Assessment of the serotonin and norepinephrine reuptake blocking properties of duloxetine in healthy subjects.

Duloxetine is a dual inhibitor of norepinephrine (NE) and serotonin (5-HT) uptake. Initial trials conducted in depressed patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy as an antidepressant. The aim of this study was to assess the effects of duloxetine on the 5-HT and NE reuptake processes in healthy human volunteers. Twenty-seven healthy young males without a history of psychiatric disorder were randomly assigned to four groups, each group receiving one of the following daily drug regimens: placebo, clomipramine (a potent 5-HT/NE reuptake blocker) 100 mg/day, duloxetine 20 mg/day, or duloxetine 60 mg/day. In order to assess the NE reuptake process, the pressor response to intravenous tyramine (4 and 6 mg) was measured. Determination of the whole blood 5-HT content was used to evaluate the 5-HT reuptake blockade. These measurements were performed at baseline and repeated after 7 and 14 days of drug intake. Both duloxetine, at doses of 20 to 60 mg/day, and clomipramine significantly interfered with the 5-HT reuptake process, as demonstrated by marked decreases in blood 5-HT concentrations. However, the same doses of duloxetine, unlike clomipramine, failed to impede the usual increase in blood pressure that follows a tyramine intravenous infusion, indicating that clomipramine but not duloxetine blocked NE reuptake. At doses tested in a population of healthy volunteers, duloxetine acted as a selective 5-HT reuptake inhibitor, having no clear effect on the NE reuptake process. Nevertheless, given that the highest dose of duloxetine increased supine systolic blood pressure, it is possible that it represents the threshold regimen for NE reuptake inhibition.

Therapeutic effects and long-term efficacy of antidepressant medication for persons with developmental disabilities. Behavioral assessment in two cases of treatment-resistant aggression and self-injury.

Recent advances in pharmacological treatment of severe behavior disorders in persons with developmental disabilities suggest the use of antidepressant medication for therapeutic management. This research evaluated two antidepressant medications for treatment-resistant aggression and self-injury exhibited by two persons with developmental disabilities. Behavioral assessment data documented that sertraline (a serotonin selective reuptake inhibitor) was effective in reducing self-injurious behaviors in a 20-year-old man with severe mental retardation and clomipramine (a tricyclic antidepressant) was associated with the elimination of aggressive behavior in a 14-year-old boy with autism. Clinical effects from the medications were measured in relation to and shown to be a function of dosage level. Extended follow-up assessments revealed maintenance of treatment gains with continued medication administration.

Sertraline and obsessive compulsive disorder: new indication. Limited assessment.

(1) Sertraline, a selective serotonin reuptake inhibitor (SSRI), is now licensed in France for the treatment of obsessive-compulsive disorder in adults. (2) In this indication the clinical file is of acceptable methodological quality, but it is incomplete: sertraline has not been compared with the other two serotonin reuptake inhibitors approved in obsessive-compulsive disorder, namely fluoxetine and paroxetine. (3) Three placebo-controlled trials have demonstrated the efficacy of sertraline in obsessive-compulsive disorder. (4) In a trial versus clomipramine, sertraline was no more effective in patients able to tolerate the drug, but the rate of treatment withdrawals for adverse events was higher on clomipramine.

Electrocardiographic assessment of antianxiety medication in dogs and correlation with serum drug concentration.

OBJECTIVES: To determine effects of tricyclic antidepressants (TCA) on the ECG of dogs treated for behavioral conditions and to examine correlations between ECG findings and serum concentrations of these medications. DESIGN: Repeated-measures study. ANIMALS: 39 client-owned dogs with behavioral problems. PROCEDURE: Two groups of dogs with behavioral problems were evaluated. In group 1 (n = 20), ECG tracings were recorded before starting treatment with TCA and again after treatment for > or = 1 month. Dogs in group 2 were already on long-term maintenance amounts of antianxiety medication when ECG tracings were recorded and serum concentrations of medications were obtained. RESULTS: Significant differences were not detected for dogs in group 1 between ECG values measured before and after TCA administration. The ECG values for dogs in group 2 did not differ significantly from the mean of group-1 dogs before receiving medication or from the reference range used at our facility. Duration of the P wave had a significant positive correlation with serum concentrations of clomipramine but significant negative correlation with serum concentrations of amitriptyline. The QT interval corrected for heart rate had a significant negative correlation with serum concentrations of amitriptyline. CONCLUSIONS AND CLINICAL RELEVANCE: Amitriptyline and clomipramine administered at standard dosages apparently do not cause ECG abnormalities in healthy dogs with behavioral problems. These medications should be used cautiously in dogs with conduction abnormalities, and clinicians should periodically monitor ECG and use good clinical judgment to weigh risks and benefits of medications for the safety of each dog.

A risk-benefit assessment of drugs used in the management of obsessive-compulsive disorder.

Established efficacy and tolerability in large multicentre controlled studies have made serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SRIs) the mainstay of monotherapy for adult obsessive-compulsive disorder (OCD). When compared with the selective serotonin reuptake inhibitors (SSRIs), the tricyclic compound clomipramine has a higher incidence of adverse effects but is well tolerated by most OCD patients and may confer the best overall antiobsessional effects. Consideration of specific adverse effect profiles, special patient population characteristics, drug interactions and relative cost of the various agents may direct clinicians in choosing the most appropriate first-line drug. Alternative agents as monotherapies have been explored, but none has consistently proven effective to date. Investigations of SRI augmentation with serotonin-enhancing agents have also failed to demonstrate substantial benefits for treatment-refractory OCD. Combination treatment with SRIs and dopamine receptor antagonist drugs appears to provide an improved response for the subpopulation of OCD patients who have comorbid 'tic-spectrum' disorders, though large-scale studies of the efficacy and tolerability of these regimens are not yet available.

Comorbid anxious signs and symptoms in major depression: impact on functional work capacity and comparative treatment outcomes.

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.

Reliability of data on haematotoxicity of antidepressants. A retrospective assessment of haematological monitoring in clinical studies on tricyclics.

At the present time, there is some concern over the haematological adverse effects of antidepressants. The present paper examines retrospectively 314 clinical trials in depression which were published in English or French between 1958 and 1986 and which used at least one of the following tricyclics: amitriptyline, clomipramine, imipramine. Two decision tables assess the depth of detail with which haematological monitoring and safety were described by the authors of each study. The results indicate that more than 98% of the papers under scrutiny either provide no information on the subject or do so in a manner which is entirely subjective. Thus, it seems that current knowledge of haematotoxicity of antidepressants is almost entirely the result of spontaneous reports from doctors, with its well-known drawbacks.

An assessment of clomipramine (Anafranil) in the treatment of premature ejaculation.

A trial of clomipramine in the treatment of premature ejaculation is described. For the first 4 weeks the drug was administered in a double-blind manner and compared with matching placebo, the two medications being randomly assigned to suitable patients. During the second month patients 'crossed over' to the alternative therapy. Following the completion of the double-blind period all patients received clomipramine for a further 3 months. The drug was administered initially in a dose of 10 mg daily with an option to increase in individual cases to 40 mg. Twenty patients entered the trial, sixteen completed it. During the double-blind study no difference could be shown between clomipramine and placebo in their effect on premature ejaculation. But during the follow-up period nine patients were found to have derived benefit from combined treatment.