Randomized, double-blind comparison of venlafaxine and sertraline in outpatients with major depressive disorder. Venlafaxine 631 Study Group.

BACKGROUND: This 8-week, double-blind, randomized trial compared the efficacy and tolerability of venlafaxine and sertraline in patients with major depression. METHOD: Outpatients (N = 147) with DSM-IV major depressive disorder and a baseline 21-item Hamilton Rating Scale for Depression (HAM-D) score of at least 18 were randomly assigned to venlafaxine, 37.5 mg b.i.d., or sertraline, 50 mg once daily. From day 15, the doses could be increased to venlafaxine, 75 mg b.i.d., or sertraline, 50 mg b.i.d. Efficacy was assessed with the 21-item HAM-D, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions scale (CGI) using a modified intent-to-treat analysis. RESULTS: No significant differences were noted between treatments for mean HAM-D, MADRS, or CGI scores. At week 8, the HAM-D response rate was 83% with venlafaxine (N = 75) and 68% with sertraline (N = 72) (p = .05). A HAM-D score less than 10 was recorded in 68% of venlafaxine-treated and 45% of sertraline-treated patients at week 8 (p = .008). Among patients who increased their dose, the remission rate (HAM-D score < 10) was 67% with venlafaxine and 36% with sertraline at week 8 (p < .05). The overall discontinuation rate was 21% with venlafaxine and 17% with sertraline. The most common adverse events with venlafaxine were nausea, headache, and sweating and with sertraline were nausea, headache, and diarrhea. CONCLUSION: Among patients who increased their dose, approximately twice as many experienced a remission with venlafaxine, which is a more clinically relevant endpoint than response and represents the proportion of patients who have recovered or are well.

Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study.

BACKGROUND: Although case reports and open studies have reported augmentation with buspirone to be beneficial in the treatment of depression refractory to treatment with a selective serotonin reuptake inhibitor (SSRI), a recently published randomized, placebo-controlled, double-blind study failed to show superiority of buspirone over placebo in this respect. METHOD: One hundred two outpatients who fulfilled DSM-IV criteria for a major depressive episode and who had failed to respond to a minimum of 6 weeks of treatment with either fluoxetine or citalopram were included in this double-blind, randomized, placebo-controlled study. After a single-blind placebo wash-in period of 2 weeks while continuing their SSRI, the patients were randomly assigned to adjunctive treatment with either buspirone, 10 to 30 mg b.i.d., or placebo for 6 weeks. Patients were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impressions scale (CGI), and visual analogue scales. RESULTS: After the first week of double-blind treatment, there was a significantly greater reduction in MADRS score (p = .034) in the buspirone group as compared with placebo. At endpoint, there was no significant difference between treatment groups as a whole, although patients with initially high MADRS scores (> 30) showed a significantly greater reduction in MADRS score (p = .026) in the buspirone group as compared with placebo. CONCLUSION: Patients with severe depressive symptoms may benefit from augmentation with buspirone. It cannot be excluded that augmentation with buspirone may speed up the antidepressive response of patients refractory to treatment with fluoxetine or citalopram.

A survey of sudden death associated with the use of antipsychotic or antidepressant drugs: 49 cases in Finland.

Phenothiazines have repeatedly been found to be associated with cases of sudden death, but the issue of causality has remained controversial. A survey of medicolegal autopsies performed in Finland over a 3-year period revealed that sudden unexpected deaths of 31 women (mean age 44 years, range 25-69) and 18 men (mean age 40 years, range 26-62) were associated with either the use of antipsychotic or antidepressant drugs. Therapeutic use of phenothiazines was documented in all but 3 of these 49 cases and thioridazine was involved in over half of them. Thus, whereas thioridazine was the only antipsychotic drug associated with 15 cases, only 5 cases were associated with any of the other antipsychotic or antidepressant drugs. The differences between the subgroups of psychotropic drugs remained clear after adjustment according to the respective data on drug use in the population. Although there are several uncontrolled confounding factors, the overrepresentation of phenothiazines, especially thioridazine, among psychiatric patients who died suddenly is striking and, taken together with their well-established arrhythmogenic effects, warrants further attention.

Long-term efficacy and safety of milnacipran compared to clomipramine in patients with major depression.

Milnacipran is a new antidepressive drug, a combined noradrenaline/serotonin (NA/5-HT) reuptake inhibitor, which has been suggested to be as effective as and better tolerated than tricyclic antidepressants. Since long-term studies are lacking, we compared the efficacy, safety and tolerability of milnacipran and clomipramine in a double-blind, randomized, parallel-group study setting during 26 weeks of treatment in patients with major depression. A total of 107 patients were treated with either milnacipran (n=52) or clomipramine (n=55). Due to active treatment of duration less than 12 days in four patients and protocol deviation in one patient, in total 47 milnacipran-treated patients were eligible for efficacy analysis. Nine patients in the clomipramine group continued on active treatment for less than 12 days. Thus 46 clomipramine-treated patients were finally included in the efficacy analysis. After 1 week of dose escalation, there was a fixed dosage regimen of either milnacipran (200 mg daily) or clomipramine (150 mg daily) during weeks 2 to 10, followed by flexible dosing of milnacipran (100, 150 or 200 mg daily) or clomipramine (75, 100 or 150 mg daily) during weeks 11 to 26. A total of 53 patients (49%) completed the 26-week study period; 21% (11/52) of the patients in the milnacipran group and 38% (21/55) of the patients in the clomipramine group discontinued their medication prematurely due to adverse events, whereas 19% (10/52) of those on milnacipran and 7% (4/55) of those on clomipramine treatment withdrew due to either lack of efficacy or clinical deterioration. The mean change (+/-SD) in the Hamilton Depression Rating Scale (HAMD) score between the baseline and the last rating ranged from 23.7+/-3.1 to 12.0+/-9.5 in the milnacipran-treated patients and from 23.1+/-3.5 to 8.0+/-8.5 in the clomipramine-treated patients, revealing a significant difference in favour of clomipramine. In total 58% of the milnacipran-treated patients vs. 72% of the clomipramine-treated patients showed a > or = 50% reduction in their baseline HAMD scores and 45% vs. 63% had an HAMD score of < or = 7 at the last rating, respectively. Moreover, the time to the onset of the antidepressant action (defined as > or = 50% reduction of the baseline HAMD score) showed a significant difference in favour of clomipramine. In addition, clomipramine was significantly more efficacious in patients with a baseline HAMD score of > or = 24 as evidenced by the analysis of the HAMD score at week 6 and at the last rating. The Montgomery Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) scale did not show significant differences between the treatment groups. The safety analysis did not reveal any differences of clinical significance in cardiovascular variables between the study drugs. Dry mouth was significantly less frequently reported by the milnacipran-treated patients during the early and later phases (weeks 6 to 26) of the study, while insomnia was more common in the milnacipran group during weeks 1 to 6. In conclusion, milnacipran appeared to be less effective than clomipramine in the long-term treatment of depression. The side-effects of the drugs differed to a certain extent, and milnacipran tended to be somewhat better tolerated than clomipramine.

Antidepressant efficacy and quality of life in depression: a double-blind study with moclobemide and fluoxetine.

The efficacy of moclobemide (300-450 mg/day) was compared with fluoxetine (20-40 mg/day) in a double-blind, multicentre study in 209 patients with new episodes of depression selected from 612 consecutive depressed patients representative of those consulting psychiatric services in Finland. Antidepressant efficacy was assessed with the Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Depression Rating Scale and Clinical Global Impression (CGI). The Medical Outcome Study Short-form General Health Survey (SF-20) and 15D Measure of Quality of Life were used to measure effectiveness in terms of health-related quality of life. Efficacy was evident with both drug treatments, with 67% in the moclobemide group and 57% in the fluoxetine group having a reduction in HDRS of more than 50%. Similarly, 77% of the patients in the moclobemide group and 67% in the fluoxetine group were assessed on the CGI as much better or very much better after 6 weeks of treatment. The most commonly reported adverse events were nausea, other gastrointestinal symptoms, nervousness, dizziness and sleep disorders. Nausea was significantly more common in the fluoxetine group and was found especially in women. Premature terminations of treatment were 18% in the moclobemide and 21% in the fluoxetine group. A significant change for the better in quality of life was found in both treatment groups, even at week 2 but especially after 6 weeks of treatment. Improvement was not only seen in dimensions measuring depression or mental health but also in other dimensions.

Remoxipride and haloperidol in schizophrenia: a double-blind multicentre study.

Ninety-two patients with schizophrenia were included in a double-blind multicentre parallel-group trial comparing remoxipride and haloperidol. The mean daily dose during the last week of treatment was 316 mg (range, 150-600 mg) in the remoxipride group and 8.7 mg (range, 5-20 mg) in the haloperidol group. The study period was six weeks with at least one day of washout. Both Clinical Global Impression (CGI) rating, and Brief Psychiatric Rating Scale (BPRS) total scores declined at the end of the trial compared with pretreatment values in both groups. No significant differences were found between the remoxipride and haloperidol groups with regard to the treatment outcome. Treatment-emergent extrapyramidal symptoms were statistically more frequent and more severe during haloperidol than during remoxipride treatment. Haloperidol-treated patients reported also significantly more concentration difficulties. Severe extrapyramidal side effects in the haloperidol group and clinical ineffectiveness in the remoxipride group were the most frequent reasons for premature discontinuation of treatment.