The behavioral toxicity of monoamine oxidase-inhibiting antidepressants.
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Biomedical subjects
Publications and source records attributed to D L Murphy.
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Altered activities of biogenic amine-related enzymes have been reported in some studies of patients with affective disorders and chronic schizophrenia. To evaluate whether any relationship between personality variations, including non-diagnosed psychopathology, and these enzymes might occur in non-psychiatric patients, 95 young adult volunteers were studied. Higher MMPI and Zuckerman sensation--seeking scale scores were found in male, but not female, volunteers with lower platelet and plasma amine oxidase activities. Males generally exhibited negative correlations, while females had positive correlations between the psychological test scores and amine oxidase activities. In contrast to the amine oxidase results, no associations were observed between plasma dopamine beta-hydroxylase activities and the personality variables.
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The treatment of depressed patients with the monoamine oxidase (MAO)-inhibiting antidepressant, phenelzine, was found to be accompanied by an 82 per cent reduction in platelet MAO activity and a 91 per cent reduction in plasma amine oxidase activity. Maximum reductions in enzyme activity occurred after 7 to 14 days of treatment; recovery of enzyme activity posttreatment required an average of 14 days for the platelet MAO and greater than 6 weeks for the plasma enzyme. Marked elevations in urinary tryptamine excretion occurred in conjunction with MAO inhibition during phenelzine treatment, but the magnitidue of urinary tryptamine change in individual patients was not closely correlated with the magnitude of enzyme activity reduction. Changes in platelet serotonin content serotonin content and in urinary catecholamine metabolites also occurred in response to phenelzine treatment.
1 The uptake of various 3H-labelled amines into a thrombin-releasable compartment of human platelets, thought to represent the platelet vesicular storage pool, has been evaluated. Measurable amounts of 5-hydroxytryptamine (5-HT), dopamine, tyramine, octopamine, and tryptamine accumulate in this pool, and also in a non-thrombin-releasable (cytoplasmic) pool during a 30 min incubation period with 10(-5) M extracellular amine concentrations. 2 No differences in the accumulation of vesicular or cytoplasmic 5-HT, dopamine, and tyramine are found in platelets treated with deprenyl to inhibit platelet monoamine oxidase as compared to controls. 3 Extracellular tyramine or dopamine in concentrations as high as 10(-5) M does not alter the initial rate of 5-HT uptake across the platelet plasma membrane. Similarly, sizable cytoplasmic pools of either amine do not alter the initial rate at which small amounts of 5-HT enter platelet cytoplasm or storage vesicles. 5-HT thus appears to be the preferred substrate for uptake into platelets and for movement from cytoplasm to vesicles.
This paper reports a marked decrease in total hours of sleep in depressed and manic patients on days 3 and 4 following discontinuation of alpha-methyl-para-tyrosine (AMPT), a specific inhibitor of the synthesis of the neurotransmitters, norepinephrine and dopamine. Discontinuation of two precursors of biogenic amines, L-dopa and L-tryptophan, produced no changes in total sleep. It is suggested that the decrease in sleep following AMPT may result from catecholamine neuronal receptor hypersensitivity induced during AMPT treatment. Animal data consistent with this hypothesis are reviewed. The importance of studying rebound phenomena following psychoactive drugs and the practical therapeutic implications of these findings are discussed.
The relationship between suicides and suicide attempts and two biological measures, platelet monoamine oxidase levels (MAO) and average evoked response (AER) augmenting, was examined in 79 off-medication psychiatric patients and in 68 college student volunteers chosen from the upper and lower deciles of MAO activity levels. In the patient sample, male individuals with low MAO and AER augmenting, a pattern previously associated with bipolar affective disorders, showed a significantly increased incidence of suicide attempts in comparison with either non-augmenting low MAO or high MAO patients. Within the normal volunteer group, all male low MAO probands with a family history of suicide or suicide attempts were AER augmenters themselves. Four completed suicides were found among relatives of low MAO probands where as no high MAO proband had a relative who committed suicide. These findings suggest that the combination of low platelet MAO activity and AER augmenting may be associated with a possible genetic vulnerability to psychiatric disorders.
1. Distributions of dense bodies per platelet were evaluated in unstimulated human platelets and in platelets stimulated to secrete by the addition of varying amounts of thrombin or the ionophore A23187. Since distributions were not Gaussian, they were compared by non-parametric methods. 2. Most distribution obtained following varying levels of dense-body release differed significantly from the control (unstimulated) distribution. In general, distribution from points widely separated in terms of per cent release of total dense-body content also differed significantly. Distributions obtained at points where the total number of dense bodies lost was approximately the same did not differ significantly, regardless of the drug and incubation conditions used to produce the dense-body loss. 3. Dense bodies were lose from platelets during the secretory process (measured as the release of either calcium or ATP), and the number of dense bodies lost correlated at a significant level with the amounts of both substances secreted. 4. Following maximal secretion produced by either thrombin or A23187, a population of dense bodies (refractory dense bodies) remained in platelets. The refractory dense bodies could not have been distributed uniformly among the control populations of either platelets or dense bodies. The distribution of refractory dense bodies could, however, be described by a model in which platelets containing large numbers of dense bodies had a greater proportion of their dense-body complement refractory than did platelets containing fewer dense bodies.
Depressed patients' treatment with the monoamine oxidase inhibiting antidepressant, phenelzine, developed marked reductions in urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion. Pretreatment levels of urinary MHPG and platelet monoamine oxidase activity were significantly correlated with each other, but the magnitude of reduction in these measurements produced by phenelzine treatment did not correspond as closely. Similarly, MHPG levels were not significantly different in patients with antidepressant responses to the drug compared to nonresponders.
Normative data on plasma amine oxidase activity were obtained for four primate species, M. mulatta, M. arctoides, C. aethiops and H. sapiens. Significant between-species differences in activity were observed. In a large sample of M. mulatta, no significant relationship between age and plasma amine oxidase activity was observed, but adult males had significantly higher enzyme activities than adult females.
Abnormal central catecholamine neurotransmission has been suggested in Gilles de la Tourette's syndrome. The authors evaluated the sympathetic nervous system in both the basal state and in its responsivity to postural and exercise stress. Plasma norepinephrine and the activities of its synthetic and degradative enzymes were not different in 33 Tourette patients, a control group of unaffected relatives, and another control group of unrelated healthy volunteers. This finding suggests that these patients have neither a generalized dysfunction of norepinephrine metabolism nor a defect in the central control of sympathetic function.
Reported reductions in the activity of platelet monoamine oxidase (MAO) in chronic schizophrenic patients might be contributed to by alterations in hormones, platelet numbers or other non-specific factors thought to affect enzyme activity. In this study, MAO activity in 27 patients with chronic schizophrenia was measured, using benzylamine as the substrate in an assay based on platelet counts instead of platelet protein, and was found to be markedly lower than mean MAO activity in 375 normal controls. These results were similar to those previously reported with tryptamine as a substrate for the enzyme. Serum testosterone, triiodothyronine, iron and iron-binding capacity were within normal ranges in individuals with reduced MAO activities. Platelet MAO activity remained stable over time in patients and controls.
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A population of individuals potentially at risk for psychiatric disorders was identified by screening 375 college student volunteers for low platelet monoamine oxidase (MAO) activity levels. The lower and upper 10 per cent in MAO activity were interviewed and family history data were obtained. Low-MAO probands reported more frequent psychiatric or psychological counseling and problems with the law. Families of low MAO probands had an eightfold increase in the incidence of suicide or suicide attempts over those of high-MAO probands. This suggests that reduced MAO levels, reported previously in patients with affective disorders and chronic schizophrenia, may predict a vulnerability to psychiatric disorder.
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Plasma amine oxidase activity increased from 23.4 nmol/ml/h during pregnancy to 49.5 nmol/ml/h during an extended post partum period in 10 rhesus monkeys. Comparison with non-pregnant control monkeys sampled at similar times indicated that the significant differences were in the extended post partum period.
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