OBJECTIVE: To investigate the recovery of monoamine oxidase (MAO) activity in the liver and gut of healthy subjects after a dose of 10 mg of the irreversible MAO inhibitor tranylcypromine (TCP).
METHODS: A bioequivalence study of TCP with a wash-out of 1 week between 2 doses of 10 mg TCP was re-analyzed for changes of the plasma concentrations of TCP enantiomers. Plasma concentrations of (+)-TCP and the ratio of (+)-TCP and (-)-TCP plasma concentrations were used as a measure of MAO activity because (+)-TCP is a more effective suicide inhibitor of MAO than (-)-TCP and, therefore considerably more metabolized by MAO.
RESULTS: The area under the curve from the first to the last measured concentration (AUCt) and the maximum plasma concentration (Cmax) of (+)-TCP increased significantly in the second dose (p < 0.0001) by 43.1% (11.8%) and 66.5% (26.4%), respectively, (mean with 95%CI in each case). The ratios (+)-TCP/(-)-TCP of AUCt and Cmax also increased significantly (p < 0.0001) by 27.3% (6.4%) and 25.9% (6.2%), respectively. No changes were found for the half-lives (T1/2) of both enantiomers.
CONCLUSIONS: For the first dose, MAO is the main drug-metabolizing enzyme of (+)-TCP. MAO activity in the liver and gut is not completely recovered within 1 week after 1 dose of TCP. One week of wash-out may be insufficient in bioequivalence studies of irreversible MAO inhibitors. Prolonged inhibition of MAO after the treatment with irreversible MAO inhibitors may explain drug interactions during the switch from another MAO inhibitor to TCP. Enantiomer plasma concentrations of TCP after a dose of racemic TCP may be used as a test for gastrointestinal and hepatic MAO activity.

All-trans-retinoic acid (ATRA) is highly active in acute promyelocytic leukemia but not in other types of acute myeloid leukemia (AML). Previously, we showed that ATRA in combination with Lysine-specific demethylase 1 (LSD1) inhibition by tranylcypromine (TCP) can induce myeloid differentiation in AML blasts. This phase I/II clinical trial investigated the safety and efficacy of TCP/ATRA treatment as salvage therapy for relapsed/refractory (r/r) AML. The combination was evaluated in 18 patients, ineligible for intensive treatment. The overall response rate was 20%, including two complete remissions without hematological recovery and one partial response. We also observed myeloid differentiation upon TCP/ATRA treatment in patients who did not reach clinical remission. Median overall survival (OS) was 3.3 months, and one-year OS 22%. One patient developed an ATRA-induced differentiation syndrome. The most frequently reported adverse events were vertigo and hypotension. TCP plasma levels correlated with intracellular TCP concentration. Increased H3K4me1 and H3k4me2 levels were observed in AML blasts and white blood cells from some TCP/ATRA treated patients. Combined TCP/ATRA treatment can induce differentiation of AML blasts and lead to clinical response in heavily pretreated patients with r/r AML with acceptable toxicity. These findings emphasize the potential of LSD1 inhibition combined with ATRA for AML treatment.

BACKGROUND: Few therapeutic options are available for patients with electroconvulsive therapy-resistant major depressive disorder (ECT-r MDD), leaving a substantial proportion of this population beyond treatment possibilities. The combination of monoamine oxidase inhibitors and tricyclic antidepressants could be a potential strategy for managing ECT-r MDD, and the specific association of amitriptyline and tranylcypromine may offer additional tolerability advantages. Although promising, in our knowledge, no studies have examined until now the effectiveness of this combination in ECT-r MDD.
METHODS: We report a retrospective cohort of 31 patients with ECT-r MDD treated in an open-label fashion with the combination of amitriptyline and tranylcypromine.
RESULTS: Overall, 80.6% of the sample met response criteria at the end of the first 12 weeks of treatment. Seventy-six percent (19 of 25) of the responders were followed for a mean of 9.37 ± 3.86 years. During this follow-up period, none of the patients had a recurring depressive episode. The combination was well tolerated, whereas minor adverse effects were common, and no severe or life-threatening events were reported throughout the study.
CONCLUSIONS: These findings indicate that the combination tranylcypromine and amitriptyline is a potentially safe and effective candidate for future investigation in the treatment and long-term maintenance of ECT-r MDD.

OBJECTIVE: To investigate the occurrence of intraoperative hemodynamic events when antidepressive treatment with monoamine oxidase inhibitors (MAOIs) was continued during anesthesia.
METHODS: A retrospective observational cohort study was conducted among patients who were admitted for elective surgery requiring anesthesia in 8 Dutch hospitals (2004-2010). The index group included current users of irreversible (tranylcypromine) and reversible (moclobemide) MAOIs. The reference group included a sample of nonusers matched to the index group on hospital, type and period of surgery, and type of anesthesia (ratio 1:3). The outcome of interest was the occurrence of the following intraoperative hemodynamic events: hypotension or hypertension and tachycardia or bradycardia.
RESULTS: Approximately 280,000 surgical procedures were performed in the participating hospitals in the total observational period of 33 years. The index group included 26 and 25 users of tranylcypromine and moclobemide, respectively. The reference groups included 149 nonusers. Intraoperative hypotension occurred less frequently in users of tranylcypromine (46%) than in nonusers (73%) (P = .01). The occurrence of hypertension, bradycardia, and tachycardia during anesthesia was not different between users of tranylcypromine (27%, 50%, and 12%, respectively) and those in the reference group (35%, 61%, and 26%, respectively). The occurrence of hypotension, hypertension, bradycardia, and tachycardia was not different between users of moclobemide and the reference group.
CONCLUSIONS: Severe adverse hemodynamic events, such as hypertension and tachycardia, did not occur more frequently in users of both the irreversible MAOI tranylcypromine and the reversible MAO-A inhibitor moclobemide compared to nonusers. These findings suggest that there is no longer much justification to discontinue these MAOIs before surgery, with the considerable risk of compromising patients\' psychiatric status.

OBJECTIVE: To compare the efficacy and tolerability of tranylcypromine vs. lamotrigine in bipolar depression not responding to conventional antidepressants.
METHODS: Bipolar depressed patients received open randomized treatment with tranylcypromine or lamotrigine as add-on to a mood stabilizer during 10 weeks. In a second treatment phase, non-responding patients could receive the opposite drug. Outcome criteria were response (measured with CGI-BP and IDS-C), switch into mania, and completion of the study.
RESULTS: Only 20 of 70 planned patients were randomized, due to problems with recruitment, and 19 patients received any medication. During the first treatment phase 5/8 patients (62.5%) responded to tranylcypromine without switch into mania, compared with 4/11 patients (36.4%) on lamotrigine with two switches (statistically not significant). Over both treatment phases, 8/10 patients (80%) receiving tranylcypromine completed the study vs. 5/13 (38.5%) on lamotrigine (likelihood 0.02).
CONCLUSIONS: There still appears to be a role for tranylcypromine in the treatment of refractory bipolar depression. Larger controlled studies are demanded.

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BACKGROUND: The aim of this study was to examine whether phenelzine is a suitable alternative to tranylcypromine in antidepressant-resistant depression.
METHODS: A total of 77 severely depressed in-patients, meeting the DSM-IV criteria for major depressive disorder, who failed to respond to fixed plasma level treatment with either tricyclic antidepressants or fluvoxamine were withdrawn from psychotropic medication and included in a double-blind flexible-dose 5-week comparison of tranylcypromine and phenelzine.
RESULTS: Of the 77 patients, 67 (87%) completed the trial, of whom 35 (52%) responded. No significant differences in response between both drugs were observed. Seventeen (44%) of 39 patients responded to tranylcypromine and 18 (47%) of 38 to phenelzine (> or = 50% reduction in Hamilton Rating Scale for Depression [HAM-D] score). The mean reduction in HAM-D score was 10.4 +/- 8.3 for the tranylcypromine sample versus 8.3 +/- 8.4 for the phenelzine-treated patients. Only a few patients (10%) used concomitant psychotropic medication. A substantial number of patients experienced severe side effects, mainly dizziness, agitation, and insomnia; the incidence was the same in both samples (21%).
CONCLUSIONS: No difference in efficacy was observed between both monoamine oxidase inhibitors in a sample of patients with severe antidepressant-refractory depression. Phenelzine appears to be a suitable alternative to tranylcypromine.

Tyramine is a biogenic trace amine that releases monoamines and is a good substrate for monoamine oxidase (MAO)-A/B. Here we investigated whether tyramine affects hydroxyl radical formation in the intact and lesioned dopaminergic system. Male C57bl/6 mice received systemic and local tyramine administrations. Hydroxyl radical formation and dopamine (DA) overflow were determined in the striatum using in vivo microdialysis in combination with the salicylate hydroxylation assay. Systemic injection of tyramine neither enhanced extracellular dopamine nor induced hydroxyl radical formation. In contrast, when tyramine was incorporated into the dialysate fluid, hydroxyl radical formation and extracellular dopamine levels were significantly enhanced. Systemic pretreatment with the MAO-A/B inhibitor tranylcypromine or with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) significantly diminished the tyramine-induced hydroxyl radical formation by 73.1% and 80.6%, respectively. We conclude that the mechanism of tyramine-induced hydroxyl free radical formation involves MAO metabolism and requires an intact dopaminergic system. Pharmacological intervention on the MAO-mediated formation of hydroxyl free radicals seems to be a promising strategy to prevent oxidative damage in the nigrostriatal dopaminergic system.

OBJECTIVE: Irritable bowel syndrome (IBS) is frequently associated with mood disorder. However, it is typically difficult to distinguish between disturbed mood as a causal agent and disturbed mood as a consequence of the experience of IBS. This report considers the association between mood and symptom severity in a patient with diarrhea-predominant IBS and stable, rapid cycling bipolar disorder with a predominantly depressive course. Such a case provides an important opportunity to determine the direction of the relationship between mood and IBS symptom severity because the fluctuations of mood in bipolar disorder are assumed to be driven largely by biological, rather than psychosocial, processes.
METHODS: The study was carried out prospectively, with ratings of mood and IBS symptom severity made daily by the patient for a period of almost 12 months.
RESULTS: The patient experienced regular and substantial changes in mood as well as fluctuations in the level of IBS symptoms during the study period. Contrary to expectation, the correlation between mood and IBS symptom severity on the same day suggested that the patient experienced less severe IBS symptoms during periods of more severe depression. However, time series analysis revealed no significant association between these two processes when serial dependence within each series was controlled for.
CONCLUSIONS: The unusual co-occurrence of IBS with bipolar disorder provides direct evidence to indicate that depression does not necessarily lead to an increase in the reported severity of IBS, at least in the context of bipolar disorder, and may under certain circumstances actually be associated with a reduction in the severity of IBS symptoms. Factors that might moderate the relationship between depression and symptom severity are discussed.

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