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Schizophrenic outcome in late life: symptom state and platelet monoamine oxidase activity.

Reported here are the results of a study of symptom state, platelet monoamine oxidase (MAO) activity, and demographic variables in a group of elderly neuroleptic-free schizophrenics. Analyzed by both bivariate and multivariate techniques, the data from this sample indicate that after the effects of demographic variables upon the variance of enzyme activity have been controlled for, the patients most likely to continue to manifest schizophrenic symptomatology in the senium are those with low platelet MAO activity. The results are discussed with respect to other studies of platelet MAO and prognosis in schizophrenia and with respect to future studies.

Aged↗

Effects of reserpine on recovery rates after inhibition of monoamine oxidase in different regions of mouse brain.

Adult mice were injected once with the monoamine oxidase (MAO) inhibitor pargyline, every 3 days with the amine storage depletor reserpine, or with both drugs. Serotonin content of brainstem and cerebrum was increased after pargyline, decreased after reserpine, and showed intermediate values following administration of both drugs. MAO activity after pargyline recovered in a time-dependent fashion, with recovery rates of hypothalamus greater than cerebellum greater than cerebrum greater than brainstem. After reserpine, recovery rates of MAO were less in hypothalamus and cerebellum, suggesting that the amount of MAO synthesized may be related to the level of substrates in these regions.

Animals↗

Pharmacokinetics and pharmacodynamics of the monoamine oxidase B inhibitor mofegiline assessed during a phase I dose tolerance trial.

The safety, pharmacokinetics, and pharmacodynamics of single oral doses of up to 48 mg and daily (for 28 days) doses of up 24 mg mofegiline were investigated in healthy male volunteers. Plasma pharmacokinetics indicated rapid absorption and elimination: time to reach maximum concentration occurred at about 1 hour; half-life ranged from 1 to 3 hours. Maximal plasma concentration and area under the plasma concentration-time curve increased and oral clearance decreased disproportionately with dose. Mofegiline rapidly and markedly inhibited platelet monoamine oxidase B (MAOB) activity, which returned to baseline within 14 days. Urinary excretion of phenylethylamine increased proportionately with doses up to 24 mg. No changes in urinary elimination of catecholamines, blood pressure, heart rate, or ECG were observed. A classic maximum tolerated dose was not achieved in these studies. However, the 48 mg single dose and the 24 mg multiple daily dose far exceeded the dose (1 mg) that was associated with > 90% platelet MAOB inhibition.

Administration, Oral↗

[Monoamine oxidase activity in rat liver in vitamin B12 deficiency].

Changes in the activity of monoamine oxidase (MAO-B) in liver homogenates and mitochondria from normal and vitamin B12-deficient rats have been studied in various functional states of the mitochondria. Preincubation of liver preparation at 32 degrees C increased the MAO affinity for benzylamine in samples of normal (but not vitamin B12-deficient rats). Succinate added to the incubation medium decreased Km and increased Vmax in both normal and vitamin B12-deficient animals. A correlation was found between the decline of MAO-B activity under vitamin B12 deficiency, deceleration of succinate oxidation and reduction of the transmembrane potential.

Animals↗

Activation of monoamine oxidase isotypes by prolonged intake of aluminum in rat brain.

Rats were fed 100 microM aluminum maltolate for one year in their drinking water. Brain aluminum contents have increased 4.2-fold in the aluminum-treated group, whereas no significant changes in the body weight, brain weight, and brain protein content were observed. Long-term aluminum feeding induced apoptosis as assessed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method and showed activatory effects on the catalytic efficiency (kcat/KM) of monoamine oxidase-A and monoamine oxidase-B up to 1.9- and 3.8-fold, respectively. The expression level of monoamine oxidase isotypes on the Western blot remained unchanged between the two groups, suggesting a change in post-translational regulation of the activities of monoamine oxidase isotypes by long-term aluminum feeding.

Administration, Oral↗

Characteristics of monoamine oxidase activity in brain and other organs of the adult bullfrog, Rana catesbeiana.

1. Monoamine oxidase (MAO) activity was measured in brain, liver, kidney and intestine of the adult bullfrog by a fluorometric method. 2. All tissues contained both type A and type B MAO, on the basis of responses to specific inhibitors, but with different ratios in each tissue. 3. MAO activity was optimum at 30 degrees C. However, MAO type B showed greater activity changes related to incubation temperature than did type A. 4. The Michaelis constant (Km) of MAO also varied with temperature, with a nadir around 20 degrees C. The functional significance of this is not clear. 5. Arrhenius plots showed that the activation energy for MAO B was higher than for MAO A.

Animals↗

Rat monoamine oxidase B expressed in Escherichia coli has a covalently-bound FAD.

Rat liver monoamine oxidase B (MAO B) was expressed in E. coli as catalytically active form, though inclusion bodies of the enzyme were also formed as a major protein in the cell. The active form of the recombinant MAO B exhibited similar properties as rat liver enzyme and localized in membrane of the bacteria. Covalent attachment of FAD to polypeptide chain of the recombinant enzyme was revealed by a labeling experiment with [3H]-pargyline, an irreversible mechanism-based inhibitor, indicating that the covalent linkage of FAD to the apoprotein was formed even in the prokaryotic cell. This observation suggests autocatalytic formation of the linkage in MAO B.

Animals↗

Platelet monoamine oxidase in healthy subjects: the "biochemical high-risk paradigm" revisited.

Activity of platelet monoamine oxidase (MAO) has repeatedly been reported to be associated with various forms of psychopathology. This investigation was designed to reexamine the "biochemical high-risk paradigm" developed by Buchsbaum et al. (1976). In 383 healthy students (193 males, 190 females) platelet MAO activity was measured. The 35 students with the lowest and 37 with the highest enzyme activities were then examined with three personality tests (16 PF of Cattell, Freiburger Persönlichkeitsinventar, Eysenck Personality Questionnaire). Furthermore, biographic data with respect to psychosocial problems were explored. There were no consistent differences between subjects with low or high MAO. Therefore, we could not confirm any correlation between psychopathology and platelet MAO in this study.

Adult↗

Role of an endogenous monoamine oxidase inhibitor, isatin, in SHRSP brain.

1. The acute effects of isatin, an endogenous monoamine oxidase (MAO) inhibitor, on norepinephrine (NE) and serotonin (5-HT) concentrations in the brain of stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) were determined in order to elucidate its pathophysiological role. 2. Isatin was identified in purified extracts of SHRSP brain. 3. A single dose of isatin significantly increased NE concentration in the cerebral cortex of WKY. Isatin also significantly increased 5-HT concentration in WKY brains. 4. After isatin administration NE and 5-HT levels in the SHRSP brain did not differ from those in WKY. 5. These data suggest that isatin, an endogenous MAO inhibitor, presents in the SHRSP brain and maintains high blood pressure.

Animals↗

Psychiatric vulnerability, monoamine oxidase, and the average evoked potential.

College students in two separate studies had platelet monoamine oxidase (MAO) activity determinations and average evoked potential (AEP) measurements taken. On the basis of Minnesota Muliphasic Personality Inventory (MMPI) or Research Diagnostic Criteria (RDC) evaluations, psychopathology, particularly affective disorder, was found to be more prevalent among both persons with the combination of low MAO activity and AEP augmenting and those with high MAO activity and AEP reducing. The same pattern is apparent whether students were selected for extremely high or low MAO activity (study 1) or for elevated or normal MMPI scores (study 2). Some psychiatric patient groups also show this pattern. An interactive model of sensation-seeking and sensory inhibition is presented.

Adolescent↗

Orphan comparisons and indirect meta-analysis: a case study on antidepressant efficacy in dysthymia comparing tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors by using general linear models.

Direct comparisons of the efficacy of competing interventions are not always available in the literature. This situation leads to the presence of clinically relevant "orphan comparisons" of therapeutic interventions which have never been compared head-to-head. To overcome this limitation, simple methods for indirect meta-analysis have been suggested. Nevertheless, their results are prone to bias when more than 1 indirect comparison is tested because of the likely duplication of data for some comparisons. In contrast, general linear models can be used to extend simple indirect meta-analysis beyond 1 indirect comparison by fitting to incomplete data using maximum likelihood within the framework of multitreatment comparisons. This study presents a tutorial application of general linear models to the comparative efficacy of several antidepressants in dysthymia (tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors. Working with previously published data comparing the efficacy of antidepressants with placebo, it is shown that tricyclic antidepressants and selective serotonin reuptake inhibitors present similar efficacy (odds ratio = 1.19, P = 0.37; relative risk = 1.10, P = 0.24; risk difference = 0.03, P = 0.53), whereas monoamine oxidase inhibitors outperform both tricyclic antidepressants and selective serotonin reuptake inhibitors, at least for some effect scales (odds ratio = 1.57, P = 0.05; relative risk = 1.25, P = 0.05; risk difference = 0.09, P = 0.08). This finding, which is an instance of a relevant orphan comparison and could not be obtained otherwise, could motivate the conduct of clinical trials or focused systematic reviews to support or refute its importance through appropriate head-to-head comparisons.

Antidepressive Agents, Tricyclic↗

Repeated experience of social defeats increases serotonin transporter and monoamine oxidase A mRNA levels in raphe nuclei of male mice.

Serotonin transporter (SERT) and monoamine oxidase A (MAOA) mRNA levels in the raphe nuclei area of the midbrain were measured by the multiplex reverse transcription-polymerase chain reaction method in male mice with repeated experience of social victories (winners) and defeats (losers) in ten daily agonistic confrontations. Experiments revealed enhanced SERT and MAOA mRNA levels in the losers compared with the winners and controls. It has been supposed that SERT and MAOA genes are involved in enhancement of serotonin inactivation in response to the increase of serotonergic activity shown earlier in the losers. A positive correlation between MAOA and SERT mRNA levels in the raphe nuclei area of the midbrain was shown.

Acute Disease↗

Association of monoamine oxidase A alleles with alcoholism among male Chinese in Taiwan.

OBJECTIVE: The role of monoamine oxidase (MAO) in alcoholism was assessed by genetic association studies separately in five ethnic groups in Taiwan. METHOD: Restriction fragment length polymorphisms (RFLP) and dinucleotide repeat polymorphisms (DNRP) were used to determine MAOA and MAOB alleles in male alcoholic patients and nonalcoholic comparison subjects among Han Chinese and four aboriginal groups. RESULTS: Significant associations of alcohol dependence with MAOA alleles (RFLP and DNRP) were found among the Han Chinese, but not among the aboriginal groups. No significant association with MAOB DNRP alleles was found in any group. CONCLUSIONS: Genetic heterogeneity may underlie alcoholism among different ethnic groups in Taiwan, and MAOA mutations may play a role in susceptibility to alcoholism among Han Chinese.

Alcoholism↗

Nucleotide sequences of putative cDNAs for guinea-pig monoamine oxidase.

To study the molecular structure of guinea pig monoamine oxidase (MAO) and its phylogenetic relationship with other mammalian MAOs, we determined nucleotide sequences of putative MAO cDNAs isolated from guinea pig tissues. Both the 5'- and 3'-ends of the cDNAs were amplified using the RACE (rapid amplification of cDNA ends) method. The sequence (1924 bp) of a putative guinea-pig MAO-B cDNA covers a complete coding region that corresponds to 521 amino acids. We also analyzed a partial sequence of a putative guinea-pig MAO-A cDNA, which corresponds to 506 amino acids, but have left the region of 66 bp at the 3'-end undetermined. The nucleotide and deduced amino-acid sequences of the putative guinea-pig MAO cDNAs showed the highest homology with that of human MAO cDNAs among the known mammalian MAO sequences. These results suggest that guinea-pig MAOs are structurally similar to human MAOs. Our molecular phylogenetic data support the idea that guinea pigs and rodents diverged before the separation between rodents and other lineage leading to Primates and Artiodactyla.

Journal Article↗

[Brain monoamine oxidase in aging wild Norway rats, chosen for lack of aggressive behavior toward humans].

Monoamine oxidase A and B (MAO A; MAO B) activity was studied in the brain stem and hemispheres of young (4 months) and old (7 months) wild Norway rats of S35-S36 bred for absence of aggressive reactions to men (tame), bred for pronounced aggressive reaction for the same number of generations (aggressive), and those not undergoing any breeding (wild). In young tame rats MAO B activity was lower than in wild ones of the same age. As the animals grew older, in 7 months, MAO B activity increased in the brain stem and hemispheres of all the rats, irrespectively of the type of behavior. Difference in MAO B activity found between tame and wild 4-month rats disappeared at the age of 7 months. MAO A activity did not change either with ageing or due to breeding for behavior.

Aggression↗

Platelet monoamine oxidase and plasma dopamine-beta-hydroxylase activities in patients with multiple sclerosis.

Platelet monoamine oxidase (MAO) and plasma dopamine-beta-hydroxylase (DBH) activities were determined in a large group of multiple sclerose patients in relapse (49 patients) and in remission (28 patients), and compared with an age- and sex-matched control group (52 normal subjects). The activities of both enzymes did not differ from normal in both patient groups. Women had higher MAO activities both in normal and in patient groups. Multiple linear regression analysis revealed an association of low platelet MAO to the score in the mental subscale in the Kurtzke Disability Status Scale. Both male and female patients with mental symptomatology had significantly (p = 0.02) lower platelet MAO activities compared to the patients without. The possibility of a relationship between MAO activity and psychiatric vulnerability in MS is considered.

Adult↗

Reversible and irreversible monoamine oxidase inhibitors in other psychiatric disorders.

In addition to being effective in depressive disorders, monoamine oxidase inhibitors (MAOIs) have been shown to be effective in controlled studies of patient with panic disorder with agoraphobia, social phobia, atypical depression or mixed anxiety and depression, bulimia, posttraumatic stress disorder (PTSD) and borderline personality disorder. Uncontrolled case reports have noted MAOI efficacy in obsessive-compulsive disorder (OCD), trichotillomania, dysmorphophobia and avoidant personality disorder. Reversible inhibitors of MAO-A (RIMAs) appear safer than the classical irreversible MAOIs since they have less potential to increase blood pressure. They have not been studied as yet, however, in most of the conditions responsive to MAOIs. If RIMAs are found effective in these disorders, they would probably achieve wider use than MAOIs because they are safer and tend to cause fewer side effects.

Antidepressive Agents↗

Inhibition of monoamine oxidase A by beta-carboline derivatives.

beta-Carbolines are endogenous inhibitors of monoamine oxidase (MAO). The interaction of nine beta-carboline derivatives and four 3,4-dihydro forms with purified MAO A was investigated. All the compounds tested were reversible competitive inhibitors selective for MAO A, in agreement with previous studies on membrane preparations. The oxidation of kynuramine by MAO A in the presence of the more effective inhibitors showed a lag period before reaching the steady state. In general, the 1-methyl and 7-methoxy substituents increased the potency. Harmine, 2-methylharminium, 2,9-dimethylharminium, and harmaline were the most effective inhibitors of the purified MAO A, with low Ki values of 5, 69, 15, and 48 nM, respectively. The inhibitors interacted with the covalently bound flavin to induce distinct spectral changes, the magnitude of which correlated with the efficacy of the inhibition. The more effective inhibitors could be in situ inhibitors of MAO A.

Carbolines↗