Recent developments in antidepressant agents.
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Biomedical subjects
Publications and source records attributed to J Claghorn.
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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.
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.
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).
This paper presents the results from a large multicenter study, performed at three clinical research units in the USA. Prior to a three to seven days of placebo washout period, patients were randomly assigned to zimelidine, a potent and selective 5-HT reuptake blocker, amitriptyline or placebo. The scheduled treatment period was four weeks. Dosage range was 75-300 mg/day for active medications. The rating instruments were the Hamilton Depression Scale and the Clinical Global Impression scale. The side effects were recorded by using a side effect inventory (TESS). Vital signs, laboratory work including clinical chemistry, ECG, and plasma levels of drugs, were performed. In the main efficacy evaluation there were 229 depressed outpatients included, all having completed at least two weeks of treatment after the washout period. The patients treated with zimelidine as well as those treated with amitriptyline showed a significant improvement relative to the placebo treated patients. For the safety evaluation 263 patients were included. Side effects, in particular anticholinergic effects but also drowsiness and cardiovascular effects, were much less pronounced in the zimelidine group as compared to the amitriptyline group. Only marginal differences regarding side effects were reported for zimelidine compared to those reported for placebo.
Zimeldine tolerability was compared to amitriptyline and placebo in a large multicentre study performed at three clinical research units in the U.S.A. Prior to a placebo washout period of 3-7 days, patients were randomly assigned to zimeldine, a potent and selective 5-HT reuptake blocker, amitriptyline or placebo. Dosage range was 75-300 mg/day for active medications, and the scheduled treatment period was 4 weeks. The side-effects were recorded by using a Treatment Emergent Symptom Scale (TESS). Vital signs were monitored and laboratory investigations, including chemistry and drug plasma levels, were performed. Two hundred and sixty-three patients were included in the safety evaluation. Side-effects, particularly anticholinergic effects but also drowsiness and cardiovascular effects, were much less pronounced in the zimeldine group compared to the amitriptyline group. Only marginal differences in side-effects were reported between zimeldine and placebo. Significantly more patients receiving amitriptyline were withdrawn from treatment as a result of adverse effects. Thus, zimeldine appears to be an effective antidepressant with marked advantages with regard to tolerability. It is therefore an important new contribution to the treatment of depressive disorders.
Plasma pseudocholinesterase activity was about 100% higher in patients with Alzheimer's type dementia than in similar age controls. Red cell acetylcholinesterase activity tended to be lower in patients than controls. Administration of lecithin substantially increased plasma choline levels but did not alter activity of either of the cholinesterase enzymes.
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