Lofepramine is a tricyclic antidepressant related to imipramine. Meta-analyses were carried out with respect to efficacy and tolerability by combining outcome and adverse reaction from over 20 controlled trials comparing lofepramine with other tricyclic antidepressants. Lofepramine was at least as effective as the comparators with fewer adverse effects. In particular, the risk/benefit ratio seemed superior to the comparators amitriptyline, imipramine, clomipramine, maprotiline and desipramine.

Following a multicentre double-blind controlled trial comparing the effects of fluvoxamine and imipramine in depressed inpatients (M.D.E.) 39 patients continued on longer term treatment with maintenance of double-blind conditions (17 on fluvoxamine, 22 on imipramine). The results regarding the reasons for premature interruption of treatment show a slight advantage in favour of fluvoxamine. There were several significant differences in favour of fluvoxamine at the 20th week. The most common side-effects were hot flushes with imipramine and dizziness with fluvoxamine. Overall, despite the small number of patients, the results show a greater clinical tolerance to fluvoxamine than to imipramine.

Zopiclone, a new hypnotic cyclopyrrolone, undergoes extensive hepatic metabolism. The carrier of hypnotic activity is the parent compound; however, knowledge of its metabolic profile is essential for the understanding of pharmacokinetic changes in various pathophysiological conditions. In 45 healthy young volunteers, zopiclone had a Tmax of 0.5. A first-pass effect of 20% resulted in an absolute bioavailability, F, of 77%. The volume of distribution ratio Vdc/Vdt was 3.2. The plasma half-life (t1/2) was 5.1 h. A metabolic ratio of 3.7 and 4.6 was found for the two main urinary metabolites, N-oxide and N-desmethyl derivatives. No modifications of kinetics were seen after chronic treatment. In eight patients with liver insufficiency, the main changes (delayed Tmax, 3.5 h, higher plasma concentrations with an increased F of 97%, prolonged t1/2 of 8.4 h) were essentially due to a reduced hepatic metabolic clearance, as shown by a decreased metabolic ratio for the two main metabolites. In 18 patients with renal insufficiency, the only major modification was an increased bioavailability (F of 115%) probably due to a relative decrease of the Vdc. In 19 elderly subjects, the main findings were a decreased metabolic clearance, as shown by decreased metabolic ratios, and an inversion of the Vdc/Vdt ratio, evoking the changes seen in renal insufficiency. The increase in F (168%) and the age-dependent increase in plasma t1/2 (8.1 h) in the oldest subjects (over 74 years of age) can be explained by this double mechanism. On the basis of these findings, a reduction of the initial zopiclone dose from 7.5 to 3.5 mg/day is recommended for patients with severe liver insufficiency and patients over 70 years of age with liver insufficiency.

The influence on memory of 7.5 mg zopiclone, given in single and repeated doses was compared with that of 2 mg flunitrazepam, 5 mg nitrazepam and placebo. Compared with placebo, all three drugs induced some impairment of memory especially after the first day of administration. Effects were more pronounced for the two benzodiazepines and more marked for flunitrazepam. There was one report of an anterograde amnestic episode after flunitrazepam.

A double-blind crossover trial was conducted in 42 outpatients of either sex in order to obtain information on the properties of 7.5 mg of zopiclone in a general practice setting compared with 2 mg of flunitrazepam. Each patient went through two periods of treatment, each period lasting 10 days. A comparison of the effect of the drugs showed a significant difference with regard to effectiveness and sleep latency favoring flunitrazepam. When patient's preferences were analyzed there was a highly significant difference favoring flunitrazepam both for effectiveness and tolerance. The side effects from both drugs were generally mild.

We carried out a randomized double-blind study. This was a crossover design with two periods of 2 days each with one compound (either zopiclone or triazolam). The next 2 days of active trial periods the patients were allowed to choose the preferred coloured capsule of which both neither the patients nor the investigators knew about its real contents. 40 volunteers were chosen from our patients suffering from chronic alcoholism who just finished their detoxification. There were given coloured coded capsules, each of them containing either 0.25 mg triazolam or 3.75 mg zopiclone. The capsules should be swallowed when patients felt a desire for alcohol. The maximal dosage was 8 capsules per day (2.0 mg triazolam and 30 mg zopiclone). There was a significant difference of degrees of freedom and probability at a level of 0.0005 for the items of the Addiction Research Centre Inventory and a level of 0.0005 for the items of the 'profile of mood states'. None of the volunteers developed a special desire for zopiclone after withdrawal of the medication.

Pharmacokinetics and metabolism of a new hypnotic, zopiclone (ZD), were studied under the following conditions: (1) rats and dogs were given oral doses of the molecule, 14C-labeled either on the side chain or on the pyrrolopyrazine nucleus; (2) rats, rabbits and dogs were given increasing oral doses of the cold compound; (3) human subjects in various physiopathological situations--young and elderly healthy volunteers, patients with liver or renal impairments, nursing mothers--were given single or repeated doses, p.o. or i.v. (range 3.5-15 mg). ZD is rapidly and efficiently absorbed: its oral bioavailability was greater than 75% in all species except rats, where a first-pass effect of about 65% was recorded. Plasma protein binding is about 45%. The radioactive material rapidly diffuses from the vascular compartment, with a marked affinity for the brain. Plasma kinetics of ZD are generally well described by a two-compartment open model; in man, terminal half-life is 4-5 h; total body clearance is large (300 ml/mn), renal clearance very low (10 ml/min). The relationship between doses and concentrations, doses and urinary excretion of unchanged compound and major metabolites was linear in all species, except rabbits. The major metabolic routes involve decarboxylation affecting more than 50% of dose (rats and dogs), N-demethylation and N-oxidation--more than 30% as N-desmethyl and N-oxide derivatives in urine (humans). Due to intensive metabolism, only 7-10% of the dose is recovered in urine and feces as unchanged compounds (all species). In nursing mothers, milk and plasma kinetics of ZD are similar with a milk/plasma ratio around 0.80. In human volunteers, plasma half-life of ZD increases with age, while patients with liver or renal impairments show little or no modification of pharmacokinetic parameters.

Phase I and phase II studies of anxiolytic compounds have been described in details in some guidelines issued by various authorities. Their methodology leads to original problems with regard to objectives, subjects, and experimental design. The performance of such studies remains difficult especially due to the use of volunteers in phase I and to the use of placebo and diagnostic criteria in phase II.

Interaction between alcohol and zopiclone or flunitrazepam as well as the residual effects of both these hypnotics were studied in 20 normal male volunteers who received each 3 of 6 different drug and drink combinations according to a balanced incomplete block design as follows: placebo, zopiclone (7.5 mg), or flunitrazepam (2 mg) was administered double-blind in identical capsules at 23.00 h, and 0.5 g/kg body weight of alcohol or placebo alcohol was given at 08.30 h the following morning. Psychomotor skills of the volunteers were measured before drinking and 30 min, 1.5 h and 2.5 h after it. As compared with placebo, zopiclone had no residual effects, while flunitrazepam had some effects on standing steadiness, tracking, and flicker recognition. Alcohol alone had a non-significant effect on skills, and the combination zopiclone plus alcohol behaved as alcohol alone. Flunitrazepam plus alcohol impaired significantly standing steadiness, tracking, and reactive skills when compared with all other treatments. Time anticipation and hand and foot proprioception were not affected by any treatment. The results suggest that flunitrazepam, unlike zopiclone, has residual effects and interacts with alcohol in the morning following overnight ingestion of the drug.

Zopiclone, a new hypnotic with an original chemical structure, was compared in a sleep laboratory study with nitrazepam according to a double-blind, parallel group randomized design. Zopiclone (7.5 mg) and nitrazepam (5 mg) were each given for 14 nights to 5 insomniacs; a placebo washout period of 4 nights and a placebo withdrawal period of 10 nights were included in the design. Both drugs were found to be immediately and lastingly effective. Some slight insomnia rebound was found with nitrazepam, but not with zopiclone. Stage 2 was decreased, slow wave sleep (SWS) increased, and rapid eye movement unchanged by both drugs: however, only nitrazepam increased rapid eye movement latency. The differences between the effects of the drugs were quite limited. However, 3 out of 50 comparisons favoured zopiclone and none nitrazepam.

20 schizophrenic patients presenting with an acute episode were treated first, whilst hospitalized, by a single oral dose of pipotiazine, then, when their symptomatology had been controlled, thus allowing their discharge, by a monthly injection of pipotiazine palmitate for 6 months. The patients were assessed with a CGI and the BPRS. The tablets provided control of the symptoms of most patients as early as the second week of treatment, the improvement bearing particularly on thought disorder, concept disorganization, excitation, anxiety, depression, tension and somatic symptoms. This led to an improvement in activities and sociability. Injections not only provided the prevention of relapses but even an improvement over the already obtained results which allowed these patients to insert themselves in the community. Adverse effects were infrequent and easily controlled. There were no abnormal modifications of the vital signs and laboratory tests. Pipotiazine appears as an extremely useful drug for countries in which the psychiatric treatment network is still being constructed.

Fifty-four depressed patients aged 18 to 65 years were treated for 4 weeks with a daily dose of either 60 mg mianserin or 150 mg imipramine in a double-blind controlled trial. The results which were measured on the Hamilton rating scale, on the Beck and on the Overall rating scale, on the brief psychiatric rating scale (BPRS) and on a global rating scale, did not show any significant difference relative to the antidepressive efficiency of both products. The frequency of side-effects however was significantly lower in the mianserin group than in the imipramine group.

Heighty two outpatients, suffering from reactive or neurotic depression have been treated with a daily 100 mg dose of nomifensine. The symptomatic status before treatment was appreciated by a self-rating scale, the Hopkins Symptoms Check List (HSCL). At the end of the study, the patient again filled out this same rating scale, and also a seven-score amelioration questionnaire. The investigator filled out this same questionnaire and a fourscore global impression scale. We tried to find out if by appreciating initial symptoms with the HSCL, it was possible to predict which patients would be responders to the treatment. The only highly significant result was obtained with a discriminant analysis, which combines 22 items of the pre-therapeutic HSCL and with which it is possible to predict the amelioration measured by the difference between the total pre- and post-therapeutic HSCL notations. The authors point out to the interest of this method in psychopharmacology.