Pharmacogenetic investigation of response to duloxetine treatment in generalized anxiety disorder.

We examined genetic associations with duloxetine response in generalized anxiety disorder (GAD). Three pooled studies in patients with GAD receiving duloxetine 60-120 mg per day (N=164) or placebo (N=95) were used. Associations between 825 single-nucleotide polymorphisms (SNPs) in 61 candidate genes with change in Hamilton Anxiety Scale scores were examined with set-based testing (adjusted for the number of SNPs within each gene); sets with two-sided adjusted P≤0.05 were examined using repeated measure analysis. Follow-up analysis explored associations of these SNPs with change in Hamilton Rating Scale for Depression-Anxiety Subscale in a 6-week study in duloxetine-treated patients with major depressive disorder (MDD) (N=241). Variants in corticotropin-releasing hormone receptor 1 (CRHR1), dopamine receptor D3 (DRD3), nuclear receptor subfamily group C, member 1 (NR3C1) and phosphodiesterase 1A (PDE1A) were associated with duloxetine response in GAD. Only rs4792888 in CRHR1 showed modest evidence of association with duloxetine response in MDD (P=0.029 in GAD, P=0.054 in MDD). In conclusion, CRHR1 variation merits investigation in pathophysiology of anxiety and its treatment response.

Candidate-gene association analysis of response to risperidone in African-American and white patients with schizophrenia.

Clinical trial data were evaluated for the association between 22 single-nucleotide polymorphisms (SNPs) and response in acutely ill patients diagnosed with schizophrenia, schizoaffective disorder or schizophreniform disorder, who were treated with oral risperidone. All patients in the exploratory (78 African Americans) and validation (65 whites) data sets received risperidone 2-6 mg per day over 2-12 weeks. Two SNPs were found to have significant associations with response to risperidone over 2-12 weeks in both African-American and white patients and had a consistent direction of effect in both cohorts. Metabotropic glutamate receptor (GRM3) SNP, rs724226, was associated with a change in the positive and negative syndrome scale (PANSS) total response. Catechol-O-methyltransferase (COMT) SNP, rs165599, was moderately associated with a change in the PANSS Negative score. The greater prevalence of poor-responder GRM3 and COMT alleles in white versus African-American patients might have a clinical significance in evaluating the ethnic-specific response to risperidone.

Predictors of risk for relapse in patients with schizophrenia or schizoaffective disorder during olanzapine drug therapy.

PURPOSE: To evaluate the relationship of dose decrease, symptom worsening, and baseline covariates on subsequent relapse during olanzapine treatment in patients with schizophrenia or schizoaffective disorder. METHODS: In two 28-week, randomized, double-blind clinical trials, a Cox proportional hazards model was used to determine potential correlates of relapse (defined as > or =20% worsening on PANSS total and CGI-Severity 3) among patients (N=271) who responded to 8 weeks of olanzapine treatment (10-20mg/day). Variables examined included: demographics, illness characteristics, baseline symptoms, symptom change, dose, adverse events, and functioning. RESULTS: Patients with a lower last dose relative to the preceding visit interval were 4 times more likely to relapse during that visit interval than other patients (p<.001). A similar finding was observed for a decrease in interval modal dose, although this variable was more predictive of relapse in the visit interval immediately following dose decrease (p=.027). In a subgroup analysis by gender, there was a significantly greater incidence of relapse in men with a dose decrease, whereas a dose decrease in women did not correlate with relapse. Relapse was also correlated with the emergence or worsening of a psychiatric adverse event during the same (p<.001) and preceding (p=.007) visit intervals, and with increased rating scale measures of psychopathology. The occurrence of a non-psychiatric adverse event was not associated with relapse. CONCLUSION: Dose decrease is a significant predictor of relapse in male but not female patients. Psychiatric adverse events also predicted relapse. Patients should be periodically reassessed to determine the need for maintenance treatment with appropriate dose.

Treatment of malignant pleural effusions with tunneled long-term drainage catheters.

PURPOSE: To assess the effectiveness of tunneled pleural catheters (TPCs) in the treatment of malignant pleural effusions (MPEs). MATERIALS AND METHODS: Twenty-eight patients with symptomatic MPEs had 31 hemithoraces treated with TPCs placed under image guidance. Chemical sclerotherapy had failed in two patients and two had symptomatic locules. Drainage was accomplished by intermittent connection to vacuum bottles. Pleurodesis was considered achieved when three consecutive outputs were scant and imaging showed no residual fluid. RESULTS: All catheters were successfully placed. Dyspnea improved in 94% (29 of 31 hemithoraces) at 48 hours and 91% (20 of 22 patients) at 30 days. Control of the MPE was achieved in 90% of hemithoraces (28/31), although five required ancillary procedures. Pleurodesis occurred in 42% (13 of 31) of hemithoraces, including both that underwent an earlier attempt at chemical sclerotherapy and one treated locule. Continued drainage without pleurodesis controlled the effusion in 48% (15 of 31). In only 7% was hospital time necessary for care related to the TPC. Early, transient catheter-related pain was common, but only three complications (in two patients) occurred. Neither of these altered patient care. CONCLUSIONS: Regardless of whether pleurodesis is achieved, TPCs provide effective long-term outpatient palliation of MPEs.

Replacement of accidentally removed tunneled venous catheters through existing subcutaneous tracts.

PURPOSE: The authors describe their experience with reinsertion of accidentally removed tunneled venous catheters using existing subcutaneous tracts. MATERIALS AND METHODS: Replacement of 13 dislodged tunneled venous catheters was attempted a median of 12 hours (range, 3 hours to 5 days) after accidental removal. The catheters were needed for hemodialysis (n = 11), plasmapheresis (n = 1), or antibiotic therapy (n = 1). The tunnel exit was probed in the same fashion as for a dislodged nephrostomy tube, and new catheters were reinserted once a guide wire was advanced into the central veins. The medical record was reviewed to determine materials used and occurrence of complications, if any. RESULTS: Replacement was successful in 12 of 13 patients. The remaining patient had a new catheter placed through a fresh puncture during the same visit. There were no infections associated with re-use of existing tunnels. In five patients, after probing the tract with a guide wire, new catheters were simply advanced into the desired position. Seven other successes required additional manipulations with use of dilators and peel-away sheaths. CONCLUSIONS: Tunneled catheters that "fall out" can be readily replace even when reinsertion is attempted up to 5 days later. This represents an important contribution that radiologists can offer in the management of venous access cases.

Xanthogranulomatous cholecystitis.

Clinical, radiological and pathological findings in 31 patients with xanthogranulomatous cholecystitis have been reviewed. The spectrum of presentation was similar to that of cholelithiasis but fewer patients had biliary colic (17 per cent) and there were more complications (32 per cent). Four patients had a biliary fistula and four a perforated gallbladder with abscess formation. Patients characteristically had gallstones. Appearances often mimicked carcinoma of the gallbladder at ultrasonography and/or laparotomy, with xanthogranulomatous tissue extending to adjacent structures. Xanthogranulomatous cholecystitis and carcinoma of the gallbladder coexisted in three patients. The possibility should be considered that an 'inoperable tumour' of the gallbladder may in fact be xanthogranulomatous cholecystitis, a benign condition that frozen-section biopsy may confirm.

Cerebrospinal fluid HVA, central brain atrophy, and clinical state in schizophrenia.

In 16 patients with chronic schizophrenia, cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA) showed a significant negative correlation with computed tomographic measures of brain third ventricle size. Clinical state during a drug-free period was also significantly correlated with CSF HVA level, but not with third ventricle size when the effect of CSF HVA was partialed out. The authors propose that these findings may reflect an atrophic process involving structures around the third ventricle and a decrease in dopaminergic activity.

EGTA-extractable calmodulin in platelet membrane is lower in alcoholics than in controls.

The purpose of this study was to determine calmodulin distribution in platelets of alcoholics. Eight alcoholics were diagnosed by DSM-III (Diagnostic and Statistical Manual of Mental Disorders, 3rd edition) criteria prior to admission to the Alcohol Unit, VA Hospital, San Antonio, TX. Whole blood was drawn after a five day washout period, and again after 30 days of disulfiram treatment. Platelets were prepared from the whole blood, suspended in Ringer's-citrate-dextrose buffer (RCD), divided into 2 aliquots, then sonicated and centrifuged (100K X g). Supernatants were assayed for calmodulin content by RIA. The pellets were resuspended by sonication in 1 mM EGTA in RCD or 1% (w/v) Lubrol-PX in RCD, then centrifuged at 100K X g. Calmodulin was measured in the EGTA and Lubrol supernatants. EGTA-extractable calmodulin in pre-disulfiram, post-disulfiram, and control subjects was 5.07 +/- 2.2 (SD), 5.19 +/- 1.7 (SD), and 10.5 +/- 6.7 (SD) ng calmodulin/mg whole platelet protein. The EGTA-extractable calmodulin was significantly lower in alcoholics pre- or post-disulfiram than in controls (p less than 0.025). These preliminary results suggest an alteration in platelet membranes of alcoholics that affects the binding of calmodulin.

Non-specific neuroleptic isomer effect on calmodulin-stimulated calcium transport in erythrocyte membrane.

Calmodulin-stimulated calcium transport by everted erythrocyte membrane vesicles was inhibited by equivalent doses of active and inactive isomers of the neuroleptic drugs butaclamol and chlorprothixene. However, the trans-isomer of flupenthixol, which lacks neuroleptic properties, inhibited calcium transport more than did the active cis-isomer. The drug concentrations required for inhibition greatly exceeded those serum levels necessary for neuroleptic activity. These results are consistent with a non-specific inhibition of calmodulin-activation of calcium transport by neuroleptic drugs and provide further evidence that this effect is unrelated to clinical antipsychotic properties of these drugs. Effects on basal calcium transport activity indicate binding of neuroleptics at a site other than cytosolic calmodulin.

Adenylate cyclase of human articular chondrocytes. Responsiveness to prostaglandins and other hormones.

Adenylate cyclase [ATP pyrophosphate lyase (cyclizing), EC 4.6.1.1] was shown to be present in cultured human articular chondrocytes. Optimal conditions of incubation time, protein and substrate concentrations and pH were determined in whole cell lysates. Maximal activity occurred at pH 8.5 with no decrease in activity up to pH 10.0. Adenylate cyclase activity of particulate membrane preparations was enhanced by the addition of crude cytosol preparations. The prostaglandins E1, E2, F1 alpha, F2 alpha, D2, B1, B2, A1 and A2, as well as adrenaline and isoprenaline, stimulated adenylate cyclase derived from either adult or foetal chondrocytes. No significant stimulation was observed in the presence of human calcitonin or glucagon. Bovine parathyroid hormone always significantly stimulated the adenylate cyclase derived from foetal chondrocytes, but not from adult chondrocytes. Preincubation of the chondrocytes in culture with indomethacin and with or without supernatant medium from cultured mononuclear cells increased the responsiveness of the adenylate cyclase to prostaglandin E1.

Clinical utility of salivary lithium concentration.

Saliva, plasma and erythrocyte lithium concentrations were studied in 40 long-term lithium users. Intersubject variation in saliva to plasma lithium ratio was too great for clinical utility, when based on a group linear regression equation. By contrast, intrasubject data from 8 patients studied on three or more occasions indicated a higher linear correlation (r = 0.91 to 1.00 for 7 of 8 patients). For individual patients the ratio remained stable over varying concentration ranges, and was not affected by time from last dose or length of use of lithium. Based on these data, use of saliva concentrations of lithium for routine monitoring appears feasible after several blood and saliva concentrations are obtained to establish a relationship for a particular patient. Saliva monitoring may facilitate accurate analysis and convenience for some patients.

Effects of smoking on free recall and organization.

Habitual smokers smoked either nicotine-free cigarettes or cigarettes containing a known amount of nicotine and then engaged in a free-recall task. Nicotine subjects recalled significantly fewer words on a 75-item list during three successive trials of immediate recall than did nicotine-free subjects. Contrary to expectations, the superiority of the nonnicotine group persisted over two days. The two groups displayed comparable organizational activity (indexed by category clustering).