60 Years of Combining Tranylcypromine: A Systematic Review of Available Evidence.

BACKGROUND: Tranylcypromine is the only irreversible monoamine oxidase inhibitor that is approved in the United States and in Europe for the management of treatment-resistant major depressive disorder. Comprehensive data in the literature regarding the efficacy and tolerability of tranylcypromine (TCP) combination strategies have not been systematically investigated yet. METHODS: We conducted a systematic review of available literature based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Study types considered eligible for inclusion were studies that reported information on efficacy and/or tolerability/adverse effects of pharmacological TCP add-on or coadministration strategies among people with psychiatric disorders. RESULTS: Ninety-six articles were included in qualitative analyses. A relevant body of evidence shows that TCP combined with first- and second-generation antipsychotics seems relatively safe and might have beneficial effects in some patients with depressive disorders, although caution is needed with some second-generation antipsychotics that have proserotonergic activity. Although evidence is not entirely consistent, amitriptyline as add-on agent might be efficacious and associated with a low rate of severe adverse events. Although available data from case reports are scarce, certain other agents, such as trazodone, but also lithium, seem to have a good risk-benefit profile with regard to TCP that should be further investigated in the context of high-quality studies. CONCLUSIONS: Any combination of a psychotropic with TCP should be preceded by an evaluation of drug-to-drug interaction and an informed consent process and followed by close monitoring. Before any combination strategy, doctors should reevaluate factors of pseudo-treatment resistance, such as rapid-metabolizing status, noncompliance, trauma, alternative diagnosis, or drug abuse.

Cardiovascular Effects of Combining Subcutaneous or Intravenous Esketamine and the MAO Inhibitor Tranylcypromine for the Treatment of Depression: A Retrospective Cohort Study.

BACKGROUND: (Es)ketamine and monoamine oxidase inhibitors (MAOIs), e.g., tranylcypromine, are therapeutic options for treatment-resistant major depression. Simultaneous administration is currently not recommended because of concern about hypertensive crises. OBJECTIVE: Our objective was to evaluate whether changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) during esketamine administration differed between patients who concomitantly received tranylcypromine and those who did not. METHODS: This was a retrospective cohort study utilizing cardiovascular monitoring data from inpatients treated for severe depression in unipolar, bipolar, and schizoaffective disorder. Primary outcomes were change in mean BP and HR during the first hour after intravenous or subcutaneous esketamine administration compared with baseline, controlled for confounders. Secondary analyses quantify differences in absolute BP during esketamine treatment and comparisons of BP peaks, temporal effects, and intraindividual comparisons before and after tranylcypromine initiation. RESULTS: Our analysis included 509 esketamine administrations in 43 patients, 14 of whom concomitantly received tranylcypromine. Controlling for creatinine and age, mean ± standard deviation (SD) BP changes were significantly increased by concomitant tranylcypromine treatment (ΔSBP: F[1,503] = 86.73, p < 0.001; ΔDBP: F[1,503] = 55.71, p < 0.001), but HR remained unaffected. Mean SBP change during esketamine administration was 2.96 ± 18.11 mmHg in patients receiving tranylcypromine (TCP+) and -8.84 ± 11.31 mmHg in those who did not (TCP-). Changes in DBP were -2.81 ± 11.20 mmHg for TCP+ and -10.77 ± 9.13 mmHg for TCP-. Moreover, we found a significant dose-response relationship between tranylcypromine dose and BP (SBP: B = 0.35, standard error [SE] = 0.12, 95% confidence interval [CI] 0.12-0.60, p = 0.004; adjusted R2 = 0.11, p = 0.008; DBP: B = 0.21, SE = 0.08, 95% CI 0.06-0.36, p = 0.007; adjusted R2 = 0.08; p = 0.023). CONCLUSIONS: Although statistically significant changes in BP were identified in patients receiving tranylcypromine and esketamine, these changes were clinically insignificant. Thus, combining esketamine and this MAOI appears to be safe at standard doses. The dose-response relationship calls for caution with higher doses of tranylcypromine.

Efficacy and Adverse Effects of Tranylcypromine and Tricyclic Antidepressants in the Treatment of Depression: A Systematic Review and Comprehensive Meta-analysis.

PURPOSE: We conducted a comprehensive meta-analysis of the comparison of tranylcypromine (TCP) and tricyclic antidepressants (TCAs) in the treatment of depression because such work is lacking in medical scientific literature. METHODS: Literature was searched for studies of TCP controlled by TCAs in multiple databases and in reviews of TCP and monoamine oxidase inhibitors. The natural logarithm of the odds ratio (logOR) and the pooled logOR according to a fixed effect model were calculated for the numbers of responders and nonresponders. RESULTS: A total of 227 studies of TCP were found including 75 controlled studies of TCP-monotherapy. Twelve of 23 studies of TCP monotherapy and TCAs were excluded for several reasons (duplicates, safety studies, retrospective, cross-over), leaving 11 prospective and parallel controlled studies of TCP monotherapy versus TCAs (6 randomized double-blind). One study was excluded from the meta-analysis because of low quality of study design according to the Food and Drug Administration guidelines of studies of antidepressant drugs and high risk of bias according to the Cochrane's tool. Two studies with equal efficacy of TCP and TCAs in continuous endpoints did not provide dichotomous response data. A pooled logOR of 0.480 (95% confidence interval, 0.105-0.857, P = 0.01) resulted for the remaining eight studies in the primary meta-analysis, which favors TCP significantly over TCAs (test for heterogeneity: Х = 8.1, df = 7, P > 0.3, not heterogenous; I = 13.6%, heterogeneity not important). The result is robust with respect to inclusion of hypothetical response data of the 2 studies with continuous data only: pooled logOR, 0.350 (95% confidence interval, 0.028-0.672, P = 0.03). Visual inspection of forest plots and subgroup analysis suggest that superiority of TCP over TCAs is determined by 2 studies in psychomotor-retarded (anergic) depression. CONCLUSIONS: Tranylcypromine and TCAs have an equal antidepressant effect in a mean sample of depressed patients with mixed psychomotor symptoms. Tranylcypromine might be superior to TCAs in depression with predominant psychomotor retardation.

Myocardial Injury from Tranylcypromine-Induced Hypertensive Crisis Secondary to Excessive Tyramine Intake.

Monoamine oxidase inhibitors (MAOIs) are known to cause hypertensive crisis when combined with intake of tyramine, classically found in cheese. We present a case of MAOI-induced hypertensive crisis leading to significant troponin release after soft cheese intake. A 51-year-old lady presented with left-sided chest pain, palpitations and headache in the context of significant hypertension after eating soft cheese. She had a similar episode 2 month prior to this presentation, which resulted in a diagnosis of non-ST elevation myocardial infarction after a troponin of 2768 ng/L (Ref < 17 ng/L) with normal cardiac investigations and CT pulmonary angiogram. She was known to be on tranylcypromine for bipolar depression. Subsequent cardiac investigations were normal, as were those for phaeochromocytoma and Conn's disease. Tranylcypromine is a non-selective irreversible MAOI used in refractory depression and bipolar disorder. MAOIs are known to cause hypertensive crisis when combined with soft cheese due to unopposed release of catecholamines from reduced tyramine metabolisation, leading to injury and possible myonecrosis. Three previous case reports have demonstrated either creatinine kinase or troponin rise with myocardial infarction due to this hypertensive crisis and our case is the fourth with significant hypertension and cardiac biomarker rise related to MAOI, specifically tranylcypromine.

Acute hypertensive crisis and severe headache after concurrent use of armodafinil and tranylcypromine: Case report and review of the literature.

Concurrent use of modafinil or armodafinil with monoamine oxidase inhibitors (MAOIs) is contraindicated due to a theoretical risk of drug synergism and acute hypertensive episodes. However, few data are available to substantiate that risk, and several case studies have suggested that the combination is safe. To our knowledge, we present the first case of a patient treated concurrently with armodafinil and tranylcypromine. The patient developed an acute hypertensive crisis with severe headache, nausea, blurry vision, and neck stiffness. Her symptoms corresponded with the predicted pharmacokinetic and pharmacodynamic response. She was also taking brexpiprazole, which could have contributed to her underlying symptoms. However, limited data suggest that the single combination of brexpiprazole with armodafinil or MAOIs would be safe. Upon review of the literature, two out of seven patients, including our own, treated concurrently with modafinil or armodafinil and an MAOI developed an adverse reaction. Physicians should exercise caution if using these classes of drugs together.

[Tranylcypromine and khat: a potentially fatal combination]. / Tranylcypromine en khat: een potentieel fatale combinatie.

It is well known that the use of tranylcypromine in combination with amphetamines may induce a potentially lethal hypertensive crisis. That such a complication may also occur when tranylcypromine is combined with khat, however, is less known. We describe the case of a young patient who received a low dose of tranylcypromine combined with a small amount of khat, subsequently developing a subarachnoid hemorrhage.

Abnormal pregnancy outcome associated with high-dose maternal tranylcypromine therapy: Case report and literature review.

BACKGROUND: Tranylcypromine is a non-selective inhibitor of monamine oxidase which also inhibits the reuptake of norepinephrine. Spontaneous hypertensive reactions to the drug have been reported. In sheep tranylcypromine has been shown to cause a dose-dependent reduction in uterine blood flow. A similar effect in a pregnant woman might induce constriction of the uterine arteries and temporary fetal hypoxia. CASES: MotherSafe is a state-based Teratogen Information service and currently provides counselling to around 22,000 consumers and healthcare professionals annually regarding exposures during pregnancy and breastfeeding We report on the outcome of 2 pregnancies in a patient treated with high dose tranylcypromine as well as pimozide, diazepam and alprazolam. The first pregnancy resulted in fetal death and autopsy revealed facial dysmorphism with ocular hypertelorism, cardiac defect and placental infarcts. The second pregnancy continued to term but the baby had similar dysmorphic features as well as an atrio-ventricular septal defect and craniosynostosis. CONCLUSIONS: Due to their unpredictable interactions with many drugs and foods, MAO inhibitors such as tranylcypromine are not commonly used to treat depression and reports of use in pregnancy are rare. We report the outcome of 2 pregnancies with exposure to high doses of tranylcypromine resulting in children with a similar pattern of malformations. The aetiology is unknown but may relate to the vasoactive properties of the drug in above-therapeutic doses.

MAOIs - does the evidence warrant their resurrection?

OBJECTIVE: The place of monoamine oxidase inhibitors (MAOIs) in psychiatry is reviewed, and the question posed as to whether they are now justifiably disregarded by prescribers. METHOD: Multiple databases (PubMed, Medline, Embase, Cochrane) were interrogated to provide an overview regarding the use, efficacy and toxicity of MAOIs. Data regarding funded use of these agents in New Zealand were obtained from PHARMAC. RESULTS: Evidence supports the use of MAOIs in major depressive disorder, certain anxiety disorders and, to lesser extent, bipolar depression. Older non-selective agents, such as phenelzine and tranylcypromine, have distinctive efficacy in 'atypical' and treatment-resistant depression, but at the cost of serious tolerability problems. Their relegation and perception by clinicians as 'last resort' medications - if considered at all - has occurred in the context of various concerns, notably dietary restrictions, potential adverse drug interactions and the usual requirement for divided doses. CONCLUSIONS: Sufficient evidence supports consideration of MAOIs in treatment-refractory and atypical depressive disorders, and in social anxiety disorder. Psychiatrists in training need to gain experience in using these agents.

Efficacy of Tranylcypromine in Bipolar Depression: A Systematic Review.

OBJECTIVE: Currently, there is a paucity of treatment options with limited efficacy for bipolar depression. The monoamine oxidase inhibitor tranylcypromine might be an effective form of treatment. The current systematic review reassesses the efficacy and safety of tranylcypromine in bipolar depression. METHODS: For this systematic review comparing tranylcypromine with placebo or active comparators in bipolar depression, relevant randomized controlled trials were identified from systematic searches of PubMed, EMBASE, and Cochrane library databases. A manual search of the references of the included studies was also performed. RESULTS: Four studies with a total of 145 participants were identified. Response rates were higher in patients treated with tranylcypromine (60.0%-80.7%; overall response rate, 73.7%) compared with placebo, imipramine, and lamotrigine (the latter as add-on to a mood stabilizer) (12.9%-47.6%; overall response rate, 27.5%). The overall switch rate was 6.3% for patients treated with tranylcypromine and 18.4% for patients in the control group. CONCLUSIONS: This systematic review provides evidence for the efficacy and safety of tranylcypromine treatment in bipolar depression. Additional research is required to establish the efficacy of tranylcypromine as add-on to a mood stabilizer.

Intoxications with the monoamine oxidase inhibitor tranylcypromine: an analysis of fatal and non-fatal events.

Tranylcypromine (TCP) is a non-selective and irreversible monoamine oxidase inhibitor and an effective agent in the treatment of major depression. It features a complex pharmacologic profile and overdoses might induce severe intoxications. To identify typical clinical presentations of TCP-intoxications, range of associated TCP-dosages and possible differences between fatal and non-fatal intoxications a systematic review of all previously published cases of TCP-intoxications was conducted. We detected n=20 reports of TCP-intoxications in the literature (fatalities n=10). Mean age was 36.7 years (median 37); the majority of patients were female (60%). Frequent findings in patients with TCP-intoxications were disturbance of consciousness/cognitive dysfunction (90%), cardio-vascular symptoms (55%), hyperthermia (50%), respiratory distress (45%), delirium (45%), muscular rigidity (30%) and renal failure (20%). Suicidal intent was present in n=18 (90%) patients. First clinical symptoms related to TCP-intoxication developed on average in less than 1 day. The average dosage related to TCP-intoxication was 677 mg. The highest survived TCP-dosage was 4000 mg and the lowest fatal dosage was 170 mg. Patients with fatal intoxications were on average older (40.5 vs. 32.8 years) and developed a more rapid onset of symptoms (0.2 vs. 0.8 days). Death occurred after a mean time of 0.6 days; symptom relief in patients with non-fatal intoxications developed on average after 3.2 days. Considering the large dose spectrum between survived and lethal TCP-dosages individual susceptibility factors might play a role regarding the severity of clinical symptoms independently of the ingested dosage.

Withdrawal and discontinuation phenomena associated with tranylcypromine: a systematic review.

Tranylcypromine (TCP) is an effective antidepressant with a complex pharmacological profile and a relevant risk of abuse and dependence. Withdrawal phenomena (WP, in the case of TCP-abuse/dependence) or discontinuation phenomena (DP, in the case of absent TCP-abuse/dependence) subsequent to abrupt termination of TCP are a potentially severe clinical syndrome. We conducted a systematic review of all previously published WP/DP cases following abrupt termination of TCP in order to identify typical clinical presentations and risk factors of WP/DP and frequency of TCP abuse or dependence within these patients. By searching the Medline and Scopus databases we identified n=25 cases (cohort WP: n=18, cohort DP: n=7). Delirium was found in n=13 patients (cohort WP: 10/55.6%; cohort DP: 3/42.9%), n=6 demonstrated WP/DP without delirium (WP: 6/33.3%; DP: 0/0%) and n=5 rapid relapse in depression (WP: 1/5.6%; DP: 4/57.1%). Mean time until development of WP/DP was 1.9 (WP) and 2.2 (DP) days. Mean duration of WP/DP was 5.7 (WP) and 11.3 (DP) days. All patients of cohort WP were described to feature TCP-abuse/dependence. Patients with delirium were on average older (41.8 years vs. 37.8 years) and featured higher mean prescribed (71.0 mg vs. 38.3 mg) and actually taken daily TCP dosages (285.8 mg vs. 187.7 mg). In conclusion, even termination of lower daily dosages of TCP may result in delirium. Thrombocytopenia features diagnostic value in patients with deliria of unknown etiology. TCP should be administered with great care, especially in dependence-prone patients.·

Antidepressive treatment with monoamine oxidase inhibitors and the occurrence of intraoperative hemodynamic events: a retrospective observational cohort study.

OBJECTIVE: To investigate the occurrence of intraoperative hemodynamic events when antidepressive treatment with monoamine oxidase inhibitors (MAOIs) was continued during anesthesia. METHOD: 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.

Anxiety-like behavior and cognitive flexibility in adult rats perinatally exposed to increased serotonin concentrations.

Serotonin (5-hydroxytryptamine, 5HT) is a biologically active amine that regulates the development of 5HT neurons and target tissues during neurogenesis, while later it assumes the function of a neurotransmitter. Serotonin mediates many essential behaviors common to all mammals, and is held responsible for anxiety-like behavior and cognitive rigidity. Proper serotonin levels, controlled through 5HT synthesis and metabolism, are crucial for normal brain development. In this study we investigated anxiety-like behavior and cognitive flexibility in adult animals after exposing their developing brains to increased 5HT concentrations. Wistar rats were treated subcutaneously from gestational day 12 to post-natal day 21 with the immediate 5HT precursor 5-hydroxytryptophan (5HTP, 25mg/kg), a non-selective MAO inhibitor tranylcypromine (TCP, 2mg/kg), or saline. After reaching adulthood, animals were tested for anxiety-like behavior (exploratory behavior, thigmotactic behavior, social contact, and reaction to stressful stimulus) and cognitive flexibility (ability for reversal learning). Results of the behavioral studies corresponded with our previous neurochemical findings. Treatment with 5HTP, which has induced mild reduction in cortical 5HT concentrations, caused reduction in only one aspect of anxiety-like behavior (increased exploratory activity). Treatment with TCP, which lead to drastic reduction in 5HT concentration/function, resulted in a highly anxiolytic phenotype (reduced thigmotaxis, reaction to stress, and social anxiety) with improved cognitive flexibility. Although further neurochemical, anatomical and gene-expression studies are needed to elucidate the mechanisms underlying the observed behavior, we hope that our results will contribute to the understanding of the role of serotonin in anxiety-like behavior and cognitive rigidity.

[Irreversible, non-selective monoamine oxidase inhibitors]. / Irreversible, uselektive monoaminoksidasehemmere.

Irreversible, non-selective monoamine oxidase (MAO) inhibitors were among the first antidepressants. No drugs in this group are currently marketed in Norway, but many physicians will see patients using them, as they can be prescribed on a named patient basis after application to the Norwegian Medicines Agency. This article presents adverse effects, interactions and precautions related to the use of these drugs.