A mechanism-based group-psychotherapy approach to aggressive behaviour in borderline personality disorder: findings from a cluster-randomised controlled trial.

BACKGROUND: Aggressive behaviour is a prevalent and harmful phenomenon in patients with borderline personality disorder (BPD). However, no short-term, low-cost programme exists that specifically focuses on aggression. AIMS: Attuning therapy modules to pathogenetic mechanisms that underlie reactive aggression in BPD, we composed a 6 week mechanism-based anti-aggression psychotherapy (MAAP) approach for the group setting, which we tested against a non-specific supportive psychotherapy (NSSP). METHOD: A cluster-randomised two-arm parallel-group phase II trial of N = 59 patients with BPD and overt aggressive behaviour was performed (German Registry for Clinical Trials, DRKS00009445). The primary outcome was the externally directed overt aggression score of the Modified Overt Aggression Scale (M-OAS) post-treatment (adjusted for pre-treatment overt aggression). Secondary outcomes were M-OAS irritability, M-OAS response rate and ecological momentary assessment of anger post-treatment and at 6 month follow-up, as well as M-OAS overt aggression score at follow-up. RESULTS: Although no significant difference in M-OAS overt aggression between treatments was found post-treatment (adjusted difference in mean 3.49 (95% CI -5.32 to 12.31, P = 0.22), the MAAP group showed a clinically relevant decrease in aggressive behaviour of 65% on average (versus 33% in the NSSP group), with particularly strong improvement among those with the highest baseline aggression. Most notably, significant differences in reduction in overt aggression between MAAP and NSSP were found at follow-up. CONCLUSIONS: Patients with BPD and aggressive behaviour benefited from a short group psychotherapy, with improvements particularly visible at 6 month follow-up. Further studies are required to show whether these effects are specific to MAAP.

Serum DBH and platelet MAO in patients with depressive disorders.

Km and V of serum dopamine-beta-hydroxylase and platelet monoamine-oxidase (MAO) were determined in the depressive and manic state as well as after recovery in patients with affective psychoses and in the depressive state of patients with neurotic depression. DBH and MAO values were measured also in age- and sex-matched controls. The Km and V values of each enzyme failed to differ between patients and healthy controls or between patients during and after an episode of illness. The ratio of V of serum DBH (tyramine as substrate) tended to be lower in patients independent of their psychopathological state than in controls. The findings fail to support the notion that characteristics of the peripheral enzymes measured provides a reliable indicator of a biological disposition to depression, but are consistent with the notion that the balance of monoamine may play a role in certain psychopathological states.

Identification of tetrahydronorharmane (tetrahydro-beta-carboline) in human blood platelets.

The present paper shows that tetrahydronorharmane (tetrahydro-beta-carboline) exists in human platelets. The concentration of tetrahydronorharmane in platelets from 10 ml platelet rich plasma was in the range of 9.3 to 25.6 pmol (n=8). Ingestion of tryptamine hydrochloride (n=4) three times daily for three consecutive days and of 19.6 mmol D,L-tryptophan (n=7) the evening (10 p.m.) before the blood collection did not lead to an increase of tetrahydronorharmane in platelets.

Depression and monoamine oxidase.

1. The first part of the paper is devoted to a critical review on the possible relationships between depression and monoamine oxidase. 2. This study describes the results of an investigation of MAO-activity in depression, using new approaches and methodology. This methodology was developed because the literature data indicated that a) previous results are difficult to compare because of varying methods and diverse target populations used; b) previous methodological deficiencies do not allow to draw definite conclusions about the relationship between MAO-activity and depression. 3. The present investigation selected 35 psychiatric patients according to clearly defined diagnostic criteria (20 endogenous depressive, 10 neurotic depressive, and 5 manic patients) matched to 25 healthy control-subjects. 4. The Michaelis-constant (Km), the maximum reaction speed (Vmax), and the 50% enzyme inhibition by tranylcypromine (IC50) of platelet-MAO were determined during and after recovery from the depressive or manic episode using 3 substrates (tyramine, tryptamine, and phenylethylamine). 5. The present investigation, in contrast to conventional methodology, utilized three different substrates at different concentrations. Significant correlations were demonstrated for the Vmax-values of each of the three substrates, whereas the Km and the IC50 (tranylcypromine)-values varied for each substrate. 6. The results show that there were no differences between the characteristics of the platelet-MAO in depressive or manic patients and those of normal subjects. Furthermore, treatment with tricyclic antidepressants had no effect on MAO-activity. A previous investigation indicated that the MAO-properties in human brain tissue were similar to that in human platelets.

Tetrahydronorharmane (tetrahydro-beta-carboline), a physiologically occurring compound of indole metabolism.

In the present paper a sensitive method is described to measure tetrahydronorharmane (THN) in the urine of man and rats as well as in the forebrain of rats. The compound is extracted into diethyl ether, separated by thin layer chromatography (TLC), acetylated with radiolabelled acetic anhydride and further isolated by two-dimensional TLC development. The existence of THN in urine of man was proven by using chromatography with different solvent systems, cocristallisation, isotope dilution technique as well as mass-spectrometry. The amount of THN in the urine varied over a wide range. With the same method it was demonstrated that THN occurs also in the forebrain of rats. The concentration increases after loading with tryptamine. The findings are discussed in view of the hypothesis that THN acts as a compound modulating neuronal mechanism.

Does long term treatment with amitriptyline alter the monoamine oxidase of rat brain?

Amitriptyline, at a concentration of 10(-5) M, inhibits the oxidative deamination of phenylethylamine, tyramine and tryptamine (by 40, 16, and 8 percent, respectively) by rat brain MAO. After the long term administration of amitryptyline, even at a dosage of 20 mg per kg body weight twice daily, there was no detectable influence on the biochemical properties of MAO. These findings indicate that the full antidepressive effect, which only appears after the first 3 weeks of long term treatment, cannot be caused by the inhibition of MAO.

Critical evaluation of measurement of platelet monoamine oxidase in man.

Some biochemical characteristics such as substrate specificity, substrate affinity and inhibitor sensitivity of monoamine oxidase of human blood platelets were investigated. Tyramine, tryptamine and beta-phenylethylamine were used as substrates. The apparent Michaelis constants, maximal velocity rates and I50 for the inhibitor tranylcypromine were determined. The data were analyzed according to Lineweaver-Burk and Dixon. The influence of amitriptyline, a prototype of tricyclic antidepressants, on the selected variables (Km, V, I50), was studied. The parameters investigated showed remarkably low interindividual differences when healthy volunteers were tested. The inhibitor activity of amitriptyline towards platelet monoamine oxidase depends on the substrate used. Amitriptyline concentrations which showed a pronounced effect on the enzyme characteristics are significantly higher than plasma levels of the drug found under therapeutic conditions.

[Comparative pharmacological effects of dl-amphetaminil and dl-amphetamine in the rat]. / Vergleich pharmakologischer Effekte von dl-Amphetaminil und dl-Amphetamin bei der Ratte

The present investigation shows that amphetamine and amphetaminil produce identical pharmacological effects (increase in motility and body temperature, anorexia, stereotypic behaviour). There was neither a qualitative difference under "open field" conditions nor a difference in the capacity of modifying the reserpine induced syndrome. In isomolar doses amphetamine was somewhat more effective. Almost the same amounts of amphetamine were found in blood and brain following amphetamine or amphetaminil administration, with exception of somewhat higher peak levels after amphetamine. These results favor the hypothesis that amphetaminil effects are produced by the amphetamine molecule.

[Determination of monoamine oxidase and catechol-O-methyltransferase in human blood components: methodical aspects (author's transl)]. / Bestimmung der Monoaminoxidase und Catechol-O-methyltransferase in menschlichen Blutbestandteilen: Methodische Aspekte

Controversal findings are reported with respect to alternations in activity of monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) in psychoses. Initially we determined the interindividual differences of some biochemical properties of the two enzymes in normal control subjects. Platelet rich plasma and lysate of red blood cells, respectively, were used for assay. Enzyme activity was referred to mg of protein or mg hemoglobin and number of platelets, respectively. Substrates used for COMT assay were: 3,4-dihydroxybenzaldehyde and 3,4-dihydroxybenzoic acid; for MAO determination: tyramine, tryptamine and phenylethylamine. Interindividual as well as intraindividual differences in the biochemical characteristics (apparent Km, Vmax, IC50, meta/para ratio of O-methylation in vitro) were remarkably low, the coefficient of variation was in the range of 30%.

Kinetics and metabolism of amphetamine in the brain of rats of different ages.

The kinetics and tissue distribution of amphetamine and its metabolites p-hydroxyamphetamine (p-PH-A) and p-hydroxynorephedrine (p-OH-NE) were investigated in young adult (3-4 months) and old (20-25 months) male rats, after i.p. injection of 5 mg/kg tritium labelled D-amphetamine. The concentrations of these drugs were determined in plasma, cerebral cortex, brainstem and hypothalamus, by thin layer chromatography. 1. From 60 min up to 4 hrs after injection of amphetamine the concentration of amphetamine in plasma and brain tissue of old rats was significantly (P less than 0.05 higher than in young adult animals. In both age groups the levels of amphetamine in cerebral cortex greater than brain stem greater than hypothalamus. 2. The blood-brain barrier is permutle to p-OH-A; 10 to 20 min afer i.v. injection of 10 muCi/kg of p-OH-A (10 mCi/m mole) the ratio of brain/blood plasma was found to be 1:3. The half life of p-OH-A in blood plasma was almost identical after injection of amphetamine and p-OH-A (90 min and 98 min respectively). 3. The levels of p-OH-NE in different brain areas were significantly lower (P less than 0.05) in old animals than in young adult rats 4 hrs after application of amphetamine. This metabolite of amphetamine shows a higher concentration in the hypothalamus earlier than in other brain regions.

Studies on the CNS-availability of amphetamine from amphetaminil.

The biotransformation of amphetaminil to amphetamine was confirmed using 3H- and 14C-labelled ampehtaminil. The metabolites were isolated, identified and quantified from blood, brain, adipose tissue and urine. These studies showed that the intact molecule of amphetaminil passes into the circulation only to a very small extent. The time spent by the amphetaminil in the alimentary canal does not appear to be a critical factor in the stability and degradation of this substance. The proportion of unchanged amphetaminil represents no more than 2% of the total radioactivity in the blood. The amphetamine, which results from the cleavage of amphetaminil, enters the CNS and is excreted in the urine after hydroxylation and glucuronidation. The other cleavage product, benzaldehyde, seems to be rapidly converted into hippuric acid, which is excreted. Amphetaminil is enriched in adipose tissue, especially after i.p. injection; but this fraction will be cleaved upon re-entering the blood, and it can only enter the brain as amphetamine.