Nemifitide is a novel pentapeptide antidepressant, which appears to be effective in the treatment of major depressive disorder (MDD). In the present study 81 patients with MDD, DSM-IV criteria were ...randomized following a 1-wk screening period to receive 30 mg/d nemifitide, 45 mg/d nemifitide or placebo in a 6-wk double-blind, multicentre, outpatient efficacy study. Nemifitide or placebo was delivered by subcutaneous injection for 2 wk daily for 5 days (Monday to Friday) in the first 2 wk and patients were followed up for a further 4 wk. The primary efficacy measure was the change from baseline on the Montgomery–Asberg Depression Rating Scale. Secondary measures included the 17-item Hamilton Psychiatric Rating Scale for Depression (HAMD), the CGI severity and improvement scale and the Carroll Self-Rating Scale for Depression. This proof-of-principle study demonstrated a statistically significant superiority of the 45-mg/d dose vs. placebo at the time-point of peak effect (1 wk after the end of treatment). There appeared to be a greater effect with the 45 mg/d nemifitide dose than with 30 mg/d. An additional exploratory analysis by stratification of all patients by severity above and below or equal to the median baseline HAMD score of 22 showed a higher percentage of responders for both doses of nemifitide with statistical separation from placebo for patients with baseline HAMD score of >22 (above the median). There was no significant difference among treatment groups for patients with baseline HAMD score of les 22. Nemifitide showed a good tolerability and safety profile. There were no dropouts due to adverse events, and the incidence of side-effects with nemifitide was comparable with that of placebo.
The effects of once-daily venlafaxine extended release (XR) 75–225 mg/day on symptoms of anxiety in depressed outpatients were assessed in two randomized, double-blind, placebo-controlled trials. In ...study 1, venlafaxine XR was significantly (
p≤0.05) more effective than placebo by week 4 in relieving anxiety symptoms among patients with moderate or greater anxiety (anxiety-psychic item score ≥2) at baseline. Among patients with severe (anxiety-psychic item score ≥3) anxiety, venlafaxine XR was significantly (
p≤0.05) more effective than placebo beginning at week 6. In study 2, among patients with moderate or greater anxiety (score ≥2) at baseline, a significant reduction (
p≤0.05–≤0.001) in HAM-D anxiety-psychic item scores was noted with venlafaxine XR compared with placebo from weeks 1 to 8. Among patients with severe anxiety (score ≥3) at baseline, venlafaxine XR produced a significant reduction (
p≤0.05–≤0.001) in the anxiety-psychic item score compared with placebo from weeks 1 to 8. Discontinuation for adverse events occurred in 11% of patients on venlafaxine XR, and the most common adverse events were nausea, dizziness, insomnia, somnolence and dry mouth. These results indicate that once-daily venlafaxine XR is effective for the treatment of anxiety symptoms associated with major depression in doses ranging from 75 to 225 mg/day.
Cardiovascular side effects from antidepressant drugs, including clinically significant blood pressure changes, conduction disturbances, and arrhythmias may complicate long-term therapy. ...Cardiovascular effects are most common with tricyclic antidepressants, but occur rarely with most antidepressants. Venlafaxine is a unique antidepressant with a broad spectrum of antidepressant activity and a safety profile that resembles serotonin selective reuptake inhibitors.
A MEDLINE search of the literature in the English language for the past 15 years was conducted, and the venlafaxine new drug application data base was reviewed.
Clinically significant conduction abnormalities or arrhythmias have not been reported with venlafaxine; however, this drug has not been studied in patients with underlying cardiovascular disease. A dose-related increase in mean blood pressure has been observed. In placebo-controlled studies with venlafaxine, clinically significant increases in blood pressure (increase in diastolic blood pressure of > or = 15 mm Hg and to > or = 105 mm Hg from baseline) were observed in 5.5% of patients at doses above 200 mg daily. The mean increase in diastolic blood pressure was 7 mm Hg after 6 weeks of treatment with doses of 300 to 375 mg daily. In comparative trials, the overall incidence of clinically significant blood pressure increases with venlafaxine was similar to that of tricyclic antidepressants.
Overall, venlafaxine has a low incidence of clinically significant increases in blood pressure at doses below 200 mg daily. As with other antidepressants that may affect blood pressure, the clinician should periodically monitor blood pressure in patients treated with venlafaxine.
The mechanism of action of the novel antidepressant bupropion remains unclear after many years of study. A review of the relevant biochemical, in vivo brain microdialysis, electrophysiologic, ...behavioral, and clinical data clarifies what is known about this unique compound and suggests possible modes of action.
A panel of 11 experts was convened for a conference to discuss bupropion's mechanism of antidepressant activity. Four of the panelists presented current research findings, followed by a discussion.
(1) Biochemical studies suggest down-regulation of postsynaptic beta-adrenoceptors and desensitization of the norepinephrine-stimulated adenylate cyclase in the rat cortex occur only after chronic administration of very high doses of bupropion. (2) In vivo brain microdialysis studies demonstrate that, after chronic administration, there is an enhancement of bupropion-induced increases in extracellular dopamine in the nucleus accumbens. (3) Electrophysiologic data show that with acute dosing, bupropion reduces the firing rates of noradrenergic neurons in the locus ceruleus. The firing rates of dopaminergic neurons are reduced by bupropion in the A9 and A10 areas of the brain, but only at very high doses, and bupropion does not alter the firing rates of serotonergic neurons in the dorsal raphe. (4) Behavioral studies show that the most active metabolite of bupropion, hydroxybupropion (306U73), appears to be responsible for a large part of the compound's effects in animal models of antidepressant activity. (5) Clinical studies indicate that bupropion enhances noradrenergic functional activity as reflected by an increased excretion of the hydroxy metabolite of melatonin, while at the same time producing a presumably compensatory decrease in norepinephrine turnover. In one study, bupropion elevated plasma levels of the dopamine metabolite homovanillic acid in nonresponders, but not in responders.
The mechanism of action of bupropion appears to have an unusual, not fully understood, noradrenergic link. The bupropion metabolite hydroxybupropion probably plays a critical role in bupropion's antidepressant activity, which appears to be predominantly associated with long-term noradrenergic effects. The mild central nervous system activating effects of bupropion appear to be due to weak dopaminergic mechanisms. There is some evidence that dopamine may contribute to bupropion's antidepressant properties. Antidepressant effects of bupropion are not serotonergically mediated.
Data from two Phase 2 clinical studies with nemifitide, a novel pentapeptide antidepressant, were evaluated. The initial double-blind, placebo-controlled study was performed on outpatients with ...DSM-IV criteria for major depressive disorder. An open-label extension study enrolled subjects either completing or having been discontinued due to lack of efficacy during the follow-up period of the initial study. In the extension study, both the investigator and the subjects were blinded to the previous treatment in the initial study. No clinically significant side-effects were observed in either study. Twenty-seven subjects have been entered and evaluated in the extension study. Eighteen of these 27 subjects (66.7%) responded to re-treatment in the extension study. Mean duration of effect between re-treatments was 3.3 months. The results of the extension study support investigating a range of doses of nemifitide from 18 to 72 mg/d in future clinical trials. Further studies are planned to determine the most effective nemifitide clinical treatment regimen.
Cluster analysis was used to evaluate the data from a placebo-controlled, double-blind clinical trial with a new
pentapeptide antidepressant (INN 00835) in major depression. The objective of this ...paper is to examine the
effect of separating the study population into homogeneous subgroups (clusters) with relatively similar
response to treatment within subgroups, and significantly different response between subgroups. The list of
variables for cluster analysis was selected only from the efficacy parameters investigated in the study. Three
to six clusters were modelled to obtain the optimal number of clusters, based on a proportional contribution
of subjects per cluster, and the maximum statistical difference between clusters. After separation, the variability
of response among drug-treated subjects by cluster was attributed to plasma drug concentration. Platelet
serotonin uptake, which is a putative biochemical marker of effective treatment of depression, also reproduced
the same effect of separation as the initially established cluster variables.
A simulation decision analytical model was used to compare the annual direct medical costs of treating patients with major depression using the selective serotonin reuptake inhibitor (SSRI) ...paroxetine or the tricyclic antidepressant (TCA) imipramine. Medical treatment patterns were determined from focus groups of general and family practitioners and psychiatrists in Boston, Dallas and Chicago, US. Direct medical costs included the wholesale drug acquisition costs (based on a 6-month course of drug therapy), psychiatrist and/or general practitioner visits, hospital outpatient visits, hospitalisation and electroconvulsive therapy. Acute phase treatment failure rates were derived from an intention-to-treat analysis of a previously published trial of paroxetine, imipramine and placebo in patients with major depression. Maintenance phase relapse rates were obtained from a 12-month trial of paroxetine, supplemented from the medical literature. The relapse rates for the final 6 months of the year were obtained from medical literature and expert opinion. Direct medical costs were estimated from a health insurance claims database. The estimated total direct medical cost per patient was slightly lower using paroxetine ($US2348) than generic imipramine ($US2448) as first-line therapy. This result was sensitive to short term dropout rates but robust to changes in other major parameters, including hospitalisation costs and relapse rates. The financial benefit of paroxetine, despite its 15-fold higher acquisition cost compared with imipramine, is attributable to a higher rate of completion of the initial course of therapy and consequent reduced hospitalisation rates.
The purpose of this study is to evaluate the novel antidepressant venlafaxine for the management of treatment-resistant unipolar depression. We gave unblinded venlafaxine to 84 consecutive ...outpatients and inpatients who met DSM-III-R criteria for major depression and who had failed to respond to at least three adequate trials of antidepressants from at least two different antidepressant classes or electroconvulsive therapy, plus at least one attempt at augmentation. Patients were evaluated after a drug free period at baseline and regular intervals with the 21-item Hamilton Rating Scale for Depression (HAM-D-21), Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions Scale Improvement item (CGI). Full response for each scale was defined as follows: HAM-D-21 score of 8 or lower, a MADRS score of 12 or lower, and CGI score of 1; partial responses was defined as a 50% decrease in the HAM-D and MADRS, with final scores greater than 8 and 12, respectively, and for the CGI, a score equal to 2. About a third of patients were considered to be either full or partial responders (32.9% by HAM-D-21, 30.0% by MADRS, and 40% by CGI) after 12 weeks of venlafaxine treatment. To date, about 46% of responders have sustained their response for at least 3 months after the acute response. Venlafaxine is effective for a significant, but small, minority of patients with rigorously defined triple-resistant depression; the improvement was maintained for about half of the responders for the first 3 months of maintenance therapy.
Alprazolam is the first of the triazolobenzodiazepines to be studied in a large population of depressed patients. In a six-week, double-blind multicenter comparison of alprazolam, imipramine ...hydrochloride, and placebo in the treatment of 723 patients with depression, the two active drugs were statistically more effective than placebo. Alprazolam was at least as effective as imipramine in relieving depressive symptoms, significantly more effective in relieving somatic symptoms, and showed an earlier onset of activity in some measurements. Anticholinergic side effects were reported most often by patients receiving imipramine, while drowsiness was the only side effect reported most often in the alprazolam group. The Feighner Diagnostic Criteria and prestudy and poststudy intercenter conferences with videotaped patient interviews ensured interrater reliability.
Fluvoxamine, a selective serotonin reuptake inhibitor, was investigated in a 6-week double-blind study among severely ill inpatients with DSM-III major depression. All but 1 patient also fulfilled ...criteria for melancholia. Following a 3-day placebo wash-out patients were randomly assigned to fluvoxamine, imipramine or placebo. Sixty of 81 patients completed at least 2 weeks following wash-out and were evaluated for efficacy. Analysis of covariance (controlling for baseline scores) showed significant (p less than 0.05) differences on CGI severity and BPRS total and a similar trend (p = 0.08) on the Hamilton Depression Scale. Fluvoxamine was superior (p less than or equal to 0.02) to both placebo and imipramine on these measures. Fluvoxamine's most common adverse effects were nausea and agitation. The number of fluvoxamine patients withdrawn for side-effects was less than imipramine and not significantly different than placebo. Fluvoxamine was not associated with significant changes in vital signs, ECG or laboratory tests. The results therefore indicate that fluvoxamine is a safe and highly effective treatment for hospitalized patients with major depression.
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