Dietary inhibitors of monoamine oxidase A

Inhibition of monoamine oxidase is one way to treat depression and anxiety. The information now available on the pharmacokinetics of flavonoids and of the components of tobacco prompted an exploration of whether a healthy diet (with or without smoking) provides active compounds in amounts sufficient to partially inhibit monoamine oxidase. A literature search was used to identify dietary monoamine oxidase inhibitors, the levels of these compounds in foods, the pharmacokinetics of the absorption and distribution, and tissue levels observed. An estimated daily intake and the expected tissue concentrations were compared with the measured efficacies of the compounds as inhibitors of monoamine oxidases. Norharman, harman and quercetin dietary presence, pharmacokinetics, and tissue levels were consistent with significant levels reaching neuronal monoamine oxidase from the diet or smoking; 1,2,3,4-tetrahydroisoquinoline, eugenol, 1-piperoylpiperidine, and coumarin were not. Quercetin was equipotent with norharman as a monoamine oxidase A inhibitor and its metabolite, isorhamnetin, also inhibits. Total quercetin was the highest of the compounds in the sample diet. Although bioavailability was variable depending on the source, a healthy diet contains amounts of quercetin that might give sufficient amounts in brain to induce, by monoamine oxidase A inhibition, a small decrease in neurotransmitter breakdown.     

'Spontaneous' hypertensive episodes with monoamine oxidase inhibitors

Hypertensive reactions occurred without obvious cause in two patients receiving monoamine oxidase inhibitors (MAOIs) while being monitored in a hospital. These patients appear to have experienced "spontaneous" hypertensive episodes temporally related to the ingestion of the MAOIs. Similar occurrences in outpatients reported in the literature are reviewed.     

Diet and monoamine oxidase inhibitors: a re-examination

Monoamine oxidase inhibitors (MAOIs) are attracting renewed attention as effective antidepressants for refractory depressions, particularly among the elderly. However, widespread fears concerning the interactions of MAOIs with tyramine-containing foods have led to the development of long and complicated diets. These diets have served as an obstacle to the ready use of MAOIs, yet very little systematic or critical review of the basis for food restriction has been undertaken. An international survey of MAOI diets was conducted and from the diets collected, foods were categorized according to frequency of restriction on the diet lists. On the basis of this survey and a critical review of the literature it was determined that only four foods clearly warrant absolute prohibition: aged cheese, pickled fish (herring), concentrated yeast extracts and broad bean pods. While there is insufficient evidence to prohibit alcohol completely (even chianti wine) true moderation must apply. It is suggested that a radically simplified diet should be investigated on a prospective basis.     

Metabolism of monoamine oxidase inhibitors

1. Despite the fact that monoamine oxidase inhibitors have been used clinically and in animal experiments for many years, much still remains unknown about their metabolism. An overview of the metabolic aspects of several monoamine oxidase inhibitors, including phenelzine, tranylcypromine, pheniprazine, pargyline and deprenyl, is presented. 2. There is still considerable controversy surrounding the role of acetylation in the metabolism of phenelzine. The possibility of ring hydroxylation as well as the formation of beta-phenylethylamine, phenylacetic acid and rho-hydroxyphenylacetic acid from phenelzine is explored. 3. Tranylcypromine has been shown to undergo acetylation and ring hydroxylation. Opening of the cyclopropyl ring is also possible, although this still remains a matter of debate. The pharmacological activity and pharmacokinetic properties of the enantiomers of tranylcypromine are discussed. Chemical substitution in the 4-position of the phenyl ring has been utilized in the design of tranylcypromine analogues with potential antidepressant activity. 4. The formation of amphetamine from pheniprazine and the metabolism of the N-propargyl drugs pargyline and deprenyl are discussed.     

Common side effects associated with monoamine oxidase inhibitors

There is relatively little documentation on the common side effects associated with monoamine oxidase inhibitors (MAOI) and their frequency of occurrence. A retrospective chart review of patient records in a Mood Disorders Service was completed. Side effects of patients receiving phenelzine (N = 42) and tranylcypromine (N = 19) were rated as mild (resulting in no change in treatment), moderate (some modification in treatment plan necessary), and severe (definite change in treatment plan or drug discontinuation due to MAOI side effect). A total of 35 reports of side effects were noted in 15 of 19 tranylcypromine patients (1.84 per patients) and a total of 125 side effect reports were noted in 39 of 42 phenelzine patients (2.98 per patient). Only two severe tranylcypromine side effects occurred (resulting in drug cessation for one of these patients - hypotension), while 9 severe reactions occurred with phenelzine, resulting in drug discontinuation in 6 of these patients. The side effects for tranylcypromine and the number of reports were insomnia (N = 10), sedation (N = 8), hypotension (N = 5), sexual dysfunction (N = 3), hypomania (N = 3), weight gain/edema (N = 2), hypertensive episode (N = 2), and myoclonic jerking (N = 2). The number of reports of phenelzine side effects were insomnia (N = 26), hypomania/mania (N = 27; most common reason for drug cessation - 4), hypotension (N = 16; three cases considered severe), weight gain/edema (N = 15), sedation (N = 15), sexual dysfunction (N = 13), hypertensive episode (N = 6), and myoclonic jerking (N = 7).(ABSTRACT TRUNCATED AT 250 WORDS)     

Protective and preventive therapeutic strategies: monoamine oxidase inhibitors.

There is convincing evidence that monotherapy with 10 mg of selegiline daily substantially delays parkinsonian disability, although whether this delay is due to a symptomatic or protective mechanism remains a matter of debate. Evidence against a symptomatic effect is that the wash-out evaluation in two double-blind, placebo-controlled studies failed to detect clinical decline 1 month after discontinuing selegiline. Yet it can be argued that 1 month was not long enough to eliminate the biologic effect of the drug. Thus further studies are required to answer this question definitively. Nonetheless, because selegiline delays the requirement for levodopa therapy and appears to be relatively safe when used as monotherapy, it seems reasonable to recommend this drug as initial treatment when Parkinson's disease is first diagnosed. There is little doubt that future therapeutic and diagnostic strategies for Parkinson's disease and other neurodegenerative diseases will be profoundly influenced if this drug is unequivocally demonstrated to slow progression of Parkinson's disease. Such a finding would be a potent argument for developing biomarkers of preclinical disease because early intervention with such protective therapy might even halt the disease before symptoms develop.     

The transdermal delivery system of monoamine oxidase inhibitors

Monoamine oxidase inhibitors (MAOIs) were once widely used as effective treatments for major depressive disorder, particularly for patients with atypical or treatment-resistant depression. Today, MAOIs have largely been replaced by newer antidepressants because of concerns over potential serious side effects due to their mechanism of action. Monoamine oxidase (MAO) is an enzyme that metabolizes serotonin, norepinephrine, and dopamine, the neurotransmitters that are most associated with depression; inhibiting MAO, therefore, makes more of these neurotransmitters available for synaptic action. However, MAO also metabolizes tyramine, a trace amine found in some foods that acts as a sympathomimetic. Allowing excess tyramine to accumulate via MAO inhibition can result in hypertensive crisis due to the release of norepinephrine; therefore, patients taking an MAOI have had to follow dietary restrictions to avoid tyramine-rich foods. Hypertensive crisis may also be precipitated by using MAOIs in conjunction with other drugs that have vasoconstrictive properties, that act as sympathomimetics, or that inhibit the reuptake of norepinephrine. Serotonin syndrome is another serious adverse effect that can potentially occur when using an MAOI with another drug that inhibits the reuptake of serotonin. In this article, the mechanism of action of MAOIs is reviewed, along with that of a newer MAOI formulation that lessens the need for dietary restrictions and has a greater safety and tolerability profile than the older oral formulations.     

Electroconvulsive therapy in patients taking monoamine oxidase inhibitors

Concerns have been expressed regarding the use of general anesthesia for electroconvulsive therapy (ECT) in patients taking monoamine oxidase inhibitors (MAOIs). We review the published literature and present 4 new cases and conclude that there is no evidence of a dangerous interaction between ECT and MAOI use. In general, a cautious approach would be to discontinue MAOIs before ECT if the medication has not been helpful; however, there is no need for a washout interval before starting ECT. Furthermore, if there is otherwise a reason for continuing the MAOI, it can be continued during index ECT or initiated during maintenance ECT.     

The use of monoamine oxidase inhibitors in primary care

Although primary care clinicians have developed considerable expertise in managing patients with major depressive disorder, and a range of treatment strategies is currently available, some patients still fail to reach remission. Two strategies have fallen out of common use: treating patients with monoamine oxidase inhibitors (MAOIs) and subgrouping patients by diagnosis when selecting antidepressant treatment. Monoamine oxidase inhibitors became less popular because other treatments were perceived to be safer and easier to use. However, a newer transdermal formulation of an MAOI that limits the need for the dietary restrictions of oral MAOIs may make it worthwhile to consider using this class of medication in patients who have failed several treatment trials. Although adverse events due to patients' diets are less likely with the transdermal MAOI, clinicians should still be alert for drug interactions and observe recommended washout periods. Patients who may benefit from MAOI treatment include those with treatment-resistant depression, atypical depression, anxiety, or anergic bipolar depression and those who have experienced intolerable metabolic or sexual side effects with other medications.     

Early effects of monoamine oxidase inhibitors on dopamine metabolism and monoamine oxidase activity in the neostriatum of the rat

Summary Dopamine levels in the neostriatum of the rat were estimated at various times after pargyline (75 mg/kg), pheniprazine (4 mg/kg) and tranylcypromine (20 mg/kg) intraperitoneal injections. Depending on the inhibitor used, the amine levels reached 135 to 150% of control values within 10 min. During the 20 min which followed this rapid linear rise, DA levels increased in tissues at a much slower rate. As indicated by the estimation of MAO activity using¹⁴C-tyramine or kynuramine as substrates, the three drugs induced a complete inhibition of the enzyme activity within 5 min. A similar effect was seen after pheniprazine and tranylcypromine with¹⁴C-dopamine as substrate, but the maximal inhibition never exceeded 80% after pargyline treatment. As revealed by the in vivo 3 min initial accumulation of³H-H²O seen at the end of a local infusion of L. 3. 5-³H-tyrosine, the rate of the first step of DA synthesis was unchanged 5 min after pargyline treatment but significantly reduced 10 min after the drug injection. This explains the sudden interruption in the rise of DA levels observed shortly after the MAO inhibitors injection. DA synthesis rate was calculated from the initial (5 min) rate of DA accumulation and was found to be 148 to 190 nmole/g/hr depending on the inhibitor used.     

Neuroleptic drug effect on platelet monoamine oxidase and plasma amine oxidase in schizophrenia

Activity levels of platelet monoamine oxidase (MAO) and plasma amine oxidase (PAO) were determined in eight chronic schizophrenic patients who had been treated with neuroleptic drugs for 3 months. The mean reduction in platelet MAO activity was 18.6%. The extent of decrease was statistically significant. The reduction in enzyme activity was unrelated to serum iron levels. PAO activity was unaltered. The implications for schizophrenia research are discussed.     

Treatment of hyperactive children with monoamine oxidase inhibitors. II. Plasma and urinary monoamine findings after treatment

Urinary monoamines and metabolites as well as plasma norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol were measured in 14 boys (mean age, 9.2 years) with Attention Deficit Disorder With Hyperactivity during an initial placebo period, after four weeks of treatment with either dextroamphetamine sulfate (N=5) or a monoamine oxidase inhibitor (N=9) and at the end of a subsequent two-week placebo "washout" period. Both dextroamphetamine and monoamine oxidase inhibitors produced persistent changes in monoamines and metabolites, which were most marked and consistent for NE and its metabolite 3-methoxy-4-hydroxyphenylglycol. These changes did not correlate in a consistent fashion with clinical response during drug treatment. Moreover, there was rapid clinical relapse following cessation of either treatment while the alterations in NE metabolism remained during the two weeks following drug, further demonstrating the independence of these changes from clinical state. Future studies with dextroamphetamine need drug-free periods that are greater than 14 days to obtain true "baseline" conditions.