealed a significantly greater benefit from treatment with olanzapine relative to haloperidol and olanzapine relative to risperidone, but no significant difference was shown between risperidone and haloperidol. The improvement related to olanzapine was apparent after 6 weeks and enhanced after 30 and 54 weeks of treatment. Exploratory within-group analyses of the 6 cognitive domains after a conservative Bonferroni adjustment revealed a significant improvement with olanzapine only on the immediate recall domain, and similar analyses of the 17 individual tests revealed a significant improvement with olanzapine only on the Hooper Visual Organization Test. CONCLUSIONS: These data suggest that olanzapine has some superior cognitive benefits relative to haloperidol and risperidone. A larger sample replication study is necessary to confirm and generalize the observations of this study and begin evaluation of the implications of this change to cerebral function and quality of life for people with schizophrenia.

A multicenter investigation of fixed-dose fluoxetine in the treatment of obsessive-compulsive disorder.

OBJECTIVES: To determine the effectiveness of fluoxetine hydrochloride at fixed doses of 20 mg/d, 40 mg/d, and 60 mg/d in patients with obsessive-compulsive disorder (OCD) and to evaluate its safety. METHODS: Fixed-dose fluoxetine hydrochloride (20 mg/d, 40 mg/d, 60 mg/d) was compared with placebo in two randomized, double-blind, parallel, 13-week trials of identical design in 355 outpatients with OCD aged 15 to 70 years (DSM-III-R criteria; 1 year's duration or longer; depression secondary if present). RESULTS: Fluoxetine (all doses) was significantly (P < or = .001) superior to placebo on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score (mean baseline-to-end-point decrease, 4.6, 5.5, and 6.5 vs 0.9, respectively, studies pooled) and other efficacy measures (P < or = .01). A trend suggesting greater efficacy at 60 mg/d was observed. Most patients (79.2%) completed the study. Eight adverse events were statistically significantly more frequent with fluoxetine and one, with placebo. For some events, incidence tended to increase with increasing dosage; however, few patients discontinued treatment for any single event. CONCLUSION: Fluoxetine was associated with a statistically significant reduction in OCD severity, including time engaged in obsessional and/or compulsive behaviors. Adverse events infrequently led to study discontinuation.

Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzipine HGGW Study Group.

BACKGROUND: We compared the efficacy and safety of olanzapine vs placebo for the treatment of acute bipolar mania. METHODS: Four-week, randomized, double-blind, parallel study. A total of 115 patients with a DSM-IV diagnosis of bipolar disorder, manic or mixed, were randomized to olanzapine, 5 to 20 mg/d (n = 55), or placebo (n = 60). The primary efficacy measure was the Young-Mania Rating Scale (Y-MRS) total score. Response and euthymia were defined, a priori, as at least a 50% improvement from baseline to end point and as a score of no less than 12 at end point in the Y-MRS total score, respectively. Safety was assessed using adverse events, Extrapyramidal Symptom (EPS) rating scales, laboratory values, electrocardiograms, vital signs, and weight change. RESULTS: Olanzapine-treated patients demonstrated a statistically significant greater mean (+/- SD) improvement in Y-MRS total score than placebo-treated patients (-14.8 +/- 12.5 and -8.1 +/- 12.7, respectively; P<.001), which was evident at the first postbaseline observation 1 week after randomization and was maintained throughout the study (last observation carried forward). Olanzapine-treated patients demonstrated a higher rate of response (65% vs 43%, respectively; P =.02) and euthymia (61% vs 36%, respectively; P =. 01) than placebo-treated patients. There were no statistically significant differences in EPSs between groups. However, olanzapine-treated patients had a statistically significant greater mean (+/- SD) weight gain than placebo-treated patients (2.1 +/- 2.8 vs 0.45 +/- 2.3 kg, respectively) and also experienced more treatment-emergent somnolence (21 patients [38.2%] vs 5 [8.3% ], respectively). CONCLUSION: Olanzapine demonstrated greater efficacy than placebo in the treatment of acute bipolar mania and was generally well tolerated.

Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group.

BACKGROUND: Patients with Alzheimer disease (AD) commonly exhibit psychosis and behavioral disturbances that impair patient functioning, create caregiver distress, and lead to institutionalization. This study was conducted to assess the efficacy and safety of olanzapine in treating psychosis and/or agitation/aggression in patients with AD. METHODS: A multicenter, double-blind, placebo-controlled, 6-week study was conducted in 206 elderly US nursing home residents with AD who exhibited psychotic and/or behavioral symptoms. Patients were randomly assigned to placebo or a fixed dose of 5, 10, or 15 mg/d of olanzapine. The primary efficacy measure was the sum of the Agitation/Aggression, Hallucinations, and Delusions items (Core Total) of the Neuropsychiatric Inventory-Nursing Home version. RESULTS: Low-dose olanzapine (5 and 10 mg/d) produced significant improvement compared with placebo on the Core Total (-7.6 vs -3.7 [P<.001] and -6.1 vs -3. 7 [P =.006], respectively). Core Total improvement with olanzapine, 15 mg/d, was not significantly greater than placebo. The Occupational Disruptiveness score, reflecting the impact of patients' psychosis and behavioral disturbances on the caregiver, was significantly reduced in the 5-mg/d olanzapine group compared with placebo (-2.7 vs -1.5; P =.008). Somnolence was significantly more common among patients receiving olanzapine (25.0%-35.8%), and gait disturbance occurred in those receiving 5 or 15 mg/d (19.6% and 17.0%, respectively). No significant cognitive impairment, increase in extrapyramidal symptoms, or central anticholinergic effects were found at any olanzapine dose relative to placebo. CONCLUSION: Low-dose olanzapine (5 and 10 mg/d) was significantly superior to placebo and well tolerated in treating agitation/aggression and psychosis in this population of patients with AD.

Short-term effects of the calcium channel blocker nimodipine (Bay-e-9736) in the management of primary degenerative dementia.

The etiology of Alzheimer's dementia (AD) is unknown, but several neurotransmitters, e.g., acetylcholine, have been implicated. Recently, the group of calcium channel antagonists have been reviewed for their potential neuropsychiatric applications. These agents are capable of enhancing cholinergic tone, neurofilament/microtubular stabilization, and regional perfusion rates. The following is a report of a randomized, double-blind, placebo-controlled, multicenter study of 227 AD patients treated with nimodipine, a 1.4 dihydropyridine derivative and calcium channel antagonist. The subgroup receiving active drug (30 mg t.i.d.) experienced a prophylactic benefit across eight measures over 12 treatment weeks when contrasted with the disease progression seen among placebo recipients. Calcium channel blockers as neurotransmitter modulators and/or via calcium's theoretical role in neurofibrillary tangles, proteolysis, or neurofilament formation may represent a therapeutic opportunity for the AD patient.

A cholinergic role in the mechanism of lithium in mania.

Based on evidence that mania may include an alteration of cholinergic function, we have previously investigated the effects of various monovalent ions on the muscarinic cholinergic receptor from human caudate nucleus utilizing the radio-labeled antagonist (3H)quinuclidinyl benzilate (QNB). In this study we observed that Li+ at 1 mM was unique in its ability to specifically reduce the affinity of 3H-QNB for the muscarinic receptor (increasing the QNB dissociation constant from 35.9 pM to 72.4 pM). The sodium-specific induction of positive cooperativity (nHill) at the muscarinic cholinergic receptor was inhibited in the presence of Li+. Both observations achieved statistical significance at p less than 0.05. A Li+-related decrease in specific QNB binding sites (Bmax) by 23% (from 2480 to 1900 pmole/g protein) was additionally manifest, albeit only achieving a statistical trend (p less than 0.10). The exact mode of Li+ action in the management of major affective illnesses remains speculative. The observations that this cation specifically mediates a reduction of muscarinic receptor affinity and number of binding sites within the human caudate suggests further consideration of the association between muscarinic cholinergic activity and mania as it relates to Li+.

A comparison of human muscarinic cholinergic receptor properties subsequent to alcohol abuse and senescence.

Neuropsychiatric impairment during senescence and consequent to alcohol abuse demonstrates several parallels in the areas of short-term memory and sensorimotor skills. In this study high-affinity binding of the muscarinic cholinergic antagonist quinuclidinyl benzilate (QNB) was determined with post-mortem human brain tissue from normal young adults, age-matched ethanol abusers, and nondemented senior adults without histories of substance abuse. Hippocampus was chosen because of its high-density cholinergic innervation and probable role in the mnemonic process. A statistical significance emerged between nonalcoholic young adults and both ethanol abusers and seniors in reference to cooperative binding interactions (Hill coefficient, nH) amongst the latter two groups. Analysis of the respective receptor affinities (KD) revealed a significant difference between each group. A trend toward an increased KD occurred from nonalcoholic young adults to alcoholic young adults to nonalcoholic seniors. Concerning the density of receptor sites (Bmax) no difference emerged between alcoholic or nonalcoholic young adults. However nonalcoholic seniors manifest a statistically significant reduction in Bmax; this feature is consistent with the reports of several other investigators. Amongst subjects with a pathologic history of ethanol abuse, a premature senescence along parameters of nH and KD emerged, albeit not including the apparent age-dependent decline in Bmax.

Chlorpromazine-induced neuroleptic malignant syndrome and its response to diazepam.

We have observed two cases of chlorpromazine-induced neuroleptic malignant syndrome (NMS); both were transiently responsive to intravenous diazepam challenge, but not to blind placebo or amyobarbitol. The interrelationship, via feedback between central dopaminergic and gamma-aminobutyric (GABA) systems is reviewed. A theoretical role for a relative DA-GABA imbalance during NMS and treatment implications are discussed.

No gender differences in placebo responses of patients with major depressive disorder.

BACKGROUND: This study was designed to compare placebo responses in men and women. METHODS: Data for 501 women and 375 men with major depressive disorder treated with placebo from seven investigational randomized double-blind trials comparing fluoxetine with placebo were analyzed. Changes in major depressive disorder symptoms with placebo administration were measured as changes in total Hamilton Depression Rating Scale scores and adverse (nocebo) effects were measured by comparing treatment-emergent signs and symptoms. RESULTS: Both women and men with major depressive disorder showed significant symptomatic improvement following placebo administration, similar in magnitude and time course of response. Women on placebo reported slightly more nocebo effects than men. CONCLUSIONS: The finding that women and men with major depressive disorder demonstrated a similar therapeutic outcome after placebo administration suggests that gender is not a predictor of placebo response.

The course of depressive symptoms in predicting relapse in schizophrenia: a double-blind, randomized comparison of olanzapine and risperidone.

BACKGROUND: Depressive symptoms are common during the course of schizophrenia and may carry prognostic relevance. METHODS: From a 28-week prospective, double-blind, randomized study of olanzapine and risperidone, a post hoc evaluation of changes on the Positive and Negative Syndrome Scale (PANSS) depression cluster (PDC) and the subsequent risk of relapse were analyzed by logistic regression. RESULTS: Olanzapine was associated with a significantly higher categorical rate of improvement on the PANSS depression cluster (> or = 7 points) (p < .05). Although the baseline severity of depressive symptoms was not a significant predictor of relapse, the degree of acute (8-week) mood improvement on the PANSS depression cluster (but neither negative or positive symptom changes) was related to the probability of a subsequent psychotic relapse. Acute mood improvement with olanzapine was inversely related to a nonsignificantly lower risk of relapse. However, an opposite and significant relationship was observed among risperidone-treated subjects. Risperidone-treated subjects with a greater degree of acute mood change were both 3.58 times more likely to relapse than their risperidone counterparts who had experienced less mood improvement (p = .008) and 8.55 times more likely than olanzapine-treated subjects who had had similar mood improvements (p = .001). CONCLUSIONS: These data suggest the underlying pharmacologic differences between the two drugs may bestow different rates of longer-term mood stabilization and relapse prevention. In a second series of analyses, worsening on the PANSS depression cluster in the 4 weeks or less preceding a clinical relapse was a significant prodromal predictor of relapse among all subjects. As a whole, subjects with a worsening on the PDC demonstrated a 1.77 times higher risk of a relapse during the subsequent 4 weeks (p = .001). Among this mood-worsening stratum, risperidone-treated patients were 3.51 times more likely to relapse in those next 4 weeks (p = .005) than their olanzapine counterparts. Future comparative drug studies in this area will further contribute to our understanding of the pathophysiology of mood change and its relationship to psychosis, including clinical relapse and how newer agents may differ in their respective delivery of long-term treatment outcomes.

Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine.

BACKGROUND: The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptic drugs is a major challenge. Clozapine has been one treatment option; however, it is not universally effective and is limited in its use by safety concerns. With the introduction of newer agents, their performance relative to clozapine is of great clinical interest. METHODS: The primary objective of this study was to evaluate the efficacy and safety of olanzapine versus clozapine among treatment resistant DSM-IV schizophrenic patients. The study was primarily designed to demonstrate the "noninferiority" of olanzapine compared to clozapine after 18 weeks of double-blind treatment. Conclusions were based on the one-sided lower 95% confidence limit about the treatment effect observed from the primary efficacy variable (Positive and Negative Syndrome Scale [PANSS] Total). RESULTS: Mean changes from baseline to end point in PANSS Total score, using a last observation carried forward technique, showed that both agents were comparably effective in neuroleptic resistant patients, i.e., demonstrated the "noninferiority" of olanzapine when compared to clozapine. Overall, significantly fewer olanzapine-treated patients (4%) discontinued for an adverse event than their clozapine-treated (14%) counterparts (p =.022). Among spontaneously reported adverse events, increased salivation, constipation, dizziness, and nausea were reported significantly more often among clozapine-treated patients, whereas only dry mouth was reported more often among olanzapine-treated patients. CONCLUSIONS: Olanzapine was demonstrated to be noninferior to clozapine and better tolerated among resistant schizophrenic patients clinically eligible for treatment with clozapine.

A double-blind, controlled comparison of the novel antipsychotic olanzapine versus haloperidol or placebo on anxious and depressive symptoms accompanying schizophrenia.

BACKGROUND: Depressive symptoms are a common feature of schizophrenia and may represent a core part of the illness. Where present, it has been associated with greater overall morbidity and mortality. Monotherapy with conventional dopamine antagonists may either worsen or bestow a limited therapeutic benefit. Accordingly the use of adjunctive thymoleptics has been explored. In contrast, olanzapine (OLZ), an atypical antipsychotic agent, offers a distinctive and pleotropic pharmacology suggestive of a broader efficacy profile than conventional neuroleptic agents. METHODS: In a 6-week placebo- and haloperidol (HAL)-controlled trial with 335 randomized subjects with chronic schizophrenia in an acute exacerbation, three fixed dose ranges of OLZ (5, 10, or 15 +/- 2.5 mg) were evaluated versus HAL (10-20 mg) or placebo. RESULTS: Baseline to endpoint change in the Brief Psychiatric Rating Scale including the anxiety-depression cluster (items 1, 2, 5, 9) was analyzed. Two dose ranges of OLZ (10 +/- 2.5, 15 +/- 2.5) were superior to placebo (p < 05) in improving mood status, whereas HAL was not. CONCLUSION: Contributions from a more selective mesolimbic dopaminergic profile, D1 or D4 activity, the release of dopamine/norepinephrine in the prefrontal cortex, and/or serotonin 5-HT2A,C antagonism may explain the differential benefit seen with OLZ in the treatment of comorbid anxious and depressive symptoms in schizophrenia.

A comparison of peripheral and central human muscarinic cholinergic receptor affinities for psychotropic drugs.

A peripheral model offers a valuable research tool for the investigation of central cholinopathic disorders. The in vitro affinities of several psychotropic drugs for the muscarinic cholinergic binding sites of human caudate and erythrocyte were compared in competition with a tritiated antagonist (quinuclidinyl benzilate). The relative affinities of the drugs for both tissues were strikingly similar. Thus, the erythrocyte muscarinic receptor may represent an accessible in vitro assay for the characterization of central cholinopathic states.

Prevalence of misuse of prescribed benzodiazepines in patients with primary anxiety disorder or major depression.

Seventy-one patients with major depression or an anxiety disorder were treated with benzodiazepines. They were followed prospectively for evidence of misuse or abuse. There was no evidence of benzodiazepine abuse. Five patients (all with major depression) misused their benzodiazepines.

Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine.

OBJECTIVE: The authors investigated whether primary negative symptoms of schizophrenia are enduring or treatment-responsive. METHODS: Previously, a double-blind, random-assignment trial of the novel antipsychotic olanzapine (in low, medium, and high dose ranges), placebo, or haloperidol (10-20 mg/day) for 335 schizophrenic inpatients was conducted for up to 52 weeks. Changes in the treatment groups from baseline to endpoint in summary scores on the Scale for the Assessment of Negative Symptoms (SANS) and several secondary measures were compared. This article describes a path analysis to determine to what extent the total treatment effect on negative symptoms was direct or indirect (i.e., mediated by differential effects on positive symptoms, extrapyramidal symptoms, or mood). RESULTS: Significantly greater improvement was achieved with high-dose olanzapine than with placebo or haloperidol. Olanzapine had a significantly greater direct effect than placebo on all SANS dimensions except anhedonia-asociality. Olanzapine also demonstrated a significantly greater direct effect than haloperidol on negative symptoms, especially on the dimensions of affective flattening and avolition-apathy. Olanzapine's superior effects were replicated in a subgroup with SANS-defined prominent negative symptoms (N = 116) and a subgroup with a BPRS-defined cross-sectional proxy for the deficit state (N = 117). CONCLUSIONS: These results suggest that the negative symptoms of schizophrenia are directly responsive to treatment. The significantly greater direct and indirect effects of olanzapine than of haloperidol on negative symptoms are likely related to olanzapine's pleotrophic pharmacology, which includes dopaminergic, serotonergic, muscarinic, and adrenergic activities. The results contribute to the hypothesis that negative symptoms may be under the influence of several neurotransmitters within one or more neuroanatomic circuits.

Alprazolam-related digoxin toxicity.

An elderly woman developed a high serum digoxin concentration resulting in toxicity when alprazolam was added to her digoxin therapy. The reduced renal clearance of digoxin is postulated as the mechanism for this interaction.