A double-blind, placebo-controlled trial of abecarnil and diazepam in the treatment of patients with generalized anxiety disorder.

In a multicenter, double-blind trial, 310 patients who had received a diagnosis of generalized anxiety disorder were treated for 6 weeks with either abecarnil, diazepam, or placebo at mean daily doses of 12 mg of abecarnil or 22 mg of diazepam administered three times daily. Patients who were improved at 6 weeks could volunteer to continue double-blind treatment for a total of 24 weeks. The maintenance treatment phase allowed the comparison of taper results for the three treatments at several study periods (0-6 weeks, 7-12 weeks, and more than 12 weeks). Slightly more diazepam (77%) and placebo (75%) patients completed the 6-week study than abecarnil patients (66%). At intake and baseline, after a 1-week placebo washout, the patient was required to have a Hamilton Rating Scale for Anxiety score of > or =20. Major adverse events for both abecarnil and diazepam were drowsiness, dizziness, fatigue, and coordination difficulties. Clinical improvement data showed that both abecarnil and diazepam produced statistically significantly more symptom relief than did placebo after 1 week of treatment. At 6 weeks treatment (using last observation carried forward analysis), however, only diazepam still differed significantly (p < 0.01) from placebo. High placebo response (56% moderate to marked global improvement) at 6 weeks, as well as a slightly lower nonsignificant improvement rate observed with abecarnil, a partial y-aminobutyric acid (GABA) agonist, when compared with diazepam, a full GABA agonist, most likely contributed to our findings. Finally, taper results showed that only diazepam and not abecarnil caused the presence of temporary discontinuation symptoms, but only in patients who had been treated for at least 12 weeks.

Pharmacodynamic comparison of single doses of IFN-beta1a and IFN-beta1b in healthy volunteers.

In a study in 75 volunteers, preparations of interferon-beta1b (IFN-beta1b) and IFN-beta1a were compared in terms of the resulting serum concentrations of three biologic markers, neopterin, human Mx protein, and 2',5' oligoadenylate synthetase. Each preparation was tested at five dose levels, the middle dose being that recommended for use in patients with multiple sclerosis on the basis of large clinical trials. Five randomly chosen volunteers each received a single subcutaneous dose of one of the IFN or of IFN-beta1a given intramuscularly. The amounts of each marker induced were dose related. There were no major differences between the results with the two IFN or in the duration of the changes in the markers after the two routes of injection. The data indicated that 8 million international units (MIU) of IFN-beta1b and 6 MIU of IFN-beta1a had very similar effects. Even after the highest single dose tested, the increase in the biologic markers were not sustained for a full week.

Abecarnil, a new beta-carboline, in the treatment of anxiety disorders.

BACKGROUND: Abecarnil, a novel anxiolytic beta-carboline, was investigated in five four-week double-blind, European multicentre studies. Overall 451 patients with generalised anxiety disorder were randomised to abecarnil, 461 to placebo and 464 to active controls. METHOD: Data includes inferential statistics based on individual studies and descriptive analysis of 323 patients in open-label abecarnil long-term continuation up to 52 weeks. RESULTS: Abecarnil was safe, the most frequent adverse event being drowsiness. Onset of effect was at week 1. At week 4 the Hamilton Anxiety Scale score had improved by 12-13 points on average. Due to notably large and variable placebo effects abecarnil was not consistently superior to placebo. No rebound or withdrawal symptoms were observed after fast-tapered discontinuation. Safety, extent of efficacy and incidence of rebound or withdrawal did not change during long-term treatment. CONCLUSIONS: Abecarnil is safe and effective. Further research into its therapeutic potential seems warranted.

Terguride in stable Parkinson's disease.

Terguride (TER) (2 mg/day) was compared with a placebo in 41 stable Parkinson's disease (PD) patients, so as to test its efficacy as an add-on treatment to spare levodopa (LD). After the 4th week of add-on treatment, LD was reduced by about 25%. The number of "stable" patients (--those with an increase of no more than 20% of the basal Columbia University Rating Scale (CURS) score--remaining after LD reduction was used to compare the two add-on treatments. Most patients, remained "stable" in spite of LD reduction, and no significant differences between the therapies were discovered; the CURS score decreased over time only in the TER group. Hence, TER was shown to be a drug that has DA-ergic properties but with minimal antiparkinsonian efficacy.

Negative symptoms in schizophrenia: considerations for clinical trials. Working group on negative symptoms in schizophrenia.

There is little agreement about the methodology of clinical trials of antipsychotic drugs in patients with negative symptoms. A literature review revealed wide variation in experimental design, rating scales and study duration. This reflects differing views as to the definition and response to treatment of negative symptoms. Some degree of standardization would improve comparability of studies and aid the development of new compounds. Patients included in such studies should have displayed negative symptoms for at least 6 months. Depressive symptoms, positive schizophrenic symptoms and extrapyramidal signs may all influence or be confused with negative symptoms and may respond to treatment; they should be at a low level at baseline and should be measured during the study period. Studies should last at least 8 weeks. Several scales are available for measuring negative symptoms and are reviewed; a global impression score should be used additionally.

Terguride in fluctuating parkinsonian patients: a double-blind study versus placebo.

Terguride (TER), a semisynthetic derivative of lisuride, has been found to display dopamine (DA) agonist and DA antagonist effects in animals, depending on the experimental model used. TER (2 mg/day) was compared to placebo in 41 fluctuating Parkinson's disease patients to test its effect on akinesia and dyskinesia. Mean hours "off" decreased at weeks 6 and 12 (p < 0.05) in the TER group but the overall difference from the placebo group was not significant. Only the TER group displayed a decrease over time in mean Columbia University Rating Scale total score "on" and "off" (p = 0.001 and p = 0.03, respectively). Duration of involuntary movements and resulting disability were not significantly different between patients on TER and those on placebo administration. In the overall evaluation, patients preferred TER (p = 0.01). Tolerance of TER was very good in all but one patient whose wearing-off increased; no one dropped out because of side effects. This 3-month double-blind study showed that TER, added to stable doses of L-dopa, may have slight antiparkinsonian efficacy.

Measures of memory and information processing in elderly volunteers.

A screening study was carried out in normal elderly volunteers to determine 1. their scores in measures of memory and information processing 2. how the measures correlate with sample characteristics 3. how the measures correlate with each other and with the EEG. We report here on 111 subjects, 56 women and 55 men aged 53-77 years (63.9 +/- 6.8) with average intelligence (Coloured Progressive Matrices CPM 26.7 +/- 5.1). In the C-normed measures of the word list from the Nuremberg Geriatric Inventory (NGI) our sample scored better than average (immediate recall of words C = 7.5, delayed recall of words C = 8.2; mean C = 5). The sample even attained ceiling scores in the test of recognition. The sample likewise had a better than average speed in a color-word test (CWT) of focused attention similar to the Stroop test (e.g., reading C = 7.5, color-naming C = 6.7, interference task C = 6.3) and in the ZVT trail-making test (C = 7.0). In contrast, speed-free focused attention was only average (C = 5.2 and C = 5.5). The following sample characteristics correlated with test measures of memory and information processing (p less than 0.01): age negatively with immediate recall, trail making, incidental episodic memory, focused attention, speed in the CWT; intelligence correlated positively with 10-min adding which relies on working memory (Pauli test) and immediate recall; education correlated positively with delayed recall, visual memory performance in a figures test, immediate recall, and reading speed in the CWT; occupation correlated positively with figures test performance; exercise of profession correlated positively with incidental episodic memory and immediate recall. Age and occupation correlated more with motor measures than with cognitive measures (pegboard, 1 min tapping at maximal speed). Sex had no bearing on memory characteristics, but did on tracking (men better) and color-naming performance in the CWT (women better). Of the semiluxuries, only regular alcohol consumption showed a relationship with the test measures (negatively with color-naming speed, immediate recall, and pegboard performance). Analysis of memory and information processing measures revealed no correlations (r greater than or equal to 0.40) between memory measures from the word list, Pauli test, figures test, and learning. Measures of the CWT correlated with Pauli test and pegboard. ZVT score was the variable with the most correlations (CWT, Pauli test, pegboard). A factor analysis with a reduced set of variables should further clarify the inner structure of our subject's performance.(ABSTRACT TRUNCATED AT 400 WORDS)

Anterograde and retrograde amnesia after lormetazepam and flunitrazepam.

In a pharmacopsychological study, memory impairments after single oral doses of benzodiazepines or placebo were investigated in 40 healthy men aged 20-40 years. The study was designed as a double-blind and placebo-controlled trial. Four independent groups of 10 subjects randomly received either 1 mg lormetazepam, 2 mg lormetazepam, 2 mg flunitrazepam, or placebo. The tests consisted of word lists, picture tests, and syllable pairs (consonant-vowel-consonant trigrams). Tests were performed before drug ingestion, and 1, 2, 3, and 5 h after application. Different test versions were used on each occasion. The target variables were immediate recall (after presentation and a 10-s distraction task) and delayed recall and recognition (after 30 min). Recognition was also tested after 24 h for all five versions. A distinction must be made between anterograde amnesic effects and retrograde amnesic effects. The greatest anterograde memory impairments were observed after 2 mg flunitrazepam (p less than 0.05). Lormetazepam 2 mg produced less marked impairments than flunitrazepam. Results after 1 mg lormetazepam did not differ from those after placebo. Performance in the memory tests was better under benzodiazepines than under placebo as regards material learned before drug ingestion, i.e. the benzodiazepines had not negative retrograde amnestic effects, but rather "promnesic" effects. The results suggest that the extent of the benzodiazepines' amnesic effects--both negative (anterograde) and positive (retrograde)--depends on the dosage and type of substance.

[Electroencephalographically determined sedative effects (vigilosomnography) of the new Thienodiazepin-derivate clotiazepam (author's transl)]. / Die elektroenzephalographisch bestimmte sedierende Wirkung (Vigilosomnographie) des neuen Thienodiazepin-Derivates Clotiazepam (Trecalmo).

In a double blind, randomized clinical study eighteen volunteers received either placebo or 5 mg diazepam or 5 mg clotiazepam at three different times at an interval of one week. Beside other parameters which have been measured a 60-minute polygraphic EEG recording was made thirty minutes after administration of the drugs. The vigilosomnograms revealed clear and reliable differences between placebo and the two active substances and suggest a sedative effect of both substances at the dose level used. There was only a slight difference between the two active substances. 5 mg clotiazepam produced a slightly stronger sedation than 5 mg diazepam. However, the records of autonomic side effects and subjective statements regarding the patients' condition showed that clotiazepam is associated with less side effects than diazepam.

[Comparison of experimental-psychological and clinical findings on the effect of a test substance (author's transl)]. / Vergleich experimentalpsychologischer und klinischer Befunde zur Wirkung einer Prüfsubstanz

The results of a pharmacopsychological study on male students high or low in emotional stability are compared to those of a clinical study on neurotic out- and inpatients. These studies examine the effects of diazepam and various doses of a thienodiazepine (Bay g 5653), a drug under investigation. Although the studies are not completely comparable (placebo control missing in the clinical study, not enough information about comparable base line measures) the differences in effects of Bay g 5653 and diazepam on the actual emotional state, as measured by an adjective check list, show a certain amount of correspondence between normal subjects and patients but also considerable discrepancies.