Multiple-Dose Pharmacokinetics and Pharmacodynamics of Adinazolam in Elderly Subjects

The pharmacokinetics and pharmacodynamics of adinazolam (AD) were evaluated in 21 elderly subjects (mean age, 69 ± 4 years) at four dose levels during a placebo-controlled, double-blind, dose escalation regimen in which the oral dose was varied from 10 to 60 mg daily, in divided doses. Fifteen subjects received adinazolam mesylate; six received placebo. Plasma samples collected during a single dosing interval in each dosing period (3 days) were assayed for adinazolam and monodesmethyl adinazolam (NDMAD) by high-performance liquid chromatography (HPLC). Urine samples were collected during a single interval during the 20- and 40-mg daily dose periods and assayed for NDMAD by HPLC. Pharmacologic effects of adinazolam were assessed using psychomotor performance tests and sedation ratings. Adinazolam pharmacokinetics were linear over the dosage range studied. Daily dose had no significant effect on dose-normalized AUC and C _max for AD. Dose-normalized NDMAD AUC values as well as values were not significantly affected by the daily dose of adinazolam. The ratio NDMAD/AD was not substantially affected by the dose. Renal clearance of NDMAD for the 20-and 40-mg daily doses were 5.6 ± 2.1 and 5.5 ± 2.2 liters/hr, respectively, and did not correlate with creatinine clearance. Adinazolam and NDMAD did not substantially accumulate in elderly subjects, even upon multiple dosing at 8-hr intervals. The dosing regimens in this experiment appeared to be well tolerated in the elderly, as performance tests and sedation scores indicated no substantial dose-related effects of adinazolam on psychomotor performance.     

Effect of bupropion SR on specific symptom clusters of depression: analysis of the 31-item Hamilton Rating Scale for depression

Principal component (PC) analysis is a statistical technique that has been used to identify core depression symptoms on the Hamilton Rating Scale for Depression (HAM-D). PC analysis is also a useful method to identify unidimensional scales of the HAM-D that are more sensitive to change following antidepressant treatment. Although there have been previous PC investigations of various versions of the HAM-D, there have been no investigations of the 31-item HAM-D scale or investigations that include subjects administered bupropion SR. We performed a PC analysis on data from 910 outpatients who participated in randomized, double-blind trials evaluating bupropion SR versus placebo for major depression. The goal of our analysis was to 1) identify components (domains) of the 31-item HAM-D and 2) determine patient response to bupropion SR using the domains identified. PC analysis produced a solution comprised of 7 domains of the HAM-D that accounted for approximately 49% of the total variance. Bupropion SR demonstrated a significant reduction (p<.01, least square mean change) in symptoms over placebo on 4 domains (cognitive, retardation, fatigue/interest, and anxiety items).     

Clinical pharmacology of adinazolam and N-desmethyladinazolam mesylate following single intravenous infusions of each compound in healthy volunteers

Summary The tolerability, pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam (NDMAD) were assessed following intravenous infusions of 5, 10, 15, and 20 mg adinazolam mesylate, 10, 20, 30 and 40 mg NDMAD mesylate, and placebo. Six subjects per dose level received treatments in a double-blind crossover design.No clinically significant changes were seen in blood pressure, pulse, respiration, or clinical laboratory parameters. Untoward effects typical of benzodiazepines were observed almost exclusively after NDMAD administration. Adinazolam and NDMAD pharmacokinetics were dose-independent. NDMAD clearance was 50% of the value for adinazolam. Adinazolam and NDMAD administrations increased uric acid clearance and decreased plasma uric acid. Adinazolam administration had no significant effect on psychomotor performance. NDMAD administration produced dose related decreases in performance; 286 ng/ml NDMAD produced a 50% decrease in DSST.These results confirm that adinazolam and NDMAD both produce uricosuria and definitively show that adinazolam is devoid of benzodiazepine-like effects at therapeutic concentrations; NDMAD mediates these effects. Uricosuric activity is present for both compounds, but the relative potencies are still unknown.Presented in part at the Nineteenth Annual Meeting of the American College of Clinical Pharmacology, Las Vegas, NV, November 4–8, 1990     

Ranitidine does not alter adinazolam pharmacokinetics or pharmacodynamics.

Adinazolam is a triazolobenzodiazepine with anxiolytic and antidepressant activity. Adinazolam is metabolized extensively; the major metabolite, N-desmethyladinazolam (NDMAD), possesses significant pharmacologic activity. NDMAD is eliminated predominantly by renal excretion. Ranitidine, a histamine H2-receptor antagonist, is also excreted renally and may compete with NDMAD for renal secretion. The purpose of this study was to examine the effect of ranitidine on the pharmacokinetics and pharmacodynamics of adinazolam and NDMAD. In a randomized, cross-over study, 12 healthy male volunteers received 300 mg of ranitidine orally followed by 30 mg of adinazolam 1 hour later (treatment A), or adinazolam alone (treatment B). Pharmacodynamic alterations were assessed using card sorting, digit-symbol substitution, and short-term memory tests. Venous blood samples were obtained over 24 hours for analysis of adinazolam and NDMAD by high-performance liquid chromatography. Urine samples also were collected and analyzed for NDMAD. No significant difference in adinazolam oral clearance (1,149 vs. 1,135 ml/hr/kg) was noted between treatments (A vs. B, respectively). Furthermore, the renal clearance of NDMAD (196 vs. 198 ml/min) and the cumulative urinary excretion of NDMAD (% dose; 61.2 vs. 62.3) were not significantly different. Repeated-measures analysis of variance indicated no significant differences in psychomotor performance or short-term memory between treatments. Results suggest that ranitidine has no effect on adinazolam disposition, NDMAD renal clearance, or the central nervous system effects mediated by the drug.     

Comparison of adinazolam pharmacokinetics and effects in healthy and cirrhotic subjects

The pharmacokinetics and pharmacodynamics of adinazolam were investigated in six patients with cirrhosis and six sex-matched control subjects. These subjects received a single 30-mg oral dose of adinazolam mesylate. Serial blood samples were collected for 24 hours after drug administration. Plasma was assayed for adinazolam and mono-desmethyl-adinazolam (NDMAD) concentrations by a specific HPLC technique. Pharmacokinetic parameters were estimated by noncompartmental methods. Psychomotor effects of adinazolam were assessed using a digit-symbol substitution test (DSST) and aiming test (AIM). Memory effects were assessed by a modification of the Randt memory test (MEM); sedation was assessed using an observer-rated scale. Differences in pharmacokinetics of the parent drug were noted: adinazolam oral clearance was lower in patients with cirrhosis (35.0 +/- 27.9 L/hr) than in normal subjects (73.7 +/- 22.1 L/hr; P = .024); Kel was significantly lower in patients with cirrhosis (.126 +/- .084 vs. .278 +/- .070; P = .007), whereas the mean t1/2 in patients with cirrhosis was 7.70 hours as compared with 2.67 hours in normal subjects. Cmax was higher in the group with cirrhosis (266 +/- 95.5 vs. 153 +/- 29.3 ng/mL; P = .019). For NDMAD, Kel was lower in cirrhotic subjects and resulted in a prolonged t1/2 in cirrhotic subjects compared with normal subjects (6.70 vs. 3.79 hr; P = .0152). NDMAD AUC tended to be higher in cirrhotic subjects (1515 +/- 254 vs. 1162 +/- 254 ng.hr/mL; P = .064). No significant differences were noted in psychomotor performance, memory, or sedation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Venlafaxine extended release versus citalopram in patients with depression unresponsive to a selective serotonin reuptake inhibitor

Findings from the National Institute of Mental Health's Sequenced Treatment Alternatives to Relieve Depression trial indicate that approximately 50% of patients with major depressive disorder do not experience a treatment response after adequate first-line treatment with a selective serotonin reuptake inhibitor (SSRI). This study was designed to test the hypothesis that, after treatment failure with an SSRI, switching to venlafaxine extended release (ER) would offer advantages over switching to another SSRI, citalopram. The objectives of this trial were to compare the efficacy and safety of venlafaxine ER and citalopram in the treatment of moderate-to-severe depression in patients who did not experience a treatment response to an SSRI other than citalopram and to investigate the effects of severity of depression by categorizing treatment groups according to baseline severity. This was a 12-week, double-blind, randomized, parallel-group, multicenter study. Participants were adult outpatients who, following 8 weeks of monotherapy with an adequate dosing regimen of an SSRI other than citalopram and had not responded, met the diagnostic criteria for depression as described in the Diagnostic and statistical manual of mental disorders, fourth edition, and had a score > or =20 on the 21-item Hamilton Rating Scale for Depression (HAM-D21). After a 7-day screening period, patients were randomly assigned to receive venlafaxine ER 75 mg/day or citalopram 20 mg/day for the first 2 weeks. Doses could be increased every 2 weeks through week 6. Treatment lasted 12 weeks and was followed by a 1-week tapering period. Maximum dosages were venlafaxine ER 300 mg/day or citalopram 60 mg/day. The primary end point was the final on-therapy total HAM-D21 score. To investigate the treatment effects of the severity of depression on efficacy, a subgroup analysis was performed for baseline HAM-D21 total score < or =31 and >31. The analyses for HAM-D21, Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions - Severity (CGI-S), and Clinical Global Impressions - Improvement scores were based on intent-to-treat (ITT) population, for both the primary analysis and subgroup analysis according to baseline HAM-D21 total scores < or =31 or >31. Safety assessments included the recording of adverse events (AEs). A total of 406 patients (200 venlafaxine ER, 206 citalopram) were randomly assigned and 396 patients were included in the ITT population (194 venlafaxine ER, 202 citalopram). Treatment groups were similar in terms of demographics and baseline psychiatric assessments. Two hundred and eighty-four patients (137 venlafaxine ER, 147 citalopram) were present in the ITT population with a baseline HAM-D21 total score < or =31 and 112 patients (57 venlafaxine ER, 55 citalopram) in the >31 group. In the primary analysis, there was no statistical difference between groups. The group with a baseline HAM-D21 total score of 20-31 did not differ significantly in any efficacy parameters. In the group with a baseline HAM-D21 total score >31, the venlafaxine ER group differed significantly from the citalopram group on the primary end point HAM-D21 total score (P=0.0121). The secondary end point CGI-S score was statistically significant (P=0.0359), although the MADRS total score (P=0.0930) was not. AEs were reported by 57.8 and 63.4% of venlafaxine ER and citalopram patients, respectively. Overall discontinuation rates were 24.5% for venlafaxine ER and 20.9% for citalopram. Discontinuation rates owing to an AE as a primary or secondary reason were 5.5% for venlafaxine ER and 5.3% for citalopram. Overall, venlafaxine ER and citalopram showed similar efficacy in patients who had an inadequate response to an SSRI. In the subset of more severely depressed patients, venlafaxine ER was significantly more effective on a number of efficacy measures. Patients who remain severely depressed following treatment with an SSRI may gain more benefit from the dual-action drug venlafaxine, rather than switching to another SSRI.     

Effect of food on the bioavailability of adinazolam from a sustained release formulation: effect of meal timing and lack of dose dumping

Food effects on adinazolam absorption from sustained release (SR) adinazolam mesylate tablets were assessed in 28 healthy male volunteers. Subjects received 15 mg SR tablets, 15 mg immediate release tablets, 15 mg oral solution, administered after an overnight fast, and 15 mg SR tablets after a high fat breakfast. Treatments were administered in a crossover design. Plasma adinazolam and N-desmethyladinazolam (NDMAD) concentrations were determined by HPLC. Adinazolam and NDMAD AUC values were unaffected by food. Cmax for SR tablets was increased 33 per cent and 18 per cent for adinazolam and NDMAD, respectively, when administered postprandially. Tmax occurred later in the fed state; no dose dumping was observed. Meal timing effects on adinazolam absorption from SR tablets were assessed in 24 healthy subjects, who received 30 mg SR tablets 1 h before, 0.5 h after, 2 h after a high fat meal, and in the fasted state. Postprandial administration had no effect on AUC, but resulted later and higher adinazolam and NDMAD Cmax. Differences in these values were less than 11 per cent. Administration of SR tablets before meals yielded Cmax and Tmax values which were similar to the fasted state. Results suggest that meal timing does not substantially affect adinazolam absorption from the SR tablet.     

Pharmacokinetic and Pharmacodynamic Comparison of Immediate-Release and Sustained-Release Adinazolam Mesylate Tablets After Single- and Multiple-Dose Administration

The effect of adinazolam release rate on psychomotor performance and sedation was assessed by administering 40 mg adinazolam mesylate immediate-release (CT) tablets, 60 mg sustained-release (SR) tablets, and placebo in a double-blind crossover study in 15 healthy male subjects. A separate panel of 16 subjects received the above single doses and multiple-dose regimens of 40 mg CT tablets every 8 hr and 60 mg SR tablets every 12 hr according to a crossover design. Psychomotor performance was assessed by digit symbol substitution test, card sorting tasks, and sedation ratings. Following single-dose administration, dose-corrected adinazolam and N-desmethyladinazolam (NDMAD) AUC values were equivalent for SR and CT tablets. Peak adinazolam and NDMAD levels were lower and occurred later for the SR tablets. Decrements in card sorting were 50 and 3% at 1 hr and 17 and 20% at 6 hr for the CT and SR tablets, respectively. Maximal sedation scores were lower for the SR tablets compared to the CT. Dose-corrected AUC was comparable between single and multiple doses for both adinazolam and NDMAD; no differences were observed in 24-hr AUC at steady-state between CT and SR tablets. Fluctuation ratios were reduced for both adinazolam and NDMAD following SR tablets. Psychomotor and sedative effects were attenuated upon multiple dosing. Thus, the reduction in peak plasma NDMAD following SR tablet administration results in a lesser sedation and psychomotor impairment on acute administration, and tolerance to these effects occurs on mulitiple dosing.     

Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database.

Some studies suggest that more severely ill patients with depression respond well to antidepressants and poorly to placebo, whereas those who are mildly ill respond equally well to antidepressants and placebo. This notion has implications for the design of clinical trials. To further assess and substantiate these putative predictors of antidepressant and placebo response, we assessed the Food and Drug Administration database of 45 phase II and III antidepressant clinical trials. The frequency of statistically significant differences between antidepressants and placebo was higher in the trials that included patients with more severe depression. In the antidepressant-treated groups, the magnitude of symptom reduction was significantly related to mean initial Hamilton Rating Scale for Depression (HAM-D) score; the higher the mean initial HAM-D score, the larger the change. With placebo treatment, however, the higher the mean initial HAM-D score, the smaller the change. Early discontinuation was more frequent among patients whose mean initial HAM-D scores were higher. These data may help inform the design of future antidepressant clinical trials.     

Comparison of adinazolam, amitriptyline, and diazepam in endogenous depressive inpatients exhibiting DST nonsuppression or abnormal contingent negative variation

Adinazolam, a triazolobenzodiazepine that has an action similar to antidepressants in several pharmacological tests, was compared with amitriptyline and diazepam in endogenous depressive inpatients exhibiting dexamethasone suppression test non-suppression and/or abnormal contingent negative variation. Three parallel groups of 22 patients received in double-blind conditions either adinazolam (60-90 mg/day), amitriptyline (150-225 mg/day), or diazepam (30-45 mg/day) over a 4-week period, with weekly assessments by the Hamilton Rating Scale for Depression. Results showed significant superiority of amitriptyline over diazepam on total Hamilton depression scores. On the endogenomorphy subscale, amitriptyline induced significantly better improvement than both diazepam and adinazolam, whereas both amitriptyline and adinazolam exhibited significantly better antidepressant efficacy on the core symptoms of depression. Moreover, the dropout rate for inefficacy after 2 weeks of treatment was higher in the diazepam group. Taken together, these findings suggest that adinazolam has an antidepressant efficacy intermediate between amitriptyline and diazepam. Adinazolam was, however, much better tolerated than amitriptyline, and produced significantly fewer anticholinergic side effects.     

A double-blind,placebo-controlled trial of sertraline in depressed adolescent alcoholics: a pilot study

In order to preliminarily evaluate the efficacy, safety and tolerability of the serotonin reuptake inhibitor, sertraline, in the treatment of adolescents with a primary depressive disorder and a comorbid alcohol use disorder, a 12-week double-blind, placebo-controlled trial of sertraline plus cognitive behavior group therapy was conducted. Subjects were 10 outpatient treatment-seeking adolescents. Baseline assessment included the K-SADS, HAM-D, SCID, and the Time-Line Follow-Back. The HAM-D and the Time-Line Follow-Back were performed weekly thereafter. Both groups showed a significant reduction in depression scores with an average reduction between baseline and endpoint HAM-D score of -9.8 (F(1,8)=26.14, p相似文献   

Weight changes on fluoxetine as a function of baseline weight in depressed outpatients

In order to test the hypothesis that weight changes on fluoxetine are a function of baseline weight, we divided a group of 39 depressed outpatients into 3 groups based on the Fogarty table: ideal, underweight, and overweight. Subjects were participants in an open label depression trial that was carried out over 3 years. Doses ranged from 20 mg to 80 mg depending on the patients' response and side effect profile. Demographic data, weights and Hamilton Rating Scale for Depression (HAM-D) scores were collected at baseline. Subsequent Hamilton scores and weights were obtained at monthly intervals until the subjects were terminated from the study. Only those subjects who remained in the study for at least 6 months were included in this analysis. Overweight subjects showed a significant weight loss of 3.3 lbs (p less than .001) in the first 2 months whereas ideal weight subjects gained 4.4 lbs (p = .02) over a 4-month period. All of these changes were maintained throughout the study. The underweight patients showed no consistent trends. All patients examined (those who completed 6 months or more in the trial) had significant decreases in their HAM-D scores (p less than .001).     

Effects of reboxetine on anxiety,agitation, and insomnia: results of a pooled evaluation of randomized clinical trials

Several recent clinical trials have established that reboxetine, a new selective norepinephrine reuptake inhibitor (selective NRI), is effective and safe for the treatment of major depression. However, the effects of reboxetine on specific symptoms of anxiety, agitation, and insomnia have not been reported. Data were obtained from nine short-term, double-blind, randomized clinical trials in patients with major depression. After initial titration, patients received reboxetine 8 to 10 mg per day. The effects on specific HAM-D symptoms of agitation, anxiety, and insomnia were compared between reboxetine-and placebo-treated patients. In addition, the incidence of treatment-emergent agitation, anxiety, and insomnia side effects with reboxetine were examined. Compared with placebo, the proportion of patients with improvement on the HAM-D agitation item and the HAM-D anxiety and insomnia factors from baseline was significantly greater with reboxetine at most assessment intervals. In general, the incidence of agitation-or anxiety-related side effects was comparable with reboxetine and placebo. Although reboxetine was associated with a significant (p < 0.05) increase in treatment-emergent insomnia reported as an adverse effect during the first week of treatment, very few reports of insomnia were made at subsequent evaluations. The incidence of treatment-emergent agitation or anxiety was comparable between treatment groups.     

Platelet 18 kDa Translocator Protein density is reduced in depressed patients with adult separation anxiety.

RATIONALE: Recent studies indicate that Adult Separation Anxiety Disorder (ASAD) may represent a discrete diagnostic entity worthy of attention. Adults with separation anxiety report extreme anxiety and fear about separations from major attachment figures (partner, children or parents). These symptoms affect individual's behavior, lead to severe impairment in social relationships and are not better accounted for by the presence of agoraphobia. In a previous study we found platelet expression reduction of the 18 kDa Translocator Protein (TSPO) (the new nomenclature for the peripheral-type benzodiazepine receptor) in patients with panic disorder who also fulfilled the diagnostic criteria for ASAD. OBJECTIVES: To explore whether separation anxiety might be a factor differentiating TSPO expression in a sample of patients with major depression. METHODS: The equilibrium binding parameters of the specific TSPO ligand [3H]PK 11195 were estimated on platelet membranes from 40 adult outpatients with DSM-IV diagnosis of MDD, with or without separation anxiety symptoms, and 20 healthy controls. Patients were assessed by SCID-I, HAM-D, the Structured Clinical Interview for Separation Anxiety Symptoms (SCI-SAS-A) and the Adult Separation Anxiety Self-report Checklist (ASA-27). RESULTS: A significant reduction of platelet TSPO density mean value was found in depressed patients with associated ASAD symptoms, while no significant differences were found between depressed patients without ASAD and the control group. Individual TSPO density values were significantly and negatively correlated with both SCI-SAS-A and ASA-27 total scores, but not with HAM-D total score or HAM-D anxiety/somatization factor score. CONCLUSIONS: The reduction of platelet TSPO density in our sample of patients with depression was specifically related to the presence of ASAD. These data suggest that TSPO expression evaluation is a useful biological marker of ASAD.     

The antidepressant effect of sertraline is not enhanced by dose titration: results from an outpatient clinical trial

A previous report suggested that 5 weeks of continued treatment with 20 mg of fluoxetine was approximately as effective as double-blind titration to a dose of 60 mg in patients who had failed to respond to 3 weeks of initial treatment at 20 mg. The current study was undertaken to evaluate whether 150 mg of sertraline was any more effective than 50 mg in treating depressed patients who were non-responders at 3 weeks. Ninety-one outpatients with DSM-IV major depressive disorder who had a 17-item Hamilton Depression Rating Scale (HAM-D) score > or = 18 were treated with open label sertraline for 3 weeks. Patients who did not achieve remission (defined as 17-item HAM-D total score < or = 8 by week 3) were then randomized to 5 more weeks of double-blind treatment with either 50 mg of sertraline or immediate titration to 150 mg of sertraline. Efficacy was assessed at each visit with the HAM-D, Clinical Global Impressions (CGI)-severity and improvement scale, and the Hopkins Symptom Checklist. There were no significant between-group differences in clinical or demographic features at baseline for the three treatment groups. After 3 weeks of open-label treatment, 16 patients were not randomized, of whom 11 (69%) met responder criteria. The remaining patients were randomized, double-blind, to 50 mg of sertraline (n = 37; HAM-D = 19.2 +/- 5.0) or 150 mg of sertraline (n = 38; HAM-D = 18.4 +/- 5.0). PROC-Mixed analyses found no significant difference in slopes for any outcome measure when comparing 50 mg and 150 mg sertraline treatment groups. At week 8 (LOCF), the overall remission rate (HAM-D < or = 8) for 3-week non-responders was 40%, with no statistically significant between-group difference for the 50 mg versus 150 mg doses of sertraline (P > 0.10). A completer analysis yielded similar results. Adverse events were mostly mild on both doses of sertraline and led to few treatment discontinuations. The results suggest that for most patients continued treatment with 50 mg dose of sertraline yields a rate of antidepressant response that is comparable to what is achieved by dose escalation from 50 mg to 150 mg of sertraline after 3 weeks of treatment. While some patients clearly benefit from higher doses, the results of the current study are consistent with the lack of any evidence for a dose-response curve with sertraline in the treatment of depression.     

Adinazolam,a new triazolobenzodiazepine,and imipramine in the treatment of major depressive disorder

This study evaluated the clinical efficacy and safety of a new triazolobenzodiazepine, adinazolam, and imipramine in 40 patients with carefully diagnosed major depressive disorder. Overall, adinazolam was found to be as effective as imipramine. In addition, when patients with more severe, melancholic, subtype of depression were examined, adinazolam was also as effective as imipramine. With the exception of sedation, adinazolam patients demonstrated fewer overall adverse events than imipramine subjects. These results suggest that adinazolam may represent an interesting antidepressant compound.     

The pharmacokinetics and pharmacodynamics of adinazolam: multi-ethnic comparisons

The pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam (NDMAD), its major active metabolite, were compared in 39 healthy male volunteers (13 Asian, 12 Caucasian and 14 African-American). In a four-way, double-blind crossover design, subjects were administered (1) 30 mg oral adinazolam mesylate SR tablets, (2) 10 mg parenteral (IV) adinazolam mesylate, (3) 30 mg IV NDMAD and (4) placebo. Venous blood samples were collected at specific time intervals after drug administration and assayed for adinazolam and NDMAD concentrations. Sedation was rated at the time of each blood draw according to the Nurse-Rated Sedation Scale, and the digit-symbol substitution test was administered to evaluate psychomotor performance. After IV administration of adinazolam, Asians manifested significantly higher C_max, larger AUC and lower CL of both adinazolam and NDMAD than their Caucasian and African-American counterparts. Likewise, after IV NDMAD Asians had significantly higher NDMAD C_max and AUC than Caucasians and African-Americans. Most of these differences remained statistically significant after controlling for body surface area. With PO adinazolam, Asians also manifested substantially higher C_max, larger AUC and lower CL for both adinazolam and NDMAD; however, with the exception of C_max, these differences did not reach statistical significance. These results are in accordance with previous observations for ethnic-related differences in drug pharmacokinetics. In contrast, pharmacodynamic differences were not noted among the three study groups. Received: 19 June 1996/Final version: 17 September 1996     

Comparison of efficacy and safety of milnacipran and fluoxetine in Korean patients with major depression

OBJECT: To compare efficacy and safety of milnacipran and fluoxetine in a population of Korean patients with major depression. RESEARCH DESIGN AND METHODS: The design was a multi-centre, randomised, comparative clinical study. Patients with major depression (DSM-IV diagnostic criteria) scoring over 17 points on the 17-item Hamilton Depression Scale (HAM-D) and over 21 points on the Montgomery-Asberg Depression Rating Scale (MADRS) were recruited and randomised to receive milnacipran (50 mg/day increasing after 1 week to 100 mg/day) or fluoxetine (20 mg/day) for 6 weeks. All previous medication was stopped at least 7 days before entry into the study. Patients were evaluated (HAM-D, MADRS and clinical global impression scale, CGI) at baseline and after 1, 2, 4 and 6 weeks of treatment. All adverse events which developed during the study period were recorded. RESULTS: 70 patients (milnacipran 39; fluoxetine 31) were included in the study. Total score on both HAM-D, MADRS and CGI decreased significantly in both groups after 1 week and continued to decrease throughout the study. There was no significant difference between the two groups for any measurement at any time point. Both antidepressants were well tolerated. In the milnacipran group, 13 patients reported 28 adverse reactions, and in the fluoxetine group 11 patients reported 18 adverse reactions. Two patients discontinued due to adverse events in the milnacipran group and three in the fluoxetine group. There were no clinically significant modifications in vital signs, routine blood laboratory tests, biochemistry or ECG throughout the study. Nausea and headache were the most frequently reported adverse events with milnacipran while digestive disturbances, diarrhoea and insomnia were more common with fluoxetine. CONCLUSION: Milnacipran, like fluoxetine, was found to be effective and well tolerated for the treatment of major depression in this population of depressed Korean patients. Principal limitations of the study were its open design, its small sample size and its relatively short duration.     

Pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam after oral and intravenous dosing in healthy young and elderly volunteers.

The pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam were studied in 18 young subjects, from 21 to 36 years of age, and 18 elderly subjects, ranging in age from 65 to 76 years. Nine men and 9 women per age group were studied in a randomized three-way crossover design. Single doses of one 30-mg adinazolam mesylate sustained release tablet, one 30-mg immediate release tablet, and 15 mg of intravenous adinazolam mesylate were administered. Plasma adinazolam and N-desmethyladinazolam were determined by high-performance liquid chromatography, and psychomotor performance tests, including digit-symbol substitution and two card-sorting tasks, were performed. An effect index, defined as the maximal performance decrement divided by N-desmethyladinazolam maximum plasma concentration was calculated as a measure of sensitivity to these effects. Adinazolam oral and systemic clearances were reduced approximately 30% and 25%, respectively, in elderly volunteers. Adinazolam half-life was prolonged approximately 40% in the elderly after oral dosing. N-Desmethyladinazolam plasma concentrations and half-life were increased approximately 40% in elderly volunteers. Psychomotor performance decrements were observed following all treatments; decrements were lowest following sustained release tablets and intravenous adinazolam. Maximal performance decrements in elderly subjects were approximately twice those observed in young subjects. No significant influence of age on the effect index for digit-symbol substitution was evident. Effect indices for card-sorting tests were significantly higher in the elderly. Lower clearances of adinazolam and N-desmethyladinazolam are observed in elderly volunteers, and increased N-desmethyladinazolam levels contribute to increased psychomotor performance decrements in elderly subjects. Results also suggest that elderly subjects may be more sensitive to certain cognitive effects of N-desmethyladinazolam.     

Effects of alcoholism, anxiety and depression on P300 in women: a pilot study.

OBJECTIVE: The present investigation was designed for the purpose of revealing functional brain impairments associated with alcoholism, anxiety and depression. METHOD: The subjects were 56 women, with an average (SD) age of 34.8 (7.3) years. None reported a history of neurological or major medical disorders, or drug abuse. Twenty-nine of the women met DSM-IV lifetime criteria for a diagnosis of alcohol abuse or dependence. Twenty-five women reported mild or higher levels of anxiety, as indexed by a Beck Anxiety Inventory (BAI) score greater than 7. Electroencephalographic activity was recorded while subjects performed a visual ("oddball") selective attention task comprised of rare target, rare nontarget and frequent nontarget stimuli. P300 event-related potentials elicited by the rare target and rare nontarget stimuli were analyzed. RESULTS: The initial analysis was structured as a 2 (alcoholism) by 2 (anxiety) factorial. Analyses revealed no significant effects of alcoholism on P300. However, women reporting a BAI score greater than 7 exhibited significantly smaller P300 amplitudes than their nonanxious counterparts. The P300 decrement remained significant when depression level (Beck Depression Inventory [BDI-II]) and age were entered as covariates. A separate analysis was conducted in which the 56 subjects were classified by alcoholism and depression level (BDI-II score < or =13 vs >13). The analysis revealed no significant P300 differences associated with these factors. CONCLUSIONS: It is hypothesized that anxiety might play a role in mediating or amplifying the P300 decrements that have been attributed to alcoholism and depression in women. Additional and more comprehensive studies are needed to discern the validity ofthis hypothesis.