Early onset of antidepressant action of venlafaxine: pattern analysis in intent-to-treat patients.

Pattern analysis has been used to distinguish between the true effect of an antidepressant and a placebo effect. The placebo effect constitutes clinical improvement that is attributable to the caregiver, treatment setting, or placebo substance. Pattern analysis allows identification of patients who have early persistent responses, delayed persistent responses, or no responses to a drug. In our study, we used this method to assess the onset and persistence of antidepressant activity of high daily doses of venlafaxine. Our analysis considered scores on the Global Improvement item of the Clinical Global Impressions scale for intent-to-treat patients in two double-masked, placebo-controlled studies of at least 6 weeks' duration. Dosages in both studies were rapidly titrated upward so patients received at least 200 mg/d within the first week of treatment. Improvement within the first 2 weeks was considered early, and improvement not followed by a relapse through the scheduled end of treatment was considered persistent. Significantly greater percentages of patients in the venlafaxine group (27% and 20% in study 1 and study 2, respectively) than in the placebo group (9% and 2%, respectively) had a clinically meaningful drug response within the first 2 weeks of treatment. This early response persisted for the duration of each trial. We concluded that venlafaxine in dosages of at least 200 mg/d demonstrates an early and persistent onset of efficacy compared with placebo.

A randomized, placebo-controlled, dose-response trial of venlafaxine hydrochloride in the treatment of major depression.

BACKGROUND: We examined the efficacy and safety of three different dosages of venlafaxine hydrochloride (75, 225, and 375 mg/day) in a multicenter, randomized, double-blind, placebo-controlled, four-group study. METHOD: Outpatients, 18 to 65 years old, who met DSM-III criteria for major depression were included (N = 358 randomized; 194 completed). Of the total patients completing the trial, 59%, 56%, 51%, and 51% were in the placebo, 75-mg, 225-mg, and 375-mg groups, respectively. The primary outcome measures were the Hamilton Rating Scale for Depression (HAM-D21) total, HAM-D21 depression item, Montgomery-Asberg Depression Rating Scale total, and Clinical Global Impressions scale. RESULTS: Each dosage of venlafaxine was associated with statistically significant improvement as compared with placebo, based on the intent-to-treat sample. The two higher dosages were associated with a modestly greater antidepressant response than was the 75-mg dosage. Nausea, dizziness, somnolence, and anorexia were the most common adverse events attributable to venlafaxine. Since headache occurred at a similar frequency in both the drug and placebo groups, we did not consider it to be attributable to venlafaxine use. Withdrawal from the study due to adverse events occurred in 5%, 17%, 24%, and 30% of the patients in the placebo, 75-mg, 225-mg, and 375-mg groups, respectively. CONCLUSION: Venlafaxine, at dosages of 75-375 mg/day, is an effective and well-tolerated antidepressant. With increasing dosage, greater efficacy and possibly more adverse effects will occur.

Effects of age and gender on venlafaxine and O-desmethylvenlafaxine pharmacokinetics.

This single- and multiple-dose, nonrandomized, inpatient study was conducted to determine the effects of age and gender on the pharmacokinetic profiles of the antidepressant venlafaxine and its equally active metabolite, O-desmethylvenlafaxine. The subjects were 18 elderly (age 60-80 yrs) and 18 young (age 21-44 yrs) subjects, 9 men and 9 women per age group. They received a single 50-mg venlafaxine dose followed by 50-mg doses every 8 hours for 5 days. No significant differences in venlafaxine single-dose pharmacokinetics were seen between age groups, but the steady-state half-life increased 24% in the elderly. For O-desmethylvenlafaxine, single doses had a significantly lower apparent clearance in the elderly (0.29 vs 0.38 L/hr/kg), longer half-life (13.2 vs 10.3 hrs), and 14% greater steady-state half-life. For the composite (venlafaxine+O-desmethylvenlafaxine), there was a nonsignificant 16% increase in elderly steady-state area under the curve (AUC* = AUC+activity factor AUCm), and AUC* was linear between doses and age groups. We conclude that venlafaxine dosage adjustments for age or gender are not necessary based on pharmacokinetics.

The safety and tolerability of venlafaxine hydrochloride: analysis of the clinical trials database.

The tolerability and safety of venlafaxine hydrochloride, a new serotonin and norepinephrine reuptake inhibitor, are reviewed in this article. The data presented here are based on a pool of 3,082 patients who were treated with this agent during clinical trials. Of these patients, 2,897 received venlafaxine for depression; 455 of these patients were treated for more than 360 days. The tolerability and safety profiles of venlafaxine were similar to those previously reported for selective serotonin reuptake inhibitors. Patients receiving venlafaxine experienced nausea, insomnia, dizziness, somnolence, constipation, and sweating more often than did patients receiving placebo but reported anticholinergic events less frequently than did patients receiving tricyclics. This is accounted for by the fact that, unlike the tricyclics, venlafaxine lacks significant affinity for muscarinic cholinergic receptors. Resolution of venlafaxine-associated nausea occurred rapidly in the vast majority of the patients who reported it at the start of therapy. Serious adverse events were rare among venlafaxine-treated patients. A small percentage of the patients given venlafaxine experienced modest but significant increases in blood-pressure readings, similar to those observed among imipramine-treated patients. At mean daily venlafaxine dosages of up to 300 mg, the percentage of venlafaxine-treated patients who had sustained elevations in supine diastolic blood pressure during treatment ranged from 2% to 6%, compared with 2% and 5% among the placebo- and imipramine-treated patients, respectively. All of the 14 patients who took an overdose of venlafaxine recovered without sequelae. Tolerability and safety in the elderly did not differ significantly from that observed in younger patients.

Zalospirone in major depression: a placebo-controlled multicenter study.

Compounds active at the serotonin (5-HT)1A receptor (mostly azapirones) have shown some evidence of antidepressant effect. We report here the results of an antidepressant trial with zalospirone, a novel cyclic imide with 5-HT1A partial agonist activity. Two hundred eighty-seven outpatients (mean age 44 years, 55% men, 45% nonfertile women) who met criteria for unipolar major depression with a minimum 21-item Hamilton Rating Scale for Depression (HAM-D) score of 20 were randomly assigned to receive 6 weeks of double-blind treatment with either placebo or one of three fixed doses of zalospirone (6, 15, or 45 mg/day), administered three times daily. The high dose (45 mg) of zalospirone produced a significant antidepressant effect compared with placebo from week 2 on with mean improvement (change from baseline) in HAM-D total score of 12.8 versus 8.4 (p < 0.05) at week 6. Clinical improvement with the high dose of zalospirone was consistent across all outcome measures, however, only in the observed cases and not the last-observation-carried-forward analyses. Improvement with the 6-mg or 15-mg doses was greater than that with placebo, but not significantly so, suggesting a dose-response effect. Although the 45-mg dose of zalospirone seemed to have significant antidepressant efficacy, it was not well tolerated. Dizziness and nausea were noted in almost half of the patients, and by week six, 51% of patients in the high-dose group had dropped out. Whether or not tolerance to this high dose might be improved by gradual drug titration, only future research can answer.

Antidepressants: can we determine how quickly they work? Issues from the literature.

Published reports of antidepressants in clinical trials were reviewed by conducting a literature search focusing on the time period between 1969 and 1994; 240 English-language articles were identified. In these, considerable variation was noted in how study data were evaluated. A few particular points of view concerning antidepressant speed of onset were abstracted. These demonstrate that both antidepressant and placebo treatment of depressed patients are associated with measurable clinical activity during the first weeks of therapy. Methods currently exist to determine speed of antidepressant onset. However, at least one proposed method (Quitkin's pattern analysis) has not yet identified any fast-acting antidepressants. Further work is needed to refine the methods of studying antidepressant onset of action. It is most important that antidepressant drugs with early, clinically relevant onset of activity be identified.

Venlafaxine: measuring the onset of antidepressant action.

Venlafaxine, a new antidepressant, inhibits reuptake of norepinephrine and serotonin without appreciable effects on histaminergic, alpha-adrenergic, or cholinergic systems. Pharmacologically the drug is unique: the half-life is short and it exerts both rapid and prolonged beta-adrenergic desensitization after single doses in a rodent model. Venlafaxine has been thought to possess a rapid onset of clinical antidepressant action. Accordingly, two clinical studies in which moderate amounts of venlafaxine were given aggressively were reviewed to examine aspects of the drug's onset of action. Three statistical methodologies were employed--traditional analysis of depression scale scores, pattern analysis based on timing and persistence of response, and survival analysis of sustained response. All three methods showed venlafaxine to have significant effects early in the course of therapy. In addition, venlafaxine is the first drug to meet criteria for early onset using the pattern analysis methodology. Depressed patients aggressively treated with venlafaxine show significant benefit on or before Day 7 of treatment using traditional methods of analysis as well as survival analysis of sustained response.

Double-blind study of lorazepam and diazepam in status epilepticus.

Lorazepam was compared with diazepam for the treatment of status epilepticus in a double-blind, randomized trial. Seventy-eight patients with 81 episodes were enrolled. Patients received one or two doses of either 4 mg of lorazepam or 10 mg of diazepam intravenously. Seizures were controlled in 89% of the episodes treated with lorazepam and in 76% treated with diazepam. The times for onset of action of the medications did not differ significantly. Adverse effects occurred in 13% of the lorazepam-treated patients and in 12% of the diazepam-treated patients. Respiratory depression and arrest, the most frequent adverse effects, were treated symptomatically; no adverse sequelae were noted.

Infantile autism. I: A prospective study of the diagnosis.

A prospective study was made of 200 consecutive children to evaluate the usefulness in the diagnosis of infantile autism of the behavioral scale reported by Clancy and coworkers in 1969. On this scale seven or more of 14 behavioral manifestations must be present before a diagnosis of autism can be made. Using this scale alone, 48 of the 200 children studied were "scale positive", i.e. could be considered autistic. However, further study of this group showed that only one child fulfilled the classical criteria of Kanner (1943) for a diagnosis of early infantile autism. Scale "positivity" was found to correlate with mental retardation and to be associated with other developmental defects, especially learning disorders and hearing loss.