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.

BACKGROUND: As a FAD (Flavin Adenine Dinucleotide) - dependent histone demethylase discovered in 2004, LSD1 (lysine specific demethylase 1) was reported to be overexpressed in diverse tumors, regulating target genes transcription associated with cancer development. Hence, LSD1 targeted inhibitors may represent a new insight in anticancer drug discovery. For these reasons, researchers in both the pharmaceutical industry and academia have been actively pursuing LSD1 inhibitors in the quest for new anti-cancer drugs.
OBJECTIVE: This review summaries patents about LSD1 inhibitors in recent 5 years in hope of providing a reference for LSD1 researchers to develop new modulators of LSD1 with higher potency and fewer adverse effects.
METHODS: This review collects LSD1 inhibitors disclosed in patents since 2016. The primary ways of patent searching are Espacenet®, Google Patents, and CNKI.
RESULTS: This review covers dozens of patents related to LSD1 inhibitors in recent five years. The compound structures are mainly divided into TCP (Tranylcypromine) derivatives, imidazole derivatives, pyrimidine derivatives, and other natural products and peptides. Meanwhile, the compounds that have entered the clinical phase are also described.
CONCLUSIONS: Most of the compounds in these patents have been subjected to activity analysis with LSD1 and multi-cell lines, showing good antitumor activity in vitro and in vivo. These patents exhibited the structural diversity of LSD1 inhibitors and the potential of natural products as novel LSD1 inhibitors.

Treatment using add-on antidepressants with antipsychotic drugs in negative symptoms of schizophrenia has been reviewed recently in comprehensive meta-analyses. Tranylcypromine (TCP), an irreversible monoamine oxidase (MAO)-A/B inhibitor applied in treatment resistant depression, was not included because of strict requirements for quality of study design. To get a clear picture of available evidence for this resource in the treatment of schizophrenia, we conducted a review and meta-analysis of add-on TCP in the treatment of predominant negative symptoms of schizophrenia (negative schizophrenia).
Seven controlled studies of add-on TCP in schizophrenia with predominant negative symptoms were found in a search of multiple databases. A subset of four studies of the prospective and parallel comparison of add-on TCP with antipsychotic drugs vs. antipsychotic drug monotherapy and meeting minimum quality criteria formed the primary meta-analysis. The effect size was calculated as the natural logarithm of the odds ratio (logOR) of responders and non-responders.
In the primary meta-analysis, a pooled logOR = 1.092 with 95%CI 0.410-1.774 (I2 = 43.4%, moderate heterogeneity) was calculated according to a fixed-effect model. Heterogeneity was reduced for three double-blind studies of add-on TCP with trifluoperazine (TFP) vs. TFP-monotherapy and resulted a pooled logOR = 0.916 with 95%CI 0.216-1.616 (I2 negative, no heterogeneity). A significant logOR = 1.558 with 95%CI 0.340-2.776 was found for TCP/TFP compared to placebo in one study. In a meta-analysis of extrapyramidal adverse effects, studies were very heterogeneous and revealed no significant differences between treatments. The risk of exacerbation of positive symptoms with add-on TCP was found to be very low for a duration of treatment of 12-16 weeks. No cases of hypertensive crisis were reported. The main methodical limitations were insufficient description of randomization or matching of patients without randomization. The main clinical limitation is a gap of data for add-on TCP with second-generation antipsychotics.
New studies are needed for add-on TCP with antipsychotic drugs in schizophrenia with predominant negative symptoms. Trials of this treatment may be possible in rare and selected cases. The therapeutic effect of add-on TCP may be explained by a strong dopaminergic activity.

OBJECTIVE: 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.

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.

It has been over 50 years since a review has focused exclusively on the monoamine oxidase (MAO) inhibitor tranylcypromine (TCP). A new review has therefore been conducted for TCP in two parts which are written to be read preferably in close conjunction: Part I - pharmacodynamics, pharmacokinetics, drug interactions, toxicology; and Part II - clinical studies with meta-analysis of controlled studies in depression, practice of TCP treatment, place in therapy. Pharmacological data of this review part I characterize TCP as an irreversible and nonselective MAO-A/B inhibitor at low therapeutic doses of 20mg/day with supplementary norepinephrine reuptake inhibition at higher doses of 40-60mg/day. Serotonin, norepinephrine, dopamine, and trace amines, such as the \"endogenous amphetamine\" phenylethylamine, are increased in brain, which leads to changes in neuroplasticity by e.g. increased neurotrophic growth factors and translates to reduced stress-induced hypersecretion of corticotropin releasing factor (CRF) and positive testing in animal studies of depression. TCP has a pharmacokinetic half-life (t1/2) of only 2h which is considerably lower than for most other antidepressant drugs. However, a very long pharmacodynamic half-life of about one week is found because of the irreversible MAO inhibition. New studies show that, except for cytochrome P450 (CYP) 2A6, no other drug metabolizing CYP-enzymes are inhibited by TCP at therapeutic doses which defines a low potential of pharmacokinetic interactions in the direction from TCP to other drugs. Insufficient information is available, however, for plasma concentrations of TCP influenced by comedication. More quantitative data are also needed for TCP metabolites such as p-hydroxytranylcypromine and N-acetyltranylcypromine. Pharmacodynamic drug interactions comprise for instance severe serotonin toxicity (SST) with serotonergic drugs and hypertensive crisis with indirect sympathomimetics. Because of the risk of severe food interaction, TCP treatment remains beset with the need for a mandatory tyramine-restricted diet. Toxicity in overdose is similar to amitriptyline and imipramine according to the distance of therapeutic to toxic doses. In conclusion, TCP is characterized by an exceptional pharmacology which is different to most other antidepressant drugs, and a more special evaluation of clinical efficacy and safety may therefore be needed.

It has been over 50 years since a review has focused exclusively on the monoamine oxidase (MAO) inhibitor tranylcypromine (TCP). A new review has therefore been conducted for TCP in two parts which are written to be read preferably in close conjunction: part I - pharmacodynamics, pharmacokinetics, drug interactions, toxicology; and part II - clinical studies with meta-analysis of controlled studies in depression, practice of TCP treatment, place in therapy. The irreversible and nonselective MAO-A/B inhibitor TCP has been confirmed as an efficacious and safe antidepressant drug. For the first time, a meta-analysis of controlled clinical trials in depression demonstrated that TCP is superior to placebo (pooled logOR=0.509, 95%CI=0.026 to 0.993, 4 studies) and equal to other antidepressants (pooled logOR=0.208, 95%CI=-0.128 to 0.544, 10 studies). In treatment resistant depression (TRD) after tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), TCP was superior to placebo (logOR=2.826, 95%CI=1.494 to 4.158, one study) and non-established antidepressants (pooled logOR=1.976, 95%CI=0.907 to 3.045, 4 studies), and was equal to other MAO inhibitors and an antidepressant combination (pooled logOR=-0.366, 95%CI=-0.869 to 0.137, 4 studies). Controlled studies revealed that TCP might provide a special advantage in the treatment of atypical depression, which was supported by a recent PET study of MAO-A activity in brain. However, TCP treatment remains beset with the need for a mandatory tyramine-restricted diet and is therefore limited to use as a third-line antidepressant according to recent treatment algorithms and guidelines for depression treatment. On the other hand, the effort needed to maintain a tyramine-restricted diet may have been overestimated in the perception of both doctors and patients, which may have led to relative underuse of TCP. Interaction with serotonergic drugs bears the risk of severe serotonin toxicity (SST) and combination with indirect sympathomimetic drugs may result in hypertensive crisis which both adds to the risks of TCP. At the same time, TCP has low to no risks of central anticholinergic, sedative, cardiac conduction, body weight, hemostatic effects, or pharmacokinetic drug interactions. Neuroprotection by MAO inhibitors due to reduced oxidative stress is becoming increasingly studied. Taken together, TCP is being increasingly recognized as an important option in systematic treatment approaches for patients suffering from severe courses of depression, such as TRD and atypical depression, by offering a MAO-related pathophysiological rationale.

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.
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.
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.

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.

Monoamine oxidase-(MAO)-inhibitors are a treatment of last resort in treatment resistant depression, which is regarded as a condition of increased psychiatric risk. General and regional anesthesia for elective surgery during use of long-term MAO-inhibitors remains a matter of debate because of an increased risk of drug interactions and decreased sympathetic stability. A series of case reports and new comparative studies reveal the safety of anesthesia/analgesia in non-cardiac surgery without discontinuation of the MAO-inhibitor if best effort is made for maintenance of sympathetic homeostasis and if known drug interactions are avoided. Very few reports with severe adverse incidents have been noted. Severe cardiovascular morbidity, a contraindication of MAO-inhibitors, probably contributed to peri- and postoperative complications. According to new studies, the risk of pharmacokinetic drug interactions is lower for tranylcypromine than for phenelzine. In the present case, a 66-year-old psychiatric patient on permanent treatment with 20 mg/day tranylcypromine was admitted for forefoot surgery. Anesthetic premedication consisted of 7.5 mg oral midazolam. Intravenous midazolam (0.5 mg) was dispensed for intraoperative sedation. After local anesthesia of the puncture site with 30 mg isobar prilocaine, spinal anesthesia was achieved by a single shot of 13.5 mg hyperbar bupivacaine (0.5%) intrathecally. Postoperative regional and general analgesia were accomplished by a peripheral nerve block with 50 mg isobar bupivacaine as well as oral etoricoxib and oxycodone. No peri- or postoperative complications were encountered. It is concluded that general or regional anesthesia for noncardiac surgery without discontinuation of MAO-inhibitor treatment may be a safe intervention after careful evaluation of an individual\'s perioperative and psychiatric risk. The increased psychiatric risk in patients treated with MAO-inhibitors outweighs the increased, however manageable, perioperative risk from continuing treatment during surgery.