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Social dysfunction is often associated with depressive disorders and its evaluation is an important measure of treatment outcome. The aim of this study was to assess the effect of two treatments, venlafaxine and amitriptyline, on the social functioning of depressed patients. Twenty-eight outpatients, meeting criteria for recurrent or single major depressive episodes, took part in a double-blind, 8-week trial with amitriptyline or venlafaxine (maximum of 150 mg/day) and were assessed by the Self-Report Social Adjustment Scale (SAS-SR) before and at the end of treatment. The scale was also applied to a carefully selected non-psychiatric sample. Both drugs showed the same efficacy on a clinical scale, but venlafaxine improved social functioning more than amitriptyline as only venlafaxine-treated patients reached SAS-SR values estimated for normal subjects. This effect might be linked to the higher rate of side-effects observed with amitriptyline.

Although common in clinical settings, major depressive disorder with associated anxious symptoms ('anxious depression') has not been well studied in antidepressant clinical trials. The aim of this study was to compare the effects of fluoxetine versus amitriptyline in this group of patients. After a single-blind placebo run-in period of 2 weeks, patients were treated on a double-blind basis with fluoxetine or amitriptyline for 8 weeks. Assessment instruments included: 21-item Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, Clinical Global Impressions, Raskin Depression Scale and Covi Anxiety Scale. A total of 157 patients were randomized to either fluoxetine or amitriptyline. Fluoxetine was given at a fixed dose of 20 mg/day and amitriptyline was given in a range of 50-250 mg/day (mean of 138.1 mg/day). Fluoxetine was comparable to amitriptyline in all efficacy measures except the HAMD sleep factor. Unwanted effects were more frequent and more severe in the amitriptyline-treated patients. Fluoxetine was comparably efficacious to amitriptyline in the treatment of major depression with associated anxiety. Since fluoxetine was far better tolerated, it is a promising alternative for this frequent and disabling condition.

Of 580 patients randomly assigned to short-term, double-blind treatment with either mirtazapine, amitriptyline or placebo, a total of 217 patients clinically judged to be responders subsequently continued on the same medication for up to 2 years in the long-term treatment study (mirtazapine, n = 74; amitriptyline, n = 86 and placebo, n = 57). The efficacy of mirtazapine in relapse prevention was seen in an analysis of the first 20 weeks data. Significantly fewer patients relapsed during treatment with mirtazapine compared with placebo (p < 0.05), and a significantly longer time to relapse was shown on the survival analysis. There was a significant advantage for amitriptyline compared with placebo in the first 20 weeks, with fewer patients relapsing. There was a significant advantage for mirtazapine compared with amitriptyline at 20 weeks seen on the survival analysis (p < 0.05). The significant advantage for mirtazapine compared with placebo was also seen in the prophylactic phase of treatment after 20 weeks. At the endpoint there were significantly more patients in the placebo group with a return of symptoms and significantly fewer showing sustained response. Amitriptyline was better than placebo with fewer patients suffering a recurrence of symptoms, but there was no difference from placebo in the proportion of patients with sustained response. Mirtazapine was well tolerated with a side-effect profile similar to that of placebo. The only adverse event reported significantly more frequently on mirtazapine than on placebo was weight gain. Objectively measured weight gain was more frequent with amitriptyline (22% of patients) compared with mirtazapine (13% of patients). Amitriptyline was associated with significantly more adverse events than either mirtazapine or placebo, in particular sedative and anticholinergic side effects. The efficacy of mirtazapine in reducing the risk of relapse and the recurrence of depression, which on some measures showed an advantage compared with amitriptyline, coupled with its improved side-effect profile, commends this antidepressant for the long-term treatment of depression.

Two dimensions of compliance (drop-outs and adherence) were investigated in patients treated with antidepressant drugs. Efficacy, compliance and its determinants were investigated in 66 patients suffering from major depressive disorder and treated in a double-blind manner with fluoxetine 20 mg/day or amitriptyline 150 mg/day for 9 weeks. Overall effectiveness [50% decrease in the initial Hamilton Rating Scale for Depression (HAM-D)] was similar in both groups (62.8% for fluoxetine, 58.1% for amitriptyline). The dropout rate due to side effects was 35.5% for amitriptyline and 5.7% for fluoxetine. A logistic regression analysis revealed that the initial HAM-D score was not predictive for dropping out, but this outcome was instead determined by sex (increased risk for males), age (increased risk for being younger) and occurrence of severe side effects. Adherence was estimated using electronic Medication Event Monitoring System and defined as the percentage of days when the correct dose was taken out of the medication container. Of the patients studied 37% had an adherence of less than 70%. There was no relationship between adherence and efficacy and adherence was similar in patients on fluoxetine or amitriptyline. Side effects were not predictive of being adherent or not, but a higher initial HAM-D score predicted a higher adherence to the medication regimen. The demographic variables had no significant effect. The present study suggests that the link between efficacy, side effects and compliance or adherence is more complex than is generally believed and that early termination and non-adherence seem to be determined by different factors.

The interaction between plasma concentrations of the tricyclic antidepressant amitriptyline and the metabolism of the new antipsychotic risperidone was studied in 12 patients with chronic schizophrenia. Each patient received 3 mg risperidone twice a day for 28 days. Amitriptyline was coadministered at doses of 50 mg/day on day 15 and 100 mg/day on days 16 to 21. Amitriptyline did not significantly affect the mean plasma concentrations or pharmacokinetics of risperidone in schizophrenic patients or influence the antipsychotic fraction (the total concentration of risperidone and 9-hydroxyrisperidone, its primary and biologically active metabolite). These results suggest that risperidone dose need not be adjusted when coadministered with amitriptyline at doses up to 100 mg/day in schizophrenic patients.

We describe a patient treated with trazodone, amitriptyline and lithium carbonate who developed anxiety, restlessness, tremor, myoclonus, hyperreflexia, diaphoresis, rigidity and hyperthermia. The constellation of findings was diagnostic of serotonin syndrome. Although doses of trazodone and amitriptyline were relatively low, serotonin syndrome developed in this patient. It is suggested that the combination with lithium facilitated the effect of central serotonergic responses mediated by trazodone and amitriptyline.

The clinical trial development programme of mirtazapine (Org 3770), performed in Europe and the United States, demonstrated an outstanding safety profile of this compound. The evaluation of the safety was based on data from all patients who took at least one dose of study medication during studies comparing mirtazapine with placebo, amitriptyline or other active comparators. A general indication of mirtazapine's safety is the significantly lower percentage of patients (65%) who complained of any adverse clinical experiences compared with the placebo- (76%) or amitriptyline-treated group (87%). Moreover, drop-out rates due to adverse clinical experiences were significantly lower than in the amitriptyline-treatment group. Mirtazapine has virtually no anticholinergic, adrenergic or typical selective serotonin reuptake inhibitor (SSRI) side effects. The only significantly higher incidences versus placebo were seen in the adverse clinical effects of drowsiness (23% versus 14%), excessive sedation (19% versus 5%), dry mouth (25% versus 16%), increased appetite (11% versus 2%) and weight increase (10% versus 1%). These complaints were typically mild and transient in nature, and decreased over time despite increased doses of mirtazapine. In contrast, significantly higher incidences of headache (5% versus 10%) and weight decrease (2% versus 6%), symptoms commonly seen in depressed patients, were recorded in the placebo-treated patients. Also, typical SSRI adverse events, such as nausea, vomiting, diarrhoea and insomnia, and symptoms of sexual dysfunction were registered less frequently in mirtazapine-treated patients than in the placebo-treated patients. Approximately 10% of the mirtazapine-treated patients in the clinical trial programme were older than 65 years. The pattern of adverse clinical experiences seen in this group of patients is fully in line with that seen in the overall patient population. The analysis of vital sign indices, i.e. blood pressure and heart rate, showed that no changes occurred with mirtazapine treatment; this pattern was fully comparable to that seen with placebo. Furthermore, very low incidences of clinically relevant changes in laboratory indices, such as the liver enzymes alanine aminotransferase and aspartate aminotransferase or neutropenia, were recorded in each treatment group. Mirtazapine has a very low seizure-inducing potential: only one case was recorded in a patient with a history of seizures during previous treatment with clomipramine. The low seizure-inducing potential combined with a lack of cardiotoxic properties allows safety in an overdose of mirtazapine, even in elderly patients. The only symptom seen in the patients taking an overdose of mirtazapine alone or in combination with other drugs was excessive but transient somnolence, which resolved spontaneously within a few hours. In conclusion, the new antidepressant mirtazapine offers clinicians a unique combination of strong efficacy and good safety.

This report describes a case of encephalopathy developed in the course of amitriptyline therapy, during a remission of unipolar depression. This patient could have been diagnosed as having either neuroleptic malignant syndrome (NMS) or serotonin syndrome (SS). The major determinant of the symptoms may have been dopamine/serotonin imbalance in the central nervous system. The NMS-like encephalopathy that develops in association with the use of antidepressants indicates that NMS and SS are spectrum disorders induced by drugs with both antidopaminergic and serotonergic effects.

There are a number of criteria that can be used when selecting an antidepressant. In particular safety criteria are important, and a distinction can be drawn between "safe" and "less safe" antidepressants. The relative safety of different antidepressants has been assessed by looking at answers to the questions: how safe is the drug in overdose; how dangerous are its side effects at therapeutic dose; and does it have any dangerous interactions with other drugs or substances? Based on current data it can be said with reasonable confidence that fluvoxamine, fluoxetine, paroxetine and moclobemide are "safe" antidepressants, and mianserin and trazodone are also "safe" but to a lesser extent (mainly because of hypnosedation). In conclusion, "safe" antidepressants should be considered as the first choice in the treatment of depression.

After 1 week of a single-blind placebo period, and prior to being randomly assigned to receive treatment with either fluoxetine or amitriptyline, patients meeting strict criteria for a diagnosis of major depressive disorder were given an auditory verbal learning test of working memory, and a blood sample was drawn. After 3 weeks of drug treatment with either amitriptyline or fluoxetine, the patients' symptoms were evaluated, the verbal learning test was repeated, and a second blood sample was taken. The clinical evaluation, the verbal learning test and the blood drawing were repeated a third time 3 weeks after the second assessment. The amount of anticholinergic activity in the blood samples was measured by a competitive radioligand binding assay and expressed in atropine equivalents. Analyses of variance indicated that there were no significant differences at the predrug Assessment 1 between patients subsequently assigned to the fluoxetine group compared with those assigned to the amitriptyline group. At Assessments 2 and 3, the fluoxetine and the amitriptyline groups showed equal clinical improvement but patients receiving amitriptyline did not perform as well on the verbal learning task. Serum anticholinergic activity at Assessments 2 and 3 was considerably higher in the amitriptyline group. This supports the hypothesis that blockade of muscarinic receptors impairs working memory formation. Equally effective antidepressant drugs with little or no anticholinergic action, such as fluoxetine, may be preferable in patients with pre-existing mild cognitive impairment or in patients where a slight reduction in cognitive performance is not acceptable.

Forty-three out-patients with depression of a moderate degree were enrolled in a randomized, double-blind parallel group study comparing amitriptyline and alprazolam for 6 weeks of treatment. Patients were evaluated at the end of placebo washout and at Weeks 1, 2, 3 and 6 of drug therapy using the Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Beck Depression Inventory (BDI) and Clinical Global Impression (CGI). Drug dosage was determined in a fixed-flexible design resulting in mean final doses of alprazolam 3.2 mg/day and of amitriptyline 115 mg/day. Although both drug groups improved there were statistically significant differences in favour of amitriptyline at the end of the study on the HAM-D, BDI and HAM-A scales. Patients on amitriptyline reported more side effects overall than patients taking alprazolam with significantly more reports of dry mouth in the amitriptyline group.

Psychological distress is a driver both of direct and indirect health care costs. Depression compromises functional well-being, such as work productivity. Comorbid anxious features often complicate the recognition of depression and may herald a poor prognosis. We report the results of a cross-sectional naturalistic study to determine the impact of three interventions (no antidepressant, fluoxetine, or tricyclic antidepressant therapy) on relative risk of work days lost in 454 French outpatients with either major or minor depression. Most depressed patients also manifested anxious features (76% with a Hamilton Rating Scale for Anxiety score > or = 12). The presence of anxiety was related to the severity of depression, work absenteeism, and current social instability. Depression severity (Hamilton Rating Scale for Depression score > or = 26, including the contributions of anxious symptoms), psychiatric comorbidity, and psychomotor retardation best predicted continued work absenteeism. Patients with major depression were more likely to receive an antidepressant if they had a past history of depressive episodes and/or previous work disability. Patients with minor depression were less likely to receive drug therapy than patients with major depression, despite their current work disability. Among patients who received fluoxetine or a tricyclic antidepressant for at least 8 weeks, fluoxetine was associated with statistically significantly lower mean anxiety and depression scores and fewer work days missed.

Fluoxetine, a serotonin uptake inhibitor, and amitriptyline, a tricyclic antidepressant, were compared in a 5-week, multicenter, double-blind, randomized trial in 136 out-patient men and women, aged 21-70 years, with major depressive disorder. Overall efficacy was comparable with fluoxetine and amitriptyline [Hamilton 21-Item Rating Scale for Depression (HAM-D21), Raskin, Covi, Clinical Global Impressions-Severity and -Improvement, Patient's Global Impressions]. Mean +/- standard deviation decreases in HAM-D21 total score were 12.9 +/- 9.9 and 11.6 +/- 10.3 (p = 0.423), respectively. Response rates (> or = 50% decrease in HAM-D21 total score) for patients treated > or = 4 weeks were 46.7% and 66.0% (p = 0.039) and remission rates (HAM-D21 total score < or = 7) were 18.3% and 28.3% (p = 0.209), respectively. Response and remission rates for all patients were comparable with fluoxetine and amitriptyline. Study completions were higher with fluoxetine than amitriptyline (87.7% vs 66.2%; p = 0.003). Discontinuations for adverse events were higher with amitriptyline than fluoxetine (22.5% vs 6.2%; p = 0.007). More treatment-emergent nausea and insomnia were reported with fluoxetine (p < or = 0.05); more anticholinergic and orthostatic events and weight gain were reported with amitriptyline (p < or = 0.05). Statistically, but not clinically, significant changes were observed in vital signs. Both fluoxetine and amitriptyline were effective treatments for out-patients with major depressive disorder. Fluoxetine had a more favorable safety profile than amitriptyline.

A comparative double-blind study of paroxetine and amitriptyline in the treatment of depressed hospital outpatients was undertaken at 15 centres in Italy. Three hundred and nine patients of either sex were admitted to the study. The starting dose of paroxetine was 20 mg daily and of amitriptyline 75 mg daily in divided doses; at week 3 these doses could be increased at the investigators' discretion. Efficacy was measured on the Hamilton Depression Rating Scale and on Clinical Global Impression. Both treatment groups showed significant improvement at week 6 with no significant between-group differences. Significantly fewer patients receiving paroxetine reported adverse events compared with those on amitriptyline (44% vs 62%; p < 0.01 in favour of paroxetine).

A total of 101 patients entered a double-blind, parallel-group study in general practice, comparing the efficacy and tolerability of paroxetine and amitriptyline in elderly depressed patients. All patients received placebo for 1 week followed by active therapy for a total of 6 weeks. Medication was randomly allocated, two-thirds of the patients took paroxetine (20 mg daily) and one-third received amitriptyline (50 mg daily); this dose was increased to 30 mg and 100 mg, respectively, after 1 week. Of the patients who entered the placebo run-in, 90 took active treatment and were evaluable on an intention-to-treat basis (56 paroxetine, 32 amitriptyline). The mean age of the patients was 72 years. Significant reductions in Hamilton Depression Rating Scale (HAMD) from baseline to the end of treatment were seen for both groups (p < 0.01), with no difference between treatments. The HAMD score was reduced by half, or more, for 76% of patients taking paroxetine and 86% taking amitriptyline. Significant improvement was observed in the investigators' Clinical Global Impression (CGI) score for 57% of patients taking paroxetine and 52% on amitriptyline. Improvements after treatment were also observed in the Leeds Sleep Evaluation Questionnaire (LSEQ) scores. Significantly fewer patients taking paroxetine reported adverse events (34% vs 63% taking amitriptyline, p = 0.02). Those taking paroxetine experienced significantly fewer anticholinergic side effects (7% vs 25% taking amitriptyline, p = 0.04). Overall, this study confirmed the effectiveness of paroxetine as an antidepressant drug.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical trial programme of sertraline, a selective serotonin re-uptake inhibitor, has shown the drug to have a favourable safety and toleration profile. In contrast, the tricyclic antidepressant, amitriptyline, produced a significant level of side effects, particularly anticholinergic. The side-effect profile of sertraline was similar in young and old, and individual side effects did not make a notable contribution to the discontinuation rate. The incidence of side effects was related to both dosage and dosage regimen. An initial dose of 50 mg increased at 2-weekly intervals to 100 mg and then 200 mg daily produced a very low incidence, no side effect occurring with a frequency greater than 10%. In the long term (after 8 weeks' study), sertraline was well tolerated with little difference in side-effect reporting from placebo. There were no significant problems with safety. Sertraline was without effect on vital signs or electrocardiogram, and had no clinically relevant effects on laboratory values. In contrast to amitriptyline there was no significant effect on body weight. The overall incidence of mania was 0.4% and skin rash less than 2%. There were no cases of drug-related convulsions. Overdose with sertraline (four cases) was satisfactorily overcome with no significant sequelae and without the need for intensive monitoring.

Three 6-8 week comparative studies have shown sertraline to be an effective, safe and well-tolerated treatment for acute depressive illness. The first, a double-blind fixed-dose study, demonstrated the efficacy of sertraline over placebo; the second, a forced upward titration, active- and placebo-controlled, double-blind study, showed that sertraline was of equal efficacy to amitriptyline. The third was a double-blind comparison of sertraline and amitriptyline in elderly depressives, with the dose being increased as necessary and as tolerated. The overall results showed sertraline to be consistently superior to placebo and equivalent in therapeutic effect to amitriptyline on a number of measures including depression, anxiety, insomnia and suicidal ideation. Efficacy was found in both moderately and severely depressed patients whose primary psychiatric diagnoses included single-episode and recurrent major depression, with and without melancholia. Sertraline was also found to be effective in patients with a high baseline anxiety score on the Hamilton Rating Scale for Depression.

Fluoxetine, a new serotonin uptake blocking antidepressant, was compared with amitriptyline in a double-blind study. Patients were diagnosed as having major depression, according to DSM-III criteria, when interviewed with the Diagnostic Interview Schedule. There was significant improvement in patient and observer ratings of depression in both groups, with no difference between groups. Recent memory improved significantly in the fluoxetine group but not in the amitriptyline group. Numbers of patients reporting side-effects were similar but the profiles of side-effects were different, with more patients on amitriptyline reporting anticholinergic and intolerable side-effects.

Twenty-eight elderly in-patients suffering from major depressive episodes received randomly, on a double-blind basis, amitryptiline or fluoxetine for 5 weeks. There were 4 drop-outs in the amitryptiline group and 2 drop-outs in the fluoxetine group. Both groups showed a significant amelioration at the end point for HRS-D scores compared to the baseline value. Anticholinergic side-effects were significantly more severe in the amitryptiline group. Weight gain was detected only in patients receiving amitryptiline.

The treatment of depressed patients with a fixed dose of amitriptyline is compared to treatment with an individualized dose calculated by means of a simple pharmacokinetic test. Clinical response and the development of side-effects are compared between the two groups of patients. Although the numbers in the groups were small, the clinical results lend little support to the concept of a therapeutic range of plasma drug concentrations for amitriptyline, and none of the plasma concentrations was high enough to produce serious toxic effects. No obvious clinical advantage was observed in the predicted dose treatment group as assessed by a reduction in depression ratings. The dose prediction test did however more than halve the variance in blood drug concentrations, and its usefulness in preventing high and potentially toxic concentrations is indisputable.