Fluvoxamine for children and adolescents with obsessive-compulsive disorder: a randomized, controlled, multicenter trial.

OBJECTIVE: To determine the safety and efficacy of fluvoxamine for the treatment of children and adolescents with obsessive-compulsive disorder (OCD) with a double-blind, placebo-controlled, multicenter study. METHOD: Subjects, aged 8 to 17 years, meeting DSM-III-R criteria for OCD were recruited from July 1991 to August 1994. After a 7- to 14-day single-blind, placebo washout/screening period, subjects were randomly assigned to fluvoxamine 50 to 200 mg/day or placebo for 10 weeks. Subjects who had not responded after 6 weeks could discontinue the double-blind phase of the study and enter a long-term, open-label trial of fluvoxamine. Analyses used an intent-to-treat sample with a last-observation-carried-forward method. RESULTS: Mean Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) scores with fluvoxamine were significantly (p < .05) different from those with placebo at weeks 1, 2, 3, 4, 6, and 10. Significant (p < .05) differences between fluvoxamine and placebo were observed for all secondary outcome measures at all visits. Based on a 25% reduction of CY-BOCS scores, 42% of subjects taking fluvoxamine were responders compared with 26% taking placebo. Forty-six (19 fluvoxamine, 27 placebo) of 120 randomized subjects discontinued early. Adverse events with a placebo-adjusted rate greater than 10% were insomnia and asthenia. CONCLUSIONS: Fluvoxamine has a rapid onset of action and is well tolerated and efficacious for the short-term treatment of pediatric OCD.

Fluvoxamine maleate in the treatment of depression: a single-center, double-blind, placebo-controlled comparison with imipramine in outpatients.

The efficacy and safety of fluvoxamine maleate, a selective serotonin reuptake inhibitor, was compared with placebo and imipramine in patients with major depressive disorder. Previous literature has cited a dose range of 100 to 300 mg/day of fluvoxamine maleate for the treatment of major depression; however, this study demonstrates that a dose range of 50 to 150 mg/day is as effective as imipramine (80-240 mg/day). After a 1- to 2-week, single-blind, placebo washout phase, 150 depressed outpatients were randomized to double-blind treatment with fluvoxamine maleate (50-150 mg/day), imipramine (80-240 mg/day), or placebo for 6 weeks. Fluvoxamine produced a significant therapeutic benefit over placebo (p < or = 0.05) as assessed by the total score on the Hamilton Rating Scale for Depression; imipramine (80-240 mg/day) produced similar results. The secondary outcome variables (i.e., Clinical Global Impression severity of illness item and 56-Item Hopkins Symptom Checklist depression factor) also showed significant differences between fluvoxamine maleate and placebo during three of the four final weeks of the study. Both fluvoxamine maleate and imipramine appeared to be safe and well tolerated by the majority of patients. As expected from the pharmacology of these agents, the imipramine groups reported more anticholinergic effects (dry mouth, dizziness, and urinary retention) and electrocardiographic effects, whereas the fluvoxamine group reported more nausea, somnolence, and abnormal ejaculation. The majority of these adverse events were mild to moderate and, with the exception of dry mouth (imipramine) and abnormal ejaculation (fluvoxamine), were transient. The data clearly demonstrate the antidepressant activity and tolerability of fluvoxamine maleate (50-150 mg/day) as compared with placebo; it is also as effective as the tricyclic antidepressant imipramine (80-240 mg/day) in patients with major depressive disorder.

Pilot study of MK-462 in migraine.

MK-462 is a potent, selective 5HT1D receptor agonist which may be useful in treating acute migraine. We conducted a double-blind placebo-controlled inpatient study to assess the preliminary efficacy and safety of oral doses of MK-462 20 mg (n = 8) and 40 mg (n = 36) vs placebo (n = 21), administered to 65 male and post-menopausal female migraine patients aged 22-51 with moderate or severe migraine headache. Headache severity and functional disability were measured at 0.5, 1, 1.5, and 2 h post-dose. The 20 mg dose was well tolerated and 4/8 patients obtained relief in headache severity at the 2 h time point. The 40 mg dose was well tolerated and was significantly (p < 0.05) superior to placebo at the 1.5 and 2 h time points (with 27/36 or 75% obtaining relief at 2 h compared to 7/21 or 33% for placebo). Adverse events occurred in 50% of patients on 20 mg MK-462, 72% of those on 40 mg MK-462, and in 52% of placebo-treated subjects. The most common adverse events associated with MK-462 were drowsiness (20 mg 12%; 40 mg 44%; placebo 24%), dry mouth (40 mg 36%; placebo 19%), and lightheadedness/dizziness (40 mg 17%; placebo 10%). Based on these preliminary results, MK-462 appears worthy of continued study for the treatment of acute migraine.

Sertraline safety and efficacy in major depression: a double-blind fixed-dose comparison with placebo.

In a 6-week, randomized, double-blind, multicenter trial, sertraline 50 mg, 100 mg, or 200 mg, or placebo, was administered once daily to 369 patients with DSM-III-defined major depression. Efficacy variables included changes from baseline scores for total Hamilton Rating Scale for Depression (HAMD), HAMD Bech Depression Cluster, Clinical Global Impressions (CGI) Severity, CGI Improvement, and Profile of Mood States Depression/Dejection Factor. For the evaluable-patients analysis, all sertraline groups showed significantly (p < 0.05 or better) greater improvements in all efficacy variables except one when compared with the placebo group. For the all-patients analysis, all efficacy variables in the 50 mg group were statistically significantly (p < 0.05) better than placebo. Side effects increased with increasing dosage but were usually mild and well tolerated. The results of this study show that sertraline 50 mg once daily is as effective as higher dosages for the treatment of major depression with fewer side effects and therapy discontinuations.

A double-blind placebo-controlled study of Org 3770 in depressed outpatients.

90 patients between 18 and 65 years, with a DSM-III diagnosis of moderate or severe major depressive episode, were randomized to 6 weeks of treatment with Org 3770 or placebo in a double-blind trial. On main efficacy parameters, the 17-item HAMD, MADRS and CGI, Org 3770 was significantly superior to placebo (P < or = 0.05) in weeks 1-4 and at endpoint and recommended as continuation treatment to significantly more patients. The tolerability of Org 3770 was good: the only significant differences as compared with placebo were in the incidences of somnolence and increased appetite. The results show that Org 3770 is an effective and well-tolerated drug for the treatment of major depressive disorder.

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 pharmacotherapy (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.

A comparison of paroxetine and placebo in depressed outpatients.

To compare the safety and efficacy of paroxetine (n = 167) and placebo (n = 169), data from 4 centres using the same protocol were pooled. A double-blind parallel group design was used, with therapy lasting 6 weeks. Significant differences between paroxetine- and placebo-treated patients were found on the major efficacy outcome variables by week 2 and on all efficacy variables by week 4 of the study. Improvement on the sleep factor of the Hamilton Rating Scale for Depression was found after 7 d. Observer and patient global efficacy ratings were in agreement by week 4. No serious adverse events occurred, and paroxetine had no clinically significant effects on vital signs or laboratory safety data. Side effects were more common on paroxetine and were similar to other serotonin reuptake inhibitors. In general, these were well tolerated and did not lead to dropout. Symptoms of increased arousal were not seen during early therapy.

Paroxetine versus placebo: a double-blind comparison in depressed patients.

BACKGROUND: Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI). The present study assessed the efficacy and tolerability of paroxetine against placebo in depressed outpatients. METHOD: A double-blind, parallel-group study was undertaken in four stand-alone centers. Patients aged 18-65 years, meeting DSM-III criteria for major depression, and having a Hamilton Rating Scale for Depression (HAM-D) score > or = 18 on the first 17 items of the HAM-D-21 were randomized to paroxetine or placebo for 6 weeks of treatment. Efficacy outcome variables included the HAM-D, the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impressions Scale (CGI), and the Covi Anxiety Scale. Tolerability was assessed by asking a non-leading question. Routine laboratory safety and vital sign data from all four centers were pooled. The primary analysis used the intention-to-treat sample and for efficacy variables the last-observation-carried-forward data set was employed. Statistical methods included one-way analysis of variance for parametric and Fisher exact test for nonparametric variables. RESULTS: Significant differences (p < or = .05) were found between paroxetine and placebo on the HAM-D and CGI by Week 2 and on all efficacy outcome variables by Week 4. Improvement on the HAM-D sleep factor occurred 2 weeks prior to that seen on the retardation factor. Similar results were obtained when an adequate treatment group (therapy for > or = 28 days) was considered. A full clinical response (CGI-severity of illness score 1 or 2) was seen in over 40% of subjects. Adverse events were more common for paroxetine compared with placebo (p < or = .01). Somnolence was twice more common than nervousness. Dropout due to adverse events was similar between therapies. Paroxetine had no clinically significant effect on laboratory safety data or vital signs. CONCLUSION: Paroxetine was an effective, well tolerated, and safe antidepressant. Side effects were typical of the SSRI class of drugs. Symptoms indicative of a nonalerting profile were more common than those associated with alerting effects.

A double-blind comparison of paroxetine and placebo in the treatment of depressed outpatients.

A double-blind, placebo-controlled, randomized trial was carried out to compare the efficacy and tolerability of paroxetine in outpatients with moderate to moderately severe depression without mania. Paroxetine was found to be an effective antidepressant drug when compared to placebo. For most of the measures of efficacy the benefit appeared after two weeks of therapy, but sleep was improved after one week. Patients taking paroxetine complained of more adverse effects than those on placebo; they were mainly gastrointestinal with nausea the most commonly reported.

The safety and efficacy of paroxetine compared with placebo in a double-blind trial of depressed outpatients.

Considerable research shows that serotonin dysfunction is implicated in major depression. Paroxetine is an investigational antidepressant that appears to act by selectively blocking neuronal serotonin uptake. Seventy-two outpatients with moderate-to-severe major depression entered this 6-week, double-blind comparison of paroxetine and placebo. The results showed clear and significant superiority of paroxetine on all of the major outcome variables. These included physician-rated measures such as the Hamilton Rating Scale for Depression and its four factor scores, the Clinical Global Impressions scale, the Montgomery and Asberg Depression Rating Scale, and the Raskin Depression Scale. Results on these agreed well with patient-rated measures like the Hopkins Symptom Checklist and Patient Global Evaluation Scale. Paroxetine was also very well tolerated. Nausea and constipation occurred significantly more often with paroxetine, but only 9% of paroxetine patients dropped out of the study due either in whole or in part to an adverse effect. This compares to 8% of the placebo patients who were discontinued for the same reason. This study suggests that paroxetine is a safe and effective medication for the treatment of major depression.

Double-blind, multicenter comparison of sertraline and amitriptyline in elderly depressed patients.

Two hundred forty-one elderly depressed patients entered the 8-week, double-blind phase of this parallel-group, multicenter study; 161 patients were randomized to receive sertraline (50-200 mg/day) and 80 were randomized to receive amitriptyline (50-150 mg/day). Among evaluable patients, there were no statistically significant differences between treatments in any of the primary efficacy variables: change in total Hamilton Rating Scale for Depression (HAM-D) score (17 items), percentage change in HAM-D score, change in HAM-D Item 1, change in Clinical Global Impressions (CGI) Severity score, change in the Depression Factor of the 56-item Hopkins Symptom Checklist, and the CGI Improvement score at the last visit. Similar results were obtained using data from all patients (intention-to-treat analysis), except that amitriptyline was superior in HAM-D Total score (p = .044). The two drugs produced a similar degree of response: on the basis of the HAM-D criterion, 69.4% of sertraline patients and 62.5% of amitriptyline patients responded, and, on the basis of CGI criterion, 79.5% of sertraline and 73.4% of amitriptyline patients responded. Twenty-eight percent of the sertraline patients withdrew from the study because of a treatment-related side effect and 2.5% (4) because of a laboratory abnormality. In comparison, 35% of the amitriptyline patients withdrew because of treatment-related side effects. Sertraline was associated with a statistically lower frequency of somnolence, dry mouth, constipation, ataxia, and pain and a higher frequency of nausea, anorexia, diarrhea/loose stools, and insomnia; thus, anticholinergic effects were less common and gastrointestinal effects were more common with sertraline than with amitriptyline.(ABSTRACT TRUNCATED AT 250 WORDS)

The risks and benefits of clozapine versus chlorpromazine.

Clozapine is an atypical antipsychotic drug with reduced risk of unwanted neurological effects in comparison with other drugs. In this multicenter study, 151 hospitalized schizophrenic patients were randomly assigned to treatment under double-blind conditions to assess the antipsychotic efficacy and safety of clozapine versus chlorpromazine. All patients exhibited tardive dyskinesia or other extrapyramidal side effects associated with at least two prior neuroleptics. Eleven patients were dropped from treatment due to extrapyramidal symptoms while being treated with chlorpromazine; only one clozapine patient's treatment was terminated for this reason. Clozapine patients exhibited clinical improvement superior to that of chlorpromazine patients as assessed by the Brief Psychiatric Rating and Clinical Global Impression scales. These results suggest that clozapine is well tolerated and may be therapeutically superior to chlorpromazine in treating psychotic behavior. Agranulocytosis potential can be minimized by frequent white blood cell counts and removing nonresponding patients from treatment prior to the peak risk period (months 2 through 6).

Review of clinical and laboratory experiences with molindone hydrochloride.

The literature concerning the pharmacokinetics, pharmacodynamics, receptor physiology, and clinical use of molindone is reviewed. Unanswered questions about the drug are addressed. Although molindone is reputed to have a short half-life (1.5 hours), clinical observations report a prolonged effect from a once-daily dose. Early in treatment, some patients show intolerance due to akathisia or extrapyramidal symptoms. This may be withdrawal dyskinesia due to discontinuation of another drug or an early adverse effect of molindone. Different effects on dopamine receptors have been described, but the significance of these properties for the development of tardive dyskinesia remains unclear.

Comparison of the electrocardiographic effect of dothiepin and amitriptyline.

Electrocardiograms of 65 patients treated with dothiepin, a sulphur substituted tricyclic antidepressant, were compared to those of 57 patients receiving amitriptyline and 62 patients given placebo. Amitriptyline produced an average heart rate increase of 10 beats/minute as compared to 5 beats/minute for dothiepin (p less than .02). Amitriptyline also produced a significant prolongation of the corrected QT interval as compared to both dothiepin and placebo (p less than .01 and p less than .001, respectively). Dothiepin had no significant effect on any index of myocardial conduction (PR interval, corrected QT interval, and QRS duration) as compared to placebo.

Multicenter placebo-controlled evaluation of nomifensine treatment in depressed outpatients.

Outpatients aged 18-65 who met Feighner et al. criteria for primary affective disorder-depression and had Hamilton Depression Rating Scale (HDRS) scores greater than or equal to 20 were randomly assigned to receive nomifensine (N = 61) or placebo (N = 63) for 4 weeks. On all measures of efficacy (HDRS, Clinical Global Impressions, Hopkins Symptom Check List, Brief Psychiatric Rating Scale), patients treated with nomifensine showed significant improvement compared to placebo patients; improvement was evident after 1 week on some scales. No clinically important changes were seen over the course of treatment in findings of physical examinations, ECGs, and clinical laboratory evaluations. Side effects associated with active treatment were mild to moderate in severity and rarely led to cessation of therapy. Thus, significant clinical improvement was seen in these moderately to severely depressed outpatients, without significant adverse experiences.

Kinetic evaluation of platelet monoamine oxidase following relaxation in chronic anxiety.

The effect of relaxation training, utilizing EMG biofeedback, on platelet monoamine oxidase (MAO) activity was examined in patients with a history of chronic anxiety. Anxiety scores and MAO activity were significantly lowered after 4 weeks of therapy. Kinetic studies, using phenylethylamine as substrate, indicated a significant increase of the Km constant while the Vmax showed no significant or consistent variation. It is thought that this phenomenon represents an adaptive response by the individual to maintain a homeostatic level of the biogenic amines.

Somatic symptoms in depression and antidepressants.

Somatic side effects of antidepressant medications and of depression and anxiety were quantified in depressed patients before and after 4 weeks of treatment with amitriptyline (N = 11), or desipramine (N = 12). The entire group showed significant posttreatment decreases in depression. Side-effect symptoms were significantly reduced after treatment in the amitriptyline group; less reduction was seen in the desipramine group. Significant correlations were demonstrated between levels of anxiety and side effect symptoms both before and after treatment. The reduction in side effect symptoms in the amitriptyline group can be explained by the drug's anxiolytic property. Our findings suggest that symptoms resembling antidepressant side effects seen in medicated depressed patients are influenced by the patient's clinical condition more than by the anticholinergic activity of moderate dosages of the antidepressant.