Charles C. Weise

Placebo-controlled trial of venlafaxine for the treatment of major depression.

Results are presented of the first double-blind, placebo-controlled trial of a novel antidepressant venlafaxine, which preclinically has demonstrated serotonin, norepinephrine, and dopamine reuptake inhibiting effects. Sixty outpatients meeting DSM-III-R criteria for major depression were randomized to receive 6 weeks of treatment with one of three fixed doses of venlafaxine—25 mg three times a day, 75 mg three times a day, or 125 mg three times a day—or placebo. Significant improvement was observed in depression scores at all doses, with the high dose resulting in earlier improvement, by week 2. For the combined venlafaxine treatment groups, 68% achieved a moderate or marked improvement on the Clinical Global Impression scale, compared with only 31% for the placebo group. Venlafaxine was well tolerated, and nervousness, sweating, and nausea were the only adverse effects observed more frequently with drug compared with placebo.

A placebo-controlled, double-blind, clinical trial of paroxetine in depressed outpatients

A placebo‐controlled, randomized, double‐blind study was carried out in outpatients suffering from major unipolar depressive disorder to assess the efficacy and tolerability of paroxetine in the treatment of depression. The study lasted for six weeks. After a placebo washout period of 4 to 14 days patients took 20mg of paroxetine or matched placebo as a morning dose for one week; thereafter the dose of paroxetine could be titrated between 10 and SOmg/day. Patients were evaluated at baseline, weekly during the first four weeks of the study, and at the end of sixweeks; patients who entered a six‐week extensionphasewere evaluated at 9 and 12 weeks. Evaluations were carried out using HAMD (including ECDEU factors), MADRS, HSCL, Covi anxiety and Raskin depression scales, CGI, and a seven‐point rating of global improvement. Adverse events and laboratory values were also recorded at each assessment. One hundred and eleven patients entered the study, and efficacy data were available for 102 of these (49 on paroxetine and 53 on placebo). Efficacy measurements demonstrated significantly greater clinical improvement with paroxetine than placebo after two weeks of treatment, and this became even more marked after six weeks. Patients who continued treatment for a further six weeks maintained their clinical improvement. When adverse events were examined, statistically significant differences between paroxetine and placebo were seen only for sweating, diarrhoea, nausea, and somnolence. No significant changes were seen in any of the laboratory parameters measured. If these results are confirmed in future studies, paroxetine will represent an important addition to the treatments available for depression.

Setting, patient, and doctor effects on drug response in neurotic patients

Diazepam was compared to placebo and phenobarbital sodium in a double-blind study with 472 anxious psychoneurotic patients. Patients were treated in 3 settings — medical clinic, general practice, and private psychiatric practice. The treatment setting was found to be at least as important as the medication in producing a treatment response. Drug effects were pronounced. Compared to phenobarbital patients, diazepam patients more often completed the study, followed prescribed dosage, and reported fewer side reactions. Diazepam patients did not differ from placebo patients in dosage intake or side effects, only in higher completion rate. Population effects indicated clinic patients to drop out and deviate from dosage more than private patients. General practice patients reported the most and private psychiatric patients reported the least side effects. These differences are explained in terms of patient background and behavioral patterns and of a medical as opposed to a psychiatric orientation toward treatment.

Pemoline and methylphenidate in mildly depressed outpatients

Pemoline and methylphenidate hydrochloride were compared to placebo in a double‐blind stUdy of mildly to moderately depressed outpatients with target symptoms of fatigue, apathy, anorexia. Patients attended either the psychiatric clinic of a large city hospital or the offices of several general practitioners and private psychiatrists. Clinic patients had Significantly lower educational and occupational levels than the middle‐ class private practice patients. At 2 and 4 weeks, both pemoline and methylphenidate produced significantly more improvement than placebo in clinic and general practice patients. Private psychiatric patients, however, improved as much or even slightly more on placebo than on either drug. A number of explanations are put forward.

Pills and improvement: A study of placebo response in psychoneurotic outpatients

SummaryThe hypothesis that clinical improvement would be significantly correlated with number of daily placebo pills prescribed was supported for clinic and general practice patients but not for private psychiatric practice patients. Patients in the 3 treatment settings differed in other ways, particularly in treatment orientation, i.e., their awareness of having emotional problems and the most suitable treatment recommended for them by their physicians, as well as in social class. Treatment orientation was found not to account for the demonstrated “pill effect”, and social class differences, seen only in general practice, also did not appear to modify the relationship between pills and improvement within the entire patient sample.Our findings in this study have methodological as well as clinical implications. The fact that higher placebo intake levels resulted in reduced drug-placebo differences in improvement poses a practical problem for the clinical researcher, while the lack of placebo improvement observed at lower placebo intake levels indicates that 1 placebo pill per day is not a very effective agent in the symptomatic treatment of neurotic outpatients. Further research is needed to determine the optimal dosage for placebo therapy. Perhaps dosage intake norms, which probably vary within different treatment settings and social classes, represent a major factor influencing the “pill effect” on placebo response.

Controlled psychopharmacological research in private psychiatric practice

In an a t tempt to develop new means of drug evaluation, as well as to utilize more appropriate study populations than low socio-economic clinic patients, the authors have conducted the present, primarily methodological study, choosing a standard rather than experimental agent for this purpose. The selection of meprobamate (Equanil, Mfltown) was influenced by the fact that still, after more than 10 years of use [1], no clear cut evidence has come to the fore supporting its claim of efficacy in patients being treated simultaneously with analytically oriented psychotherapy. The upshot of many placebo controlled studies is that most demonstrated clinical efficacy of meprobamate in the symptomatic t rea tment of anxious neurotic patients [11,24,8,25], but others were not able to differentiate significantly between drug and placebo [25,15,14]. Among the former are several controlled studies, performed by one of the authors (Dr. RICKELS) during the past 6 years at the University of Pennsylvania, using medical and psychiatric clinic patients [16,21,10], as well as patients encountered in general medical practice in North Carolina [22]. Significant meprobamate-placebo differences in clinical improvement were demonstrated after 2 and 4 weeks of therapy. Patients. were usually seen for short visits of only 10--15 min duration, thereby receiving only minimal additional supportive psychotherapy, if any. The position may be different when meprobamate and psychotherapy are combined, but the authors at present can cite only two controlled

Tricyclic plasma levels in depressed outpatients treated with amitriptyline

Seventy-four patients were treated with 150 mg/day amitriptyline (AT) to determine possible correlations between clinical improvement, demographic variables, and AT and nortriptyline (NT) plasma levels. Plasma level determinations after 2 and 6 weeks of treatment revealed that moderately significant correlations existed between AT plasma levels and clinical improvement, dosage intake, age, weight, sex, and coffee intake. Some of these findings were more pronounced after 2, and some after 6 weeks of treatment.

Doxepin and amitriptyline-perphenazine in mixed anxious-depressed neurotic outpatients: A collaborative controlled study

Doxepin was compared to the combination of amitriptyline-perphenazine in a double-blind controlled study conducted with 100 clinic, general practice, and private psychiatric practice outpatients diagnosed as suffering from a mixed anxiety-depressive reaction. The relatively few statistically significant differences found in the study indicated amitriptyline-perphenazine to be more effective than doxepin (main drug effects), general practice patients to improve the most and private psychiatric patients the least (main population effects), and clinic patients to respond better to doxepin, while general practice and private psychiatric patients improved most with the drug combination (drug×population interaction effects).Amitriptyline-perphenazine was found to produce more improvement in high and doxepin in low depressed patients, and doxepin was observed to be more effective in lower than in higher social class patients. Patients on doxepin tended to report more side effects, but to drop out less frequently than patients on the drug combination.

Lofepramine and imipramine in unipolar depressed outpatients

This is a double‐blind study involving 158 outpatients diagnosed ac‐cording to the DSM‐III as suffering from major depressive disorder. Both active drugs produced significantly more improvement than placebo on both physician and patient ratings, and lofepramine produced slightly less sedation and anticholinergic effects when compared with imipramine.

Ketazolam and Diazepam in Anxiety: A Controlled Study

Ketazolam (both in once-daily and three-times-daily dosing), diazepam, and placebo were compared for effectiveness in relieving anxious symptomatology in a clinical trial conducted with a total of 222 anxious, non-psychotic outpatients. Results indicated that improvement occurred early in treatment, that ketazolam was equally effective in both once-daily and three-times-daily dosing, and that ketazolam was similar in effect to diazepam. Ketazolam (both once-daily and three-times-daily) and diazepam were significantly (P < 0.05) better than placebo in alleviating symptoms of anxiety, as measured by the Hamilton Anxiety Scale, the Covi Anxiety Scale, and a physician-rated measure of global improvement.