Double-blind comparative study of the antidepressant, unwanted and cardiac effects of minaprine and amitriptyline.

1. A double-blind, multicentre study comparing the efficacy and safety of minaprine and amitriptyline in patients with major depression was carried out. Five hundred and thirty-one patients were randomly assigned to treatment with either minaprine 100 mg, 200 mg or 300 mg day-1 or with amitriptyline 150 mg day-1 (75 mg during the first week). The medication was administered for 6 weeks. 2. Efficacy was assessed using the Hamilton rating scale for depression (HDRS), the Montgomery-Asberg depression rating scale (MADRS) and visual analogue assessments of depression carried out by both the investigators and patients. Unwanted effects were assessed by a questionnaire and spontaneous reporting. In a subgroup of patients cardiovascular effects were investigated by high speed ECG and systolic time intervals. 3. Patients in each treatment group showed a significant clinical improvement (P < 0.01) from baseline. The mean HDRS and MADRS scores adjusted for baseline differences, showed significantly less improvement in the minaprine 100 mg once daily (P < 0.01) and the minaprine 300 mg daily (P < 0.01) groups than in the amitriptyline group at both week 4 and week 6. The MADRS score at week 4 suggested that 200 mg day-1 minaprine was less effective than amitriptyline (P < 0.05), but there was no difference between the two groups at week 6 on either the HDRS or the MADRS. 4. Both drugs were well tolerated and there were no significant differences between treatment groups in any of the safety and tolerance assessments. In the ECG, amitriptyline produced a significant increase in the heart rate and PR interval while minaprine had no effect on electrocardiographic measurements. Neither drug produced changes in the systolic time intervals.

Effects of ethanol on the NMR characteristics of rat brain. Acute administration, dependency, and long-term effects.

In rats, neither acute administration of ethanol nor the establishment of ethanol dependence by chronic administration for 28 days produced significant 1H-NMR relaxation changes. However, chronic ethanol intake for six months produced a transient rise in T1, with no change in T2 or water content. The significance of these results for study in man is discussed and a hypothesis is proposed to explain discrepant differences between T1, T2 and water content. It is suggested that T1 change with long-term ethanol exposure is related to altered free/bound water state secondary to cell membrane changes.

Regional variation in rat brain proton relaxation times and water content.

Relaxation times (T1 and T2) and water content are measured in frontal cortex, amygdaloid cortex, hippocampus, mid-brain and cerebellum of rat brain. Differences are found in relaxation times, between areas containing a mixture of grey and white matter, and grey matter only. Differences were also found between certain grey matter areas. Relaxation times correlated with water content.

Drugs which stimulate or facilitate central GABAergic transmission interact synergistically with delta-9-tetrahydrocannabinol to produce marked catalepsy in mice.

In experiments in which mice were placed with their forelegs over a 4 cm high horizontal bar, pretreatment with delta-9-tetrahydrocannabinol (THC; 10 mg/kg i.p.) significantly delayed descent from the bar. This response to THC was markedly enhanced by doses of amino-oxyacetic acid, flurazepam, cis(Z)-flupentixol, muscimol, (-)-baclofen and NO-328 having little or no effect when given alone. No synergism was detected between THC and (+)-baclofen or trans(E)-flupentixol. The interactions between THC and flurazepam, amino-oxyacetic acid and NO-328 were attenuated by (+)-bicuculline and by homotaurine, but not by strychnine. The interaction between THC and (-)-baclofen was prevented by homotaurine but not by (+)-bicuculline whereas only (+)-bicuculline reduced the interactions of THC with muscimol and cis(Z)-flupentixol. Flumazenil prevented the interaction between THC and flurazepam but not that between THC and NO-328. The results suggest that the synergistic interactions observed in this study depended on the activation of GABAA and/or GABAB receptors, probably located in extrapyramidal GABAergic pathways.

Delta-9-tetrahydrocannabinol-induced catalepsy in mice is enhanced by pretreatment with flurazepam or chlordiazepoxide.

Pretreatment with flurazepam (3 mg/kg s.c.) or chlordiazepoxide (5.5-30 mg/kg s.c.) at an ambient temperature of 34 degrees C, markedly enhanced the cataleptic response of mice to delta-9-tetrahydrocannabinol (THC; 5-20 mg/kg i.p.) as measured in a bar test. Also, the incidence of loss of the righting response was significantly greater in mice receiving a subhypnotic dose of flurazepam (0.3-3 mg/kg s.c.), followed by THC (5-20 mg/kg i.p.), than in animals receiving THC preceded by saline. Loss of the righting response was not associated with any gross reduction in skeletal muscle tone (inclined screen and wire grip tests) and it was proposed that the animals were not anaesthetized but instead could be placed on their backs because flurazepam had enhanced the cataleptic effect of THC. Loss of the righting response produced in mice by pentobarbitone (60 mg/kg i.p.) or by a large dose of flurazepam (300 mg/kg s.c.) was associated with a marked loss of muscle tone and probably indicated the induction of anaesthesia. It is possible that THC interacts with benzodiazepines by increasing synaptic concentrations of gamma-aminobutyric acid (GABA). However, many other possible mechanisms exist and these cannot yet be excluded.