Effects of reboxetine on Hamilton Depression Rating Scale factors from randomized, placebo-controlled trials in major depression.

Reboxetine is the first selective norepinephrine reuptake inhibitor (NRI) approved for the treatment of major depressive disorder (MDD). Although reboxetine has demonstrated efficacy for the treatment of depression, its effects on specific depressive symptoms have not been reported. We evaluated the effects of reboxetine on four Hamilton Depression Rating Scale (HAM-D) factors: psychomotor retardation, anxiety, cognitive disturbance and insomnia. Data were obtained from four short-term (4-8-week), randomized, placebo-controlled trials of reboxetine for the treatment of MDD. For each study, mean changes in HAM-D symptom factor scores from randomization to the study endpoint were compared between reboxetine and placebo. In addition, data from all four studies were pooled to determine the proportions of patients who either improved or worsened with treatment were compared between placebo (n = 353) and reboxetine (n = 350) treatment groups. Compared to placebo, reboxetine significantly improved psychomotor retardation in all four trials. Cognitive disturbance and anxiety were improved in three of four trials, and insomnia was improved in one trial with a positive trend in the second trial. Reboxetine, a selective NRI, improves symptoms of psychomotor retardation, anxiety and cognitive disturbance during treatment of MDD.

Double-blind comparison of citalopram and placebo in depressed outpatients with melancholia.

This multicenter study compared the efficacy and safety of citalopram and placebo in a population of moderately to severely depressed patients with melancholia. This randomized, double-blind, parallel-group study compared citalopram (flexible dose; 20-80 mg/day) with placebo in 180 psychiatric outpatients with a DSM-III diagnosis of major depression or bipolar disorder, depressed, who also met DSM-III criteria for melancholia. Following a 1-week placebo washout period, patients meeting study entry criteria were randomized to 4 weeks of double-blind treatment with either citalopram or placebo. Efficacy measures included the Hamilton Rating Scale for Depression (HAM-D), the Clinical Global Impressions (CGI) Scale, and the Zung Self-Rating Depression Scale. Patients treated with citalopram showed significantly greater improvement at endpoint than placebo patients on the HAM-D, CGI, and Zung scales. On the HAM-D, citalopram patients exhibited significantly greater improvement than placebo patients after 1 week of double-blind treatment and at all subsequent study visits. Endpoint analyses of the HAM-D subscales demonstrated that citalopram produced significant improvement of the psychomotor retardation, cognitive disturbance, sleep disturbance, and melancholia symptom clusters. Nausea, dry mouth, somnolence, dizziness, and increased sweating were reported at higher rates by citalopram-treated patients than by placebo-treated patients, but there were no significant citalopram-placebo differences in the incidence of activation (e.g., anxiety, nervousness, insomnia) or sexual dysfunction. Analysis of electrocardiograms, vital signs, and laboratory tests did not reveal any clinically significant effects of citalopram treatment. The results of this study indicate that citalopram is safe and effective in the treatment of depressed patients with melancholia, and is associated with a favorable side effect profile and a potentially rapid onset of action.

Sibutramine produces dose-related weight loss.

OBJECTIVE: Sibutramine is a weight control drug that inhibits the reuptake of both serotonin and norepinephrine. In animals, it reduces food intake and increases thermogenesis and preliminary data in human beings showed weight loss. This paper reports a 24-week dose-ranging study to determine the effect of sibutramine on body weight of patients with obesity. RESEARCH METHODS AND PROCEDURES: Seven clinical centers screened 1463 patients with obesity and randomized 1047 to 24 weeks of treatment with 1 of 6 doses of sibutramine (1, 5, 10, 15, 20, or 30 mg) or placebo once daily. Six hundred eighty-three patients completed the study. A two-week placebo run-in period was used to initiate a standardized program of diet, physical activity, and lifestyle changes. RESULTS: Weight loss was dose-related and statistically significant vs. placebo (p<0.05) across all time-points for a 5 mg/day to 30 mg/day dosage of sibutramine. At week 24, percent weight loss from baseline for completers was: placebo, 1.2%; 1 mg, 2.7%; 5 mg, 3.9%; 10 mg, 6.1%; 15 mg, 7.4%; 20 mg, 8.8%; and 30 mg, 9.4%. Weight loss achieved at week 4 was predictive of weight loss achieved at week 24. Patients losing weight demonstrated an increase in serum high density lipoprotein cholesterol and reductions in serum triglycerides, total cholesterol, low density lipoprotein cholesterol, and uric acid. Small mean increases in blood pressure and pulse rate (with considerable individual variability) were observed in patients treated with sibutramine. The most frequent adverse events were dry mouth, anorexia, and insomnia. DISCUSSION: Sibutramine administered once daily for 24 weeks in the weight loss phase of treatment for uncomplicated obesity produced dose-related weight loss and was well tolerated. Improvements in serum lipids and uric acid accompany sibutramine-induced weight loss. Most of the adverse events observed on sibutramine are related to its pharmacology, including small mean increases in blood pressure and heart rate.

A 2-year study of sertraline in the treatment of obsessive-compulsive disorder.

The present study investigated the tolerability, safety profile, and anti-obsessional efficacy of sertraline, a selective serotonin reuptake inhibitor, during long-term treatment of patients with obsessive-compulsive disorder (OCD). Fifty-nine OCD patients who had completed a 1 year double-blind, fixed dose study comparing sertraline and placebo subsequently entered a 1-year open extension. Among the 51 patients who had been treated with sertraline during the double-blind phase, the mean total duration of sertraline treatment was 690 days. Only treatment responders who completed the 52-week double-blind treatment phase were permitted to enter the open extension. The higher rate (p < 0.02) of sertraline patients (51 out of 241) than of placebo patients (eight out of 84), who responded to treatment and entered the open-label phase is therefore consistent with the greater mean improvement observed in the sertraline group during double-blind treatment. Placebo responders differed from sertraline responders in that they were less impaired at baseline of the double-blind study [Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) of 18.5 versus 23.4] and they exhibited less improvement during double-blind treatment (-6.1 versus -11.4). In the open-label phase all patients received sertraline at a starting dose of 50 mg once a day, titrated in 50 mg increments to a maximum dose of 200 mg according to clinical response. At end-point the mean Y-BOCS score for all patients decreased by a further 3.6 points. Patients previously treated with placebo showed greater improvement after being switched to sertraline than those who received continued sertraline treatment. Patients who completed the study and received 2 full years of sertraline treatment (n = 38) exhibited a mean improvement of 15.6 points using the Y-BOCS. Sertraline was well tolerated during both the double-blind phase and the open extension, and the incidence of adverse experiences was generally reduced during the second year of treatment. Three patients discontinued open treatment because of adverse experiences. Long-term sertraline treatment did not appear to be associated with the emergence, increased incidence, or increased severity of adverse experiences or clinically significant abnormalities in laboratory tests, vital signs, or the electrocardiogram. The study supports the long-term safety and tolerability of sertraline over a 2-year treatment course and the sustained efficacy of sertraline in patients with OCD.

Nefazodone in the treatment of severe, melancholic, and recurrent depression.

The development of a new antidepressant medication is usually accompanied by a concern as to whether or not the compound will be sufficiently effective in clinically important subgroups of patients (e.g., depressed patients with increased severity of symptomatology, patients with melancholic features, and patients whose illness is recurrent). This paper describes results of a pooled analysis of four placebo-controlled studies included in the development program of the antidepressant nefazodone. These studies involved a total of 247 patients receiving nefazodone in a dose of up to 600 mg/day, 251 patients on placebo, and 166 patients receiving imipramine. For purposes of the analysis, patients were defined as being more severely depressed (Clinical Global Impressions scale [CGI] psychopathology score of at least markedly ill), having melancholia using DSM-III-R criteria, or having recurrent major depression (using DSM-III-R criteria). Efficacy was assessed by improvement in the Hamilton Rating Scale for Depression (17 items; HAM-D-17) Total score and CGI scale. Nefazodone (mean dose at endpoint = 379 mg/day) was effective in the management of depressed patients with moderate or severe symptomatology, depressed patients with or without melancholic features, and patients with single or recurrent episodes of depression.

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.

Sertraline treatment for premature ejaculation.

This study was designed to examine the efficacy and safety of sertraline as a treatment for premature ejaculation. Fifty-two heterosexual male patients with self-reported premature ejaculation were randomly assigned to receive either sertraline or placebo. After a 1-week placebo washout period, the dose was titrated during treatment weeks 1 to 3 from 50 to 200 mg of sertraline per day until clinical response was optimal or dose-limiting adverse experiences emerged. Medication was maintained at this level through week 8. The primary outcome measures used to assess efficacy included patient assessment of time to ejaculation (from penetration), number of successful attempts at intercourse, and incidence of ejaculation during foreplay. Sertraline treatment produced significant improvements relative to placebo in time to ejaculation and number of successful attempts at intercourse, as well as overall clinical judgements of improvement. Medication was well tolerated by most patients. Because sertraline therapy caused significant prolongation of time to ejaculation, this agent may be useful as a treatment for selected patients with premature ejaculation.

A placebo-controlled trial of L-365,260, a CCKB antagonist, in panic disorder.

The functional role of cholecystokinin in the central nervous system is unknown. The tetra peptide CCK-4 was previously observed to induce panic attacks in a majority of normal volunteers and patients with panic disorder. Furthermore, it had been demonstrated that pretreatment with 10-50 mg of L-365,260, a selective CCKB antagonist, blocked CCK-4 induced panic in patients with panic disorder. Therefore, the present multicenter, placebo-controlled, double-blind trial was designed to investigate the efficacy of L-365,260, a CCKB antagonist, in patients with panic disorder with or without agoraphobia. Following a 1-week, single-blind placebo period, 88 patients were randomized to double-blind treatment in which they received either L-365,260, 30 mg qid, or placebo for 6 weeks. At the dose tested, there were no clinically significant differences between L-365,260 and placebo in global improvement ratings, Hamilton anxiety rating scale scores, panic attack frequency, panic attack intensity, or disability measures. The possible reasons for lack of effect with L-365,260 are discussed.

A double-blind, placebo-controlled trial of two dose ranges of nefazodone in the treatment of depressed outpatients.

BACKGROUND: Nefazodone hydrochloride, a 5-HT2 receptor antagonist that selectively inhibits serotonin reuptake, was evaluated in a double-blind, dose-finding study of novel design, involving 240 patients with major depression. METHOD: Patients were randomly assigned to three treatment groups and received either placebo (2-6 capsules per day), a lower-dose range of nefazodone (50-300 mg/day), or a higher-dose range of nefazodone (100-600 mg/day) for 6 weeks. RESULTS: At the end of treatment, the Hamilton Rating Scale for Depression and the clinician- and patient-rated Inventory for Depressive Symptomatology scores showed significant improvement (p < or = .05) for patients receiving higher-dose range nefazodone (mean = 392 mg/day) compared with placebo treatment. The percentage of responders (at least "much improved" on the Clinical Global Impressions-Improvement scale) in the higher-dose range nefazodone group (58%) was significantly greater (p < or = .05) than in the placebo group (39%). The treatment group receiving nefazodone in the lower-dose range was not differentiated in clinical response from placebo controls. The rate of discontinuation for adverse experience (14%) was similar for patients treated with higher-dose range nefazodone and placebo. CONCLUSION: The findings of this study indicate that nefazodone is an effective and well-tolerated antidepressant drug, with a recommended therapeutic dose range of 100 to 600 mg/day and a starting dose of 100 mg b.i.d.

Dothiepin versus doxepin in major depression: results of a multicenter, placebo-controlled trial. Prothiaden Collaborative Study Group.

BACKGROUND: The tricyclic antidepressant dothiepin is well established in Europe, but clinical experience with the drug in the United States is limited. METHOD: In a 10-week, multicenter, randomized, double-blind, placebo-controlled study in the United States, the efficacy and tolerability of dothiepin and doxepin (both administered as a 150-mg nightly dose) were compared in 579 outpatients with major depression. RESULTS: Patients in both active treatment groups showed significant improvements in depressive symptoms, associated anxiety, and sleep parameters compared with the placebo-treated group. The adverse effect profile of dothiepin was superior to that of doxepin, particularly with respect to drowsiness, weight gain, and increased appetite. CONCLUSION: These results confirm that dothiepin is useful when a tricyclic agent is indicated for the treatment of depression.

Evaluation of the safety and efficacy of quazepam for the treatment of insomnia in psychiatric outpatients.

BACKGROUND: This study was conducted to further evaluate the safety and efficacy of the benzodiazepine hypnotic quazepam within the context of a clinical practice setting of psychiatric outpatients who had insomnia. METHOD: A total of 2,813 adult, psychiatric outpatients were evaluated in an open-label study design. Each subject was instructed to take one 15-mg quazepam tablet each night at bedtime for 7 consecutive nights and was given a questionnaire to be completed at home upon arising each morning. RESULTS: Insomnia improved after 1 night of treatment with 15 mg of quazepam. Eighty-five percent of patients rated their quality of sleep as fair-to-excellent after 1 week of treatment. Similar efficacy outcomes also were observed on the second through sixth nights of treatment. Improvement occurred for patients who had an initial sleep latency complaint or unsatisfactory duration of sleep and for those who either had difficulty in staying asleep or complained of early morning awakening. The mean number of insomnia complaints was significantly (p < .001) reduced after the first and the seventh nights of treatment both in the population of all evaluable patients and in a subset of patients with more severe insomnia. CONCLUSION: This open-label study in 2,813 outpatients provided evidence that quazepam reduces the complaints of insomnia in a difficult-to-treat psychiatric population after 1 night and after 7 nights of treatment. Quazepam was well tolerated, even when coadministered with psychotherapeutic medications, some of which can cause insomnia.

Expressive characteristics of anxiety in depressed men and women.

This study was aimed at identifying the expressive, movement, and social behaviors associated with anxiety in the syndrome of major depression. The sample consisted of 97 hospitalized male and female depressed patients. Expressive and social behaviors were evaluated prior to treatment in a structured videotaped interview. Anxiety was measured using a multi-vantaged approach including doctor's rating, nurse's rating, patient self-report, and a separate video rating. Results indicate that anxiety was significantly associated with agitation, distressed facial expression, bodily discomfort, and poor social interaction in both sexes. Men and women differed in certain respects: anxiety was highly related to motor retardation in women only, and to hostility in men only. Differences in the pattern of expressive behavior between high and low anxious, depressed patients were clearly significant, and several were large enough to serve as clinical indicators. These findings help to characterize the expressive features of anxiety in the context of severe depression, and add to the growing literature on sex differences in depression.

A study comparing paroxetine placebo and imipramine in depressed patients.

These data provide evidence for the antidepressant efficacy of paroxetine. Paroxetine- and imipramine-treated patients were significantly different from placebo-treated patients, but little different to each other, on all depressive outcome measures. However, paroxetine appeared to have a possibly greater and earlier beneficial effect on anxiety symptoms associated with depression, when compared with imipramine. Both active therapies were effective in treating patients with severe depression. Side effects for paroxetine were typical of other serotonin (5-HT) uptake inhibitors but different from those of imipramine. In particular, anticholinergic and cardiovascular symptoms were reduced, and premature withdrawal less likely.

Clinical management of the depressed geriatric patient: current therapeutic options.

Depression is probably the most common psychiatric illness affecting the elderly. Although depression in the elderly usually responds to treatment, it often goes unrecognized and, left untreated, may lead to considerable morbidity and mortality. Reversible causes of depression (e.g., medications; infectious states; endocrine, collagen, neurologic, and neoplastic disorders; and nutritional deficiencies) must all be ruled out before instituting therapy. Psychotherapy, electroconvulsive therapy (ECT), and pharmacologic therapy are the main therapeutic approaches used to manage depression. The pharmacologic options--tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, aminoketones, and triazolopyridines--each appear to be efficacious; however, the side-effect profile of some of the agents makes them more appropriate for use in elderly patients. It is imperative for clinicians, when choosing therapy for elderly depressed patients, to keep firmly in mind all risks, as well as benefits, inherent in each choice.

Efficacy and safety of b.i.d. doses of venlafaxine in a dose-response study.

In this study, 312 depressed outpatients received either placebo or one of three venlafaxine doses twice daily (b.i.d.) for up to 6 weeks. The total daily doses of venlafaxine were 25, 50-75, and 150-200 mg/day. Hamilton Rating Scale for Depression (HAM-D) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores at Week 6 were significantly lower for the high-dose group than for the placebo group. A positive dose-response trend for the primary efficacy parameters was demonstrated as early as Week 1. Venlafaxine was well tolerated at all dose levels. The most common side effects of clinical interest were nausea and dry mouth. The frequency of nausea in the venlafaxine groups was essentially the same (25-29%), whereas the frequencies of dry mouth, somnolence, and sweating were dose related. The results indicate that b.i.d. doses of venlafaxine are safe and effective in treating depression.

The acute and long-term treatment of major depression.

Millions of depressed patients do not receive appropriate treatment in spite of the substantial increase in our knowledge about this major medical problem. In addition to individual suffering, there are tens of thousands of deaths by suicide, an increase in morbidity and mortality from medical illnesses whose course is aggravated by an associated depression, a disruptive effect on family life and childrearing, and an economic loss of billions of dollars. Among the many reasons for the inadequate treatment of depression is the fact that the side effects (anticholinergic, antihistaminic, etc.) of traditional antidepressants result in many patients receiving inadequate doses of medication or discontinuing treatment prematurely. The availability of a new class of antidepressant medications--the selective serotonin reuptake inhibitors (SSRIs)--heralds a new phase in the treatment of depression. Although these drugs are not free of side effects, an increased number of depressed patients now seem able to receive adequate doses of medication and to stay on treatment much longer than in the past. The increased acceptance of SSRIs by patients represents an important phase in our ability to effectively treat larger numbers of patients and to prevent relapse in many of them.

Milacemide: a placebo-controlled study in senile dementia of the Alzheimer type.

OBJECTIVE: Milacemide, a MAO-B inhibitor that is also a prodrug for glycine, was tested as a treatment for senile dementia of the Alzheimer type (SDAT) because of its potential for enhancing cognition in animal models of impaired learning and memory. DESIGN: Double-blind, placebo-controlled, randomized clinical trial. SETTING: Sixteen study sites, both university-affiliated and private. PATIENTS: A total of 228 outpatients (116 men and 112 women) with SDAT, ranging in age from 49-93 years. INTERVENTION: 1200 mg/day milacemide treatment for 1 month (113 patients received milacemide, and 115 patients received placebo). MAIN OUTCOME MEASURES: Alzheimer's Disease Assessment Scale and the Mini-Mental State Examination. RESULTS: Milacemide-treated SDAT patients did not show significant improvement in any of the outcome measures used. Significant elevations in liver enzymes in four subjects were of sufficient magnitude to necessitate withdrawal from the study. CONCLUSIONS: Milacemide does not appear to be an effective treatment in enhancing cognition in SDAT patients.

The effectiveness of labetalol compared to hydrochlorothiazide in hypertensive black patients.

Labetalol and hydrochlorothiazide (HCTZ) were compared for their efficacy in controlling hypertension of blacks in a prospective, double-blind study. Sixty-one adult patients with mild to moderate hypertension (standing diastolic blood pressure greater than or equal to 95 mm Hg and less than or equal to 114 mm Hg) were randomly selected to receive either labetalol 100 mg twice daily (n = 30) or HCTZ 25 mg twice daily (n = 31). The study was divided into two phases: a 4-week placebo run-in phase, during which all previous antihypertensive medication was discontinued, and a 12-week drug treatment phase. Labetalol and HCTZ doses were titrated to 400 mg twice and 50 mg twice daily, respectively, during the first 6 weeks of the drug treatment phase for those patients not achieving blood pressure control (standing diastolic blood pressure less than 90 mm Hg and a decrease of 10 mm Hg from baseline) on initial dosages. By the end of the 12 weeks of drug administration, patients on labetalol experienced a mean decrease of 10 mm Hg in standing diastolic blood pressure compared to a mean decrease of 10.1 mm Hg in patients on HCTZ. No differences were observed between the two treatment groups in reductions of either standing blood pressure or heart rate. While 19 of 30 patients on labetalol (63%) achieved blood pressure control at some point during the study with a mean daily dose of 568 mg, 18 of 31 (58%) HCTZ-treated patients achieved control with a mean daily dose of 72 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Criteria for selection of appropriate benzodiazepine hypnotic therapy.

The several benzodiazepine hypnotics currently marketed differ in onset and duration of action and in side effect profile. These differences are largely based on the varying pharmacodynamic properties of these agents. The selection of a drug for treating an individual patient should be based on consideration of these pharmacologic differences, as well as assessment of the sleep-wake disorder. The initial objective for the clinician who intends to manage a patient with insomnia is to determine which factors are contributing to the sleep disturbance and to decide on a treatment strategy. If medication is to be used, then the physician should select the most effective and safest hypnotic, prescribe it at the lowest effective dose and for the fewest number of nights. Individual patient response to the chosen medication should be monitored.