Moclobemide versus clomipramine in nonmelancholic, nonpsychotic major depression. A Study group.

The efficacy and the safety of moclobemide (400-600 mg/day), a reversible and selective inhibitor of monoamine oxidase-A (RIMA) and of clomipramine (100-150 mg/day) were compared respectively in 98 and 93 nonmelancholic, nonpsychotic out-patients with a DSM-III major depressive episode over 6 weeks and up to 3 months, in a multi-center double-blind trial. No statistically significant difference between the treatments was found on the number of responders, at 6 weeks and 3 months, to the Hamilton Depression Rating Scale (HDRS), which was the main criterion for efficacy. The sample size was sufficient to detect a difference of approximatively 20% in response rates. Reduction of the total scores on HDRS and Covi anxiety scale was comparable for both treatments, but the reduction on the Retardation Depressive Scale (RDS) was significantly higher with moclobemide at the 1- and 2-week assessments. According to the RDS as well as the global impression of both patient and physician, a somewhat earlier onset of antidepressant action was evident in the moclobemide group. Tolerance was significantly better in the moclobemide group, mainly due to a lower frequency of weight gain, sedation and anticholinergic effects.

Relevance of reversible inhibitors of monoamine oxidase type A and of reuptake inhibition for noradrenaline turnover.

Noradrenaline (NA) and serotonin, monoamines that increase neurotransmission at the monoaminergic synapses, remain primary targets for antidepressant drugs. To help elucidate NA's role in the action of antidepressants, a model was set up allowing for a simulation of NA turnover under various conditions examining 3 compartments: newly synthesized vesicular NA, released synaptic NA, and vesicular NA reuptake across neuronal membranes. We compared the influence of the reversible MAO inhibitor, moclobemide, and the NA reuptake inhibitor, desipramine, both useful in regaining baseline synaptic NA concentrations. Moclobemide appears less sensitive to fluctuations either in drug concentrations and/or physiological determinants of NA turnover; we conclude that it may influence brain function in a more regulatory way than reuptake inhibitors.

Safety and efficacy during long-term treatment with moclobemide.

Safety aspects [adverse events, blood pressure and heart rate, weight, and laboratory tests (liver parameters, hemoglobin, leukocytes)] of long-term treatment in 1,120 patients are discussed. Adverse events during this long-term treatment were also compared with those of a subgroup of these patients who, before long-term treatment, were treated on a short-term basis (n = 706). Efficacy [Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression of Efficacy (CGI), and occurrence of relapses and recurrences] in a homogeneous sample of 485 patients is also discussed. The adverse events most frequently observed during long-term treatment were insomnia, headache, and dizziness. Insomnia and headache were also most often occurring in the compared sample of patients with short-term treatment, whereas dizziness during this treatment period ranked at the fifth position. Supine and standing mean blood pressure did not consistently change during long-term treatment, the most prominent increases in comparison with baseline were seen in the period > 1 year of treatment (6.3 mm Hg supine/7.2 mm Hg standing). Comparison of blood pressure values in the hypertensive range at baseline and during long-term treatment revealed no statistical difference (McNemar test p = 0.07829). Mean heart rate slightly decreased during long-term treatment (by a maximum of 6.3 beats/min supine, 8.2 beats/min standing). Mean weight did not change between baseline and treatment end point. There were 23 patients with a weight loss of 10 kg or more and 16 patients with a weight gain of 10 kg or more. For none of the laboratory parameters tested was there a statistical significance regarding shifts from normal to pathological values. HAM-D mean total scores in the above-mentioned subgroup of patients decreased from 25.05 points at baseline (n = 485) to 7.88 points after 1 year of treatment (n = 139). Seventy-five patients who had favorably responded to treatment (total responders n = 300) relapsed during the first 6 months of treatment. During the second half-year of treatment the recurrence rate was 14.8%, and during the third 6 months the recurrence rate was 12.2%. CGI in the same subsample of patients in whom HAMD was evaluated (n = 485) compared with those patients who did not drop out during the short-term period up to 44 days and entered long-term treatment (n = 401) showed that the percentage of the ratings "no change/worse" was higher in the sample that also included patients who withdrew from treatment during the short-term period.(ABSTRACT TRUNCATED AT 400 WORDS)

RIMA--a new concept in the treatment of depression with moclobemide.

Moclobemide, a specific reversible inhibitor of monoamine oxidase that shows a preference for the A isoenzyme, has been developed as a new antidepressive agent. Unlike earlier generation monoamine oxidase inhibitors, moclobemide is devoid of any clinically significant tyramine interaction, thus making dietary restrictions during therapy unnecessary. In comparative trials, moclobemide has been found to be superior to placebo and similar to imipramine, clomipramine, and amitriptyline in clinical efficacy. Long-term trials involving moclobemide therapy for up to one year have indicated that antidepressant efficacy can be maintained for this period. Tolerance is good and is significantly better than for tricyclic antidepressants. In addition, unlike the tricyclic antidepressants, overdoses of moclobemide do not appear to be life-threatening.

RIMA: a safe concept in the treatment of depression with moclobemide.

Moclobemide--a new, safer antidepressant drug--is described and clinical studies are reviewed. Moclobemide represents a new class of drug, the so-called RIMA compounds--reversible inhibitors of MAO-A. Unlike classical monoamine oxidase (MAO) inhibitors, moclobemide is devoid of hepatotoxicity and has only a slight potentiating effect on the hypertensive action of tyramine; treatment does not require a tyramine-restricted diet. Studies comparing moclobemide with tricyclic antidepressants (TCAs) indicate that moclobemide is significantly better tolerated than TCAs and slightly less well tolerated than placebo.

Interactions of moclobemide with concomitantly administered medication: evidence from pharmacological and clinical studies.

Interactions may occur on pharmacological or pharmacokinetic grounds. Both types of interactions are discussed in relationship with the pharmacological and pharmacokinetic data of moclobemide, a reversible MAO-inhibitor. A variety of interaction studies either designed more specifically as kinetic or as dynamic studies have been performed with moclobemide. The results of these studies are presented. In view of these results as well as in view of data stemming from clinical trials it can be concluded that apart from interactions with cimetidine and pethidine, moclobemide has been shown to be devoid of relevant interactions.

Moclobemide, imipramine and placebo in the treatment of major depression.

Moclobemide was compared with imipramine and placebo in the treatment of major depressive episodes in 75 outpatients. The dosage of moclobemide (25 patients) was 300 mg daily for the first 5 days, after which it could be increased to 600 mg. Imipramine (25 patients) was given in a dosage starting with 33 mg and gradually increased to 100 mg/day in the first 5 days, after which it could be further increased; 25 patients received placebo. Both drugs were equally effective as measured by the Hamilton Rating Scale for Depression, the overall assessment of efficacy and the Zung Self-rating Scale, and clearly superior to placebo; there were no significant differences between the 2 active drugs. Moclobemide was better tolerated than imipramine, and was almost comparable to placebo in this respect.

Review of comparative clinical trials. Moclobemide vs tricyclic antidepressants and vs placebo in depressive states.

Moclobemide is a reversible monoamine oxidase inhibitor (MAOI) which preferentially inhibits type-A MAO. In the present communication the results obtained with moclobemide in various clinical trials are reviewed. To this day, the antidepressant efficacy of moclobemide has been compared to that of placebo in four trials. The antidepressant efficacy of moclobemide (300-600 mg/d; N = 164) was found to be superior to that of placebo (N = 162) and comparable to that of imipramine (100-200 mg/d; N = 164) in a 6-w., double-blind, multicentre study, in patients suffering from a Major Depressive Episode (DSM-III). Two smaller trials, strongly suggest that moclobemide is more efficacious than placebo for the treatment of endogenous depression (ICD-9) and for the treatment of Dysthymic Disorders (DSM-III). The antidepressant efficacy of moclobemide was compared to that of imipramine, desipramine, clomipramine and amitriptyline. The antidepressant efficacy of moclobemide (300-600 mg/d; N = 189) was found to be comparable to that of imipramine (100-200 mg/d; N = 192) in a 4-w., double-blind, multicentre study, in patients suffering from a Major Depressive Episode. This finding is supported by the results obtained in 12 other smaller studies, using either imipramine, desipramine, clomipramine or amitriptyline as comparator drug. When the tolerability of moclobemide, as judged by reported and observed adverse events, is compared to that of placebo, it appears that only nausea is reported significantly more frequently with moclobemide than with placebo (9.5% vs 4.8%). In the trials comparing moclobemide to tricyclic antidepressant drugs (TCAs), the tolerability of moclobemide was constantly found to be superior to that of the TCAs; in particular the incidence of anticholinergic side effects was low with moclobemide and was significantly higher with the TCAs. The cardiovascular tolerability of moclobemide tended to be superior to that of the TCAs. Physical examination, hematology and clinical chemistry did not seem to be affected by treatment in any of the studies summarized in this review.

Interaction of moclobemide, a new reversible monoamine oxidase inhibitor with oral tyramine.

In a double-blind placebo-controlled cross-over study in 8 healthy volunteers possible interactions between moclobemide and tyramine were studied. Eight volunteers received either moclobemide or placebo for a period of 6 days and received tyramine on day 5 and day 6 of each treatment period. Moclobemide was given in a daily dose of 450 mg to be taken in three divided doses at the end of the meals. Tyramine was administered in the form of an artificially tyramine enriched cheese (camembert) together with a meal at noon. The total tyramine doses administered were 50 mg on day 5 and 100 mg on day 6 of each treatment period. Comparisons of blood pressure and heart rate changes after tyramine ingestion between moclobemide and placebo conditions did not indicate any relevant moclobemide-tyramine interaction. It is concluded that tyramine in quantities of up to 100 mg does not lead to clinically relevant blood pressure reactions in moclobemide-treated subjects, if moclobemide is taken at the end of the meal.

Diclofensine and imipramine. A double-blind comparative trial in depressive out-patients.

Sixty out-patients with different nosological types of depression were assigned at random to three different treatment groups and were treated under double-blind conditions for 6 weeks. Two groups received diclofensine in capsules of either 15 or 25 mg, and a third group received capsules with imipramine 25 mg. The dosage schedule provided an initial dose of 2 capsules/day which was to be gradually increased up to a maximum dose of 9 capsules/day. The daily mean dosages actually given over the entire trial period were 64.0 mg diclofensine for group I, 97.6 mg diclofensine for group II, and 102.9 mg imipramine for group III. All treatment groups showed a good improvement of the patients' clinical states within the 6-week period, but the imipramine-treated patients improved more slowly than the diclofensine-treated patients. This was demonstrated by the mean total scores of the Hamilton Depression Rating Scale (HDRS). Evaluation of different factors of the HDRS yielded differences between the two drugs in favour of diclofensine for the factor 'inhibition' from the end of week 1 until the end of week 3 and for the factor 'somatic complaints' during week 3. Side effects were - dose dependently - less frequent, less severe, and lasted shorter in the diclofensine-treated patients than in the imipramine-treated ones. The most frequently reported side effects in the diclofensine-treated patients were dry mouth, insomnia, dizziness, and agitation. In the imipramine group side effects were mainly dry mouth, tremor, dizziness, and sleepiness. In conclusion, this study shows an impressively faster onset of efficacy of diclofensine over imipramine, a finding which should be replicated by further studies.

[Saccadic eye movements and endogenous psychoses]. / Sakkadische Augenbewegungen und endogene Psychosen.

Saccadic eye movements were examined in different psychiatric patient groups. It was found that patients with schizophrenic and schizoaffective psychoses showed significantly increased incidence of dysmetric saccades (dysmetria) as compared to manic-depressive and alcoholic patients as well as healthy controls. However, increased non-fixations (deviations of the gaze from the target point) occurred in all psychotic inpatients but not in alcoholics and schizophrenic outpatients. Significantly increased saccadic reaction times could be found in chronic schizophrenic inpatients only. Furthermore it could be shown in the latter group that the increased dysmetria remains intraindividually relatively constant, in contrast to the other parameters. The results are interpreted as the expression of an impairment of attention of psychotic inpatients, while the dysmetria could represent the equivalent of a disturbed attention typical for psychoses with schizophrenic features.

Saccadic eye movements in psychiatric patients.

Saccadic eye movements were examined in 110 psychiatric patients and 26 controls, evaluating three parameters, the frequency of dysmetric saccades, nonfixation and the saccadic reaction time. Dysmetric saccades (dysmetria) were defined as saccadic reactions undershooting the target, nonfixation was defined as a deviation of the gaze from the target with the target stationary. While the nonfixation score and the saccadic reaction time were slightly increased in most of the psychiatric patient groups as compared to controls, an increase of the dysmetria score was confined to patients with schizophrenic and schizoaffective disorders. Dysmetria is thus interpreted as the expression of a relatively specific impairment of attention in these patients.

[Influence of protein content on total CSF protein (author's transl)]. / Einfluss des Eiweissgehaltes der Nahrung auf das Liquorgesamteiweiss.

The influence of the protein content of nutrition on the total protein of the cerebrospinal fluid was examined in 24 neurological patients showing neither inflammatory diseases nor diseases where a rise of the total protein in the CSF can be expected. 14 patients were at random separated into two groups and received either a high protein or a low protein isocaloric diet for seven days. The then observed changes in the total protein content of the CSF between both groups were significant. In ten other patients whose total protein content of the first lumbal puncture was beneath 35 or above 55 mg% the observed changes after high protein or low protein diet were more pronounced, the farther a value was situated from the normal range. It is asked if the "normal range" has not to be defined depending on the protein uptake with nutrition.

Increased serum glutamate in depressed patients.

Glutamate concentration was determined in serum from endogenous and neurotic depressive patients, in persons with schizophrenia or schizoaffective disorder, and in normal subjects. The mean serum glutamate level in the endogenous and neurotic depressive patients was found to be significantly higher than in any of the other groups. No other statistically significant differences were found. Statistical analysis revealed that the elevated serum glutamate concentration in the endogenous and neurotic depressive patients was probably caused by medication. These results are discussed in view of the effect of antidepressants upon the serum glutamate in the affective disorders.

Effects of amitriptyline on serum glutamate and free tryptophan in rats.

In rats, chronic amitriptyline (14 days, 10 mg/kg, IP) administration resulted in a significant increase in the serum glutamate concentration and concomitant increase in the serum free tryptophan. In contrast, amitriptyline had no effect on the total serum tryptophan or CSF glutamate level. The data confirmed that antidepressant drugs may induce an increase of the serum glutamate concentration in depressive patients.

Disturbed smooth pursuit and saccadic eye movements in schizophrenia.

Smooth pursuit and saccadic eye movements of schizophrenic patients were examined. In a pendulum (0.5 Hz) tracking task schizophrenic inpatients had a slightly lower smooth pursuit gain than outpatients and controls, who showed no significant differences. The number of saccades, counter-saccades and velocity arrests occurring in a 20 s tracking epoque was the same in patients and controls, but patients made larger saccades. When tracking a stepping target by saccadic eye movements, schizophrenic inpatients, and to a lesser extent outpatients, exhibited longer reaction times than controls and had a higher incidence of "non-fixation" (saccades away from the target while the target is stationary). Schizophrenic patients also showed a significantly larger proportion of dysmetric saccades (undershooting the target). While similar changes of reaction time and non-fixation score were observed in manic-depressives and alcoholics, dysmetria was more often found in schizophrenics and possibly constitutes the expression of a specific impairment of attention.

Levels of total and free tryptophan in the plasma of endogenous and neurotic depressives.

The levels of total and free tryptophan were determined in the plasma of 34 endogenous depressives, 20 neurotic depressives and 25 healthy volunteers. Whilst the levels of total tryptophan were not different in the three groups, the level of free tryptophan was reduced in both endogenous and neurotic depressives.

Reduction of cerebrospinal fluid glutamic acid in Huntington's chorea and in schizophrenic patients.

Glutamic acid levels were investigated in the cerebrospinal fluid and blood serum of patients with schizophrenia, Huntington's chorea, and sciatic nerve compression by lumbar disc protrusion. In the serum the glutamic acid levels were equal in all three groups; in the cerebrospinal fluid (CSF) of schizophrenic and Hungtington's patients, however, the glutamic acid was decreased to almost half that of the lumbar disc group which served as control. Most of the patients were treated with neuroleptic drugs. However, since in one case (the daughter of a Huntington's patient) the CSF glutamic acid was decreased although this woman had had no neuroleptic treatment, it seems more likely that the glutamic acid decrease is due to the disease rather than to the neuroleptic treatment.