John P. Feighner

Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder : a 4-week placebo-controlled trial

Abstract A double-blind, placebo-controlled, multicenter study, was performed to evaluate the efficacy and safety of ziprasidone in 139 patients with an acute exacerbation of schizophrenia or schizoaffective disorder. Patients were randomized to receive ziprasidone 40 mg/day, 120 mg/day or placebo for 28 days. Ziprasidone 120 mg/day was significantly more effective than placebo in improving the BPRS total, CGI-S, BPRS depression cluster and BPRS anergia cluster scores (all P < 0.05). Similarly, the percentages of patients classified as responders on the BPRS (≥30% reduction) and the CGI improvement (score ≤2) were significantly greater with ziprasidone 120 mg/day compared with placebo (P < 0.05). The number of patients who experienced an adverse event was similar in all three treatment groups, and discontinuation due to adverse events was rare (five of 91 ziprasidone-treated patients). The most frequently reported adverse events, that were more common in either ziprasidone group than in the placebo group, were dyspepsia, constipation, nausea and abdominal pain. There was a notably low incidence extrapyramidal side-effects (including akathisia) and postural hypotension and no pattern of laboratory abnormalities or apparent weight gain. Ziprasidone-treated patients were not clinically different from placebo-treated patients on the Simpson-Angus Rating scale, Barnes Akathisia scale and AIMS assessments. These results indicate that ziprasidone 120 mg/day is effective in the treatment of the positive, negative and affective symptoms of schizophrenia and schizoaffective disorder with a very low side-effect burden.

Venlafaxine for treatment-resistant unipolar depression.

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.

Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression.

&NA; The azapirone class of anxiolytic drugs is being evaluated for clinical use in the treatment of depression. Buspirone, a serotonin (5‐hydroxytryptamine, 5‐HT) partial agonist active at the 5‐HT1A receptor subtype, was evaluated in the treatment of depression in a series of five placebo‐controlled, parallel group studies involving 382 patients with DSM‐III major depression and significant associated anxiety symptoms (both Hamilton depression [HAM‐D] and Hamilton anxiety [HAM‐A] scales ≥ 18). Buspirone therapy was initiated at 15 mg/day with individual dose titration to a maximum of 90 mg/day and resulted in marked improvement in both depressive and anxiety symptoms. Analyses of the composite data base from the five studies show significant (p < 0.05) improvement in mean HAM‐D, HAM‐A, and Clinical Global Impression‐Global Improvement scale ratings for buspirone‐treated compared with placebo‐treated patients. Of particular interest was significant improvement in cardinal depression symptoms, e.g., depressed mood, guilt, work and interest, anergia, and diurnal variation of mood. Subset analyses revealed that patients with melancholic‐type major depression and patients with more severe symptoms (judged by higher initial HAM‐D or HAM‐A total scores) responded better to buspirone than did patients who were less ill. The buspirone dose most frequently associated with clinically significant improvement was 40 mg/day. Gepirone, an analogue of buspirone with highly selective binding affinity for the 5‐HT1A receptor subtype, also shows promise of antidepressant efficacy in preliminary controlled clinical trials. These data suggest that azapirones, which as partial agonists modulate 5‐HT1A receptor function, have clinically important antidepressant properties.

Serotonin-1A Anxiolytics: An Overview

The selective serotonin-1A receptor partial agonist anxiolytics represent a new class of pharmacologic agents that have demonstrated efficacy in the treatment of generalized anxiety disorder (GAD). These compounds offer a completely different pharmacologic approach to this disorder from previous medications. The selective 5-hydroxytryptamine-1A (5-HT1A) anxiolytics buspirone, gepirone, ipsapirone, and SM-3997 have several important new and unique features that will be reviewed in this paper. These features include no cross-tolerance with alcohol or benzodiazepines, no evidence of abuse or misuse potential, and no withdrawal symptoms or rebound anxiety on cessation of therapy. The 5-HT1A anxiolytics have no muscle relaxant, sedative, or anticonvulsant properties and do not impair psychomotor functioning. They do have a slower onset of effect than standard benzodiazepines-clinical response is usually noted in 1-3 weeks. The side effect profile is quite different from that of the benzodiazepines. It includes gastrointestinal symptoms such as nausea and diarrhea, headache, dizziness, and restlessness. Some patients with GAD who have received chronic (greater than 1 month) benzodiazepine therapy may not respond as well to these compounds initially as will patients with no prior benzodiazepine treatment, especially if the benzodiazepine has been discontinued only recently. These compounds, buspirone in particular, have been shown to have excellent maintenance and prophylactic properties and to be well tolerated with long-term therapy (greater than 3 months). Because of their unique mechanism of action and side effect profile, and no evidence of misuse or abuse potential or interference with mental acuity, these compounds represent a definite advance in the pharmacologic management of GAD.

A placebo-controlled inpatient comparison of fluvoxamine maleate and imipramine in major depression.

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. Fluvoxamines 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.

A Double-blind Comparison of Fluoxetine, Imipramine and Placebo in Outpatients with Major Depression

Fluoxetine is the first selective serotonin reuptake inhibitor antidepressant to be marketed in the U.S. In this double-blind trial fluoxetine was compared with imipramine and placebo among 198 outpatients with DSM-III major depression, of whom 145 completed at least 2 weeks of active treatment and were evaluated for efficacy. Significantly fewer patients in each active drug group terminated early due to lack of efficacy compared to placebo. Both imipramine and fluoxetine were significantly superior to placebo on most measures. There were no consistently significant differences between the two active drugs although a trend favored imipramine on a number of measures. Fluoxetine was generally well tolerated. Significantly more imipramine than placebo patients terminated early due to side-effects while the fluoxetine-placebo difference was not significant. The results support previous studies which suggest fluoxetines superior side-effect profile and the approximate antidepressant equivalence of fluoxetine and TCAs.

A double-blind comparison of paroxetine with imipramine in the long-term treatment of depression.

The chronic and recurrent nature of major depression is well recognized, and recent data suggest that maintenance therapy with full-dose phar-macotherapy (i.e., the dose used to treat the index episode) is effective in preventing relapse and recurrence. We present results from a 1-year, double-blind trial of paroxetine and imipramine in patients who successfully completed a 6-week acute course of therapy. A total of 717 outpatients were included in the 6-week, randomized, double-blind, placebo-controlled comparative study of paroxetine and imipramine conducted at six centers. At the end of the acute treatment phase, patients showing a therapeutic response were eligible to enter a long-term extension of the study in which they would continue to receive the same drug (or placebo) in double-blind fashion for up to 1 year. Of the 219 patients who entered the long-term phase, 94 received paroxetine, 79 received imipramine, and 46 received placebo. During the 1-year maintenance study, both paroxetine and imipramine were more effective than placebo in maintaining euthymia among patients who had responded to short-term treatment. However, approximately twice as many imipramine-treated patients dropped out of the study prematurely because of adverse experiences compared to paroxetine-treated patients, suggesting that paroxetine is more readily tolerated than imipramine during long-term treatment.

Double-blind comparison of doxepin versus bupropion in outpatients with a major depressive disorder

A double-blind controlled study comparing the effects of bupropion to doxepin in outpatients with primary depression was conducted to evaluate efficacy and safety differences between the two drugs. Following a 7-day placebo washout period, patients could be treated for up to 13 weeks on either treatment. Antidepressant response was assessed by the Hamilton Depression and Anxiety Scales, Clinical Global Severity and Improvement Ratings, and the Zung Self-Rating Depression Scale. Comparable efficacy between the compounds was found across the 13-week study. Doxepin differed from bupropion mainly on the sleep factor of the Hamilton Depression Scale, with doxepin improving sleep to a greater extent than bupropion. Doxepin produced a greater incidence of anticholinergic side effects, including dry mouth, constipation, sleepiness, and tiredness, in comparison to bupropion. Also, increased appetite and weight gain were consistent side effects of doxepin relative to bupropion.

A placebo-controlled multicenter trial of Limbitrol versus its components (amitriptyline and chlordiazepoxide) in the symptomatic treatment of depressive illness.

In a multicenter, placebo-controlled, clinical trial, the efficacy of Limbitrol was compared with that of its components, amitriptyline and chlordiazepoxide. All patients had a diagnosis of primary depression. Data from 279 patients were evaluated using the Hamilton depression scale, the Beck depression inventory, and physician and patient global change measures.Statistically significant differences favoring Limbitrol occurred after 1 week of treatment, and a trend in favor of Limbitrol continued throughout the remaining 3 weeks. In most efficacy comparisons, the combination was as good as, or better than, amitriptyline alone. It was superior to chlordiazepoxide alone after 2 and 4 weeks of treatment. Each component produced an independent contribution to the total therapeutic effect: the chlordiazepoxide effect was more prominent in the first 2 weeks and the amitriptyline effect in the latter 2 weeks. A trend favoring amitriptyline over chlordiazepoxide was evident by week 4.The overall incidence of side effects was comparable in both Limbitrol- and amitriptyline-treated groups. Limbitrol-treated patients exhibited more sedation, but significantly fewer Limbitrol patients discontinued treatment prematurely because of side effects.

Overview of USA controlled trials of trazodone in clinical depression

Trazodones unique chemical structure reflects its distinct pharmacologic profile. Its antidepressant efficacy is postulated to occur through serotonin reuptake inhibition. It has little effect on other neurotransmitter systems. In the United States it has been studied in several double-blind trials which compared it to standard antidepressants and placebo. Both in- and outpatients spanning a spectrum of age and diagnoses have been studied. Trazodone has been shown to be at least as effective as standard antidepressants. There are few anticholinergic or cardiovascular side effects. Adverse reactions include drowsiness, dizziness, headache, nausea and rarely, priapism. It is relatively safe in overdose. Trazodone deserves special consideration in the treatment of patients with depression accompanied by marked agitation, anxiety, and insomnia, as well as those unable to tolerate anticholinergic side effects.