Synthesis and anti-cancer potential of potent peripheral MAOA inhibitors designed to limit blood:brain penetration.

Monoamine oxidases (MAOA/MAOB) are enzymes known for their role in neurotransmitter regulation in the central nervous system (CNS). Irreversible and non-selective MAO inhibitors (MAOi's) were the first class of antidepressants, thus subsequent work on drugs such as the selective MAOA inhibitor clorgyline has focussed on selectivity and increased CNS penetration. MAOA is highly expressed in high grade and metastatic prostate cancer with a proposed effect on prostate cancer growth, recurrence, and drug resistance. A Phase II Clinical Trial has demonstrated the therapeutic effects of the irreversible nonselective MAOi phenelzine for prostate cancer. However, neurologic adverse effects led to early withdrawal in 25% of the enrolled patient-population. In this work, we revised the clorgyline scaffold with the goal of decreasing CNS penetration to minimize CNS-related side effects while retaining or enhancing MAOA inhibition potency and selectivity. Using the known co-crystal structure of clorgyline bound with FAD co-factor in the hMAOA active site as a reference, we designed and synthesized a series of compounds predicted to have lower CNS penetration (logBB). All synthesized derivatives displayed favorable drug-like characteristics such as predicted Caco-2 permeability and human oral absorption, and exhibited highly selective hMAOA binding interactions. Introduction of an HBD group (NH2 or OH) at position 5 of the phenyl ring clorgyline resulted in 3x more potent hMAOA inhibition with equivalent or better hMAOB selectivity, and similar prostate cancer cell cytotoxicity. In contrast, introduction of larger substituents at this position or at the terminal amine significantly reduced the hMAOA inhibition potency, attributed in part to a steric clash within the binding pocket of the MAOA active site. Replacement of the N-methyl group by a more polar, but larger 2-hydroxyethyl group did not enhance potency. However, introduction of a polar 2-hydroxy in the propyl chain retained the highly selective MAOA inhibition and cancer cell cytotoxicity of clorgyline while reducing its CNS score from 2 to 0. We believe that these results identify a new class of peripherally directed MAOIs that may allow safer therapeutic targeting of MAOA for a variety of anti-cancer and anti-inflammatory indications.

Peripheral edema associated with antidepressant use: Systematic review of case reports.

BACKGROUND: Oedema associated with psychotropics can impose a considerable burden, leading to increased morbidity and cost. Peripheral oedema is sometimes related to the use of antidepressants, which are among the most prescribed psychotropic medications. We reviewed the reported cases of antidepressant-associated oedema to understand the risk factors, aetiology and outcome. METHODS: We searched the Medline, Web of Science and Embase databases to identify reported cases of peripheral oedema associated with antidepressant use. We included studies published in English and those with full-text availability. A systematic review of the reports was done to identify the antidepressants associated with oedema, explore possible risk factors, investigate potential mechanisms, and assess the outcome. RESULTS: We identified a total of 45 cases (27 case reports and five case series) that reported oedema associated with antidepressant use. Almost all major classes of antidepressants were found to be associated with oedema. Among these drugs, trazodone, mirtazapine, and escitalopram were the most implicated. Older age and female gender were more commonly associated with oedema. Etiologically, antagonism of α1 adrenergic receptors and 5HT2A receptors, leading to vasodilation and oedema, emerged as the most prevalent mechanisms. In most cases, the oedema subsided following the discontinuation of the antidepressants. CONCLUSIONS: Peripheral oedema associated with antidepressant use can represent a significant adverse drug reaction involving various classes of antidepressants. To ensure timely identification and proper management of oedema, regular monitoring is crucial.

The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

In vivo electrophysiological recordings of the effects of antidepressant drugs.

Antidepressant drugs are a standard biological treatment for various neuropsychiatric disorders, yet relatively little is known about their electrophysiologic and synaptic effects on mood systems that set moment-to-moment emotional tone. In vivo electrical recording of local field potentials (LFPs) and single neuron spiking has been crucial for elucidating important details of neural processing and control in many other systems, and yet electrical approaches have not been broadly applied to the actions of antidepressants on mood-related circuits. Here we review the literature encompassing electrophysiologic effects of antidepressants in animals, including studies that examine older drugs, and extending to more recently synthesized novel compounds, as well as rapidly acting antidepressants. The existing studies on neuromodulator-based drugs have focused on recording in the brainstem nuclei, with much less known about their effects on prefrontal or sensory cortex. Studies on neuromodulatory drugs have moreover focused on single unit firing patterns with less emphasis on LFPs, whereas the rapidly acting antidepressant literature shows the opposite trend. In a synthesis of this information, we hypothesize that all classes of antidepressants could have common final effects on limbic circuitry. Whereas NMDA receptor blockade may induce a high powered gamma oscillatory state via direct and fast alteration of glutamatergic systems in mood-related circuits, neuromodulatory antidepressants may induce similar effects over slower timescales, corresponding with the timecourse of response in patients, while resetting synaptic excitatory versus inhibitory signaling to a normal level. Thus, gamma signaling may provide a biomarker (or "neural readout") of the therapeutic effects of all classes of antidepressants.

Serotonin Toxicity and Urinary Analgesics: A Case Report and Systematic Literature Review of Methylene Blue-Induced Serotonin Syndrome.

BACKGROUND: Serotonin syndrome (SS) is a potentially serious side effect of serotonergic drugs. Cases of SS have been reported from the administration of methylene blue (MB), an agent with monoamine oxidase inhibiting properties. To date, the reported cases of MB-induced SS have all been with MB given parenterally. We report a case induced by the initiation of a MB-containing oral agent. METHODS: A case of SS felt to be induced by the initiation of an MB-containing orally-administered urinary analgesic, started in a patient concurrently treated with multiple serotonergic drugs, is presented. A systematic literature review of MB-induced SS follows. The review consisted of searches in MEDLINE databases using the key terms "methylene blue" and "serotonin syndrome". The authors read all abstracts, and articles related to MB and serotonin toxicity; non-associated articles were discarded. Results are summarized. RESULTS: 23 manuscripts were identified, resulting in 50 unique cases of MB-induced SS. The majority of cases were related to peri-operative use of MB in parathyroidectomies or for the treatment of vasoplegic shock. All cases were associated with MB given parenterally. Concurrent treatment with serotonergic antidepressants was described in all 50 cases. Symptoms of SS ranged from mild to severe. One fatality was reported. CONCLUSIONS: Methylene blue can induce SS, felt to be secondary to MAOI properties. Although previous reports have exclusively been associated with MB given via parental administration, our case suggests that SS can be induced by oral administration of MB-containing agents.

Hypertensive Emergency Secondary to Combining Psilocybin Mushrooms, Extended Release Dextroamphetamine-Amphetamine, and Tranylcypromine.

Data on medication interactions with psychedelics are limited. Here we present what may be the first published report of a hypertensive emergency following the combination of psilocybin mushrooms with a monoamine oxidase inhibitor (MAOI). A 42-year-old man with treatment-resistant major depressive disorder took 1 g of Psilocybe cubensis mushrooms, while prescribed tranylcypromine, extended-release dextroamphetamine-amphetamine, and other medications. Approximately half an hour later, he developed severe hypertension with chest pain, palpitations, and headache. Upon hospital presentation, the electrocardiogram demonstrated ST-elevation. The patient was diagnosed with a myocardial infarction and treated with lorazepam, nitroglycerin, and aspirin. He subsequently underwent emergency cardiac catheterization, which revealed no significant cardiac abnormalities. Following overnight hospitalization, he was discharged home with no lasting physical sequelae. Though data are few, past studies suggest that classic serotonergic psychedelics (5HT-2A receptor agonists) such as dimethyltryptamine (DMT), lysergic acid (LSD), and synthetic psilocybin should not produce hypertensive emergency when combined with MAOIs. We suspect phenylethylamine, found in Psilocybe cubensis and other species of psilocybin mushrooms, interacted with tranylcypromine and dextroamphetamine-amphetamine to produce this hypertensive emergency. Patients prescribed MAOIs should be warned of the potential for hypertensive emergency when consuming psilocybin mushrooms, particularly when also prescribed norepinephrine releasers such as dextroamphetamine-amphetamine.

On the Origins of MAOI Misconceptions: Reaffirming their Role in Melancholic Depression.

The first monoamine oxidase inhibitors (MAOIs) used for the treatment of depression in the 1950-60s were credited with treating severe melancholic depression (MeD) successfully and greatly reducing the need for electroconvulsive therapy (ECT). Following the hiatus caused by the then ill-understood cheese reaction, MAOI use was relegated to atypical and treatment-resistant depressions only, based on data from insufficiently probing research studies suggesting their comparatively lesser effectiveness in MeD. The siren attraction of new 'better' drugs with different mechanisms amplified this trend. Following a re-evaluation of the data, we suggest that MAOIs are effective in MeD. Additionally, the broad unitary conceptualisation of major depressive disorder (MDD) in the DSM model diminished the chance of demonstrating distinctive responses to different antidepressant drugs (ADs) such as SSRIs, TCAs, and MAOIs, thereby further reducing the interest in MAOIs. More reliable categorical distinction of MeD, disentangling it from MDD, may be possible if more sensitive measuring instruments (CORE, SMPI) are used. We suggest these issues will benefit from re-appraisement via an inductive reasoning process within a binary (rather than a unitary) model for defining the different depressive disorders, allowing for the use of more reliable diagnostic criteria for MeD in particular. We conclude that MAOIs remain essential for, inter alia, TCA-resistant MeD, and should typically be used prior to ECT; additionally, they have a role in maintaining remission in cases treated with ECT (and ketamine/esketamine). We suggest that MAOIs should be utilized earlier in treatment algorithms and with greater regularity than is presently the case.

Efficacy and safety of selegiline across different psychiatric disorders: A systematic review and meta-analysis of oral and transdermal formulations.

Selegiline is an irreversible, selective type-B monoamine oxidase inhibitor (MAOI) approved for Parkison's disease-oral and major depressive disorder-transdermal formulation) resulting in non-selective MAOI activity at oral doses≥20 mg/day. The present systematic review and meta-analysis appraises the evidence of different formulations/dosages of selegiline across different psychiatric conditions. We inquired PubMed/MEDLINE/Cochrane-Central/WHO-ICTRP/Clarivate-WebOfScience and the Chinese-Electronic-Journal Database from inception to 10/26/2022 for selegiline trials involving psychiatric patients. Random-effects meta-analyses assessed heterogeneity, publication/risk biases, and confidence in the evidence, followed by sensitivity, subgroup, and meta-regression analyses. Co-primary outcomes were: changes in symptom score (standardized mean difference=SMD) and author-defined response (risk ratios=RRs). RRs of adverse events and all-cause discontinuation were secondary and acceptability outcomes, respectively. Systematic-review included 42 studies; meta-analysis, 23. Selegiline outperformed placebo in depressive symptom reduction (SMD=-0.96, 95%C.I.=-1.78, -0.14, k = 10, n = 1,308), depression (RR=1.61, 95%C.I.=1.20, 2.15, k = 9, n = 1,238) and atypical-depression response (RR=2.23, 95%C.I.=1.35, 3.68, k = 3, n = 136). Selegiline failed to outperform the placebo in negative (k = 4) or positive symptoms of schizophrenia (k = 4), attention-deficit-hyperactivity disorder (ADHD) symptoms reduction (k = 2), and smoking abstinence rate (k = 4). Selegiline did not differ from methylphenidate and ADHD scores (k = 2). No significant difference emerged in acceptability, incident diarrhea, headache, dizziness, and nausea RRs, in contrast to xerostomia (RR=1.58, 95%C.I. =1.03, 2.43, k = 6, n = 1,134), insomnia (RR=1.61, 95%C.I.=1.19, 2.17, k = 10, n = 1,768), and application-site reaction for transdermal formulation (RR=1.81, 95%C.I.=1.40, 2.33, k = 6, n = 1,662). Confidence in findings was low/very-low for most outcomes; moderate for depressive symptoms reduction (transdermal). Selegiline proved effective, safe, and well-tolerated for depressive disorders, yet further evidence is warranted about specific psychiatric disorders.

[70-year history of studying the effectiveness of therapy of patients with depression with antidepressants - irreversible nonselective monoamine oxidase inhibitors]. / Semidesyatiletnyaya istoriya izucheniya effektivnosti terapii depressii neobratimymi neselektivnymi ingibitorami monoaminoksidazy.

The history of studying the effectiveness of therapy of patients with depression by irreversible non-selective monoamine oxidase inhibitors (MAOIs) is analyzed and systematized. Authors describe the stages of the appearance of the first data on the effectiveness of treatment by the first representatives (the 50s of the XX century), the targeted study of the effectiveness of the use of numerous «new¼ representatives and the emergence of disagreements in assessing the power of therapy (the end of the 50s-60s of the XX century), continuing to study the effectiveness of treatment by representatives who remained in clinical practice, and establishing its clinical predictors (80s-90s of the XX century), the appearance of the first data on the effectiveness of therapy for «atypical depression¼ (1959-1960) and further development of this issue (80s-90s of the XX century). The stage of formation and development of the idea of the effectiveness of treatment for resistant depression (late 70s-90s of the XX century) is characterized. Separately, the history of studying the effectiveness of application in the USSR and Russia (late 50s- 90s of the XX century) is outlined. The current state of the issue of assessing the effectiveness of therapy (the end of the 90s of the XX century - 2022) is shown.

The Prescriber's Guide to the MAOI Diet-Thinking Through Tyramine Troubles.

This review article features comprehensive discussions on the dietary restrictions issued to patients taking a classic monoamine oxidase inhibitor (phenelzine, tranylcypromine, isocarboxazid), or high-dose (oral or transdermal) selegiline. It equips doctors with the knowledge to explain to their patients which dietary precautions are necessary, and why that is so: MAOIs alter the capacity to metabolize certain monoamines, like tyramine, which causes dose-related blood pressure elevations. Modern food production and hygiene standards have resulted in large reductions of tyramine concentrations in most foodstuffs and beverages, including many cheeses. Thus, the risk of consequential blood pressure increases is considerably reduced-but some caution remains warranted. The effects of other relevant biogenic amines (histamine, dopamine), and of the amino acids L-dopa and L-tryptophan are also discussed. The tables of tyramine data usually presented in MAOI diet guides are by nature unhelpful and imprecise, because tyramine levels vary widely within foods of the same category. For this reason, it is vital that doctors understand the general principles outlined in this guide; that way, they can tailor their instructions and advice to the individual, to his/her lifestyle and situation. This is important because the pressor response is characterized by significant interpatient variability. When all factors are weighed and balanced, the conclusion is that the MAOI diet is not all that difficult. Minimizing the intake of the small number of risky foods is all that is required. Many patients may hardly need to change their diet at all.

Tobacco and ADHD: A Role of MAO-Inhibition in Nicotine Dependence and Alleviation of ADHD Symptoms.

Attention-deficit/hyperactivity disorder (ADHD) is a relatively commonly occurring neurodevelopmental disorder affecting approximately 5% of children and young people. The neurobiological mechanisms of ADHD are proposed to particularly center around increased dopamine receptor availability related to associated symptoms of reduced attention regulation and impulsivity. ADHD is also persistent across the lifespan and associated with a raft of impulsive and health-risk behaviors including substance abuse and smoking. Research highlighting the potentially significant levels of monoamine oxidase (MAO) inhibitory properties in tobacco smoke and e-cigarettes may provide a mechanism for increased tobacco smoke dependence among those with ADHD, in addition to the role of nicotine. Aim: This scoping review aimed to establish evidence for the above neurobiological pathway between smoking and ADHD symptom-alleviation or "self-medication" with the inclusion of the mechanism of MAO-inhibitors indirect increasing dopamine in the brain. Methodology: Scoping review methodologies were employed in this review selected to synthesize multiple sources of empirical research to identify current gaps in the knowledge base and identify key characteristics of research data related to a phenomenon. Databases searched included OVID MEDLINE(R), Embase, Cochrane, PsycINFO and SCOPUS limited to 2000 onward and empirically validated, peer-reviewed research. Findings: There is support for the role of MAO-inhibition on greater reinforcement of smoking for individuals with ADHD through a greater impact on dopaminergic availability than nicotine; potentially moderating ADHD symptoms. Conclusion: Greater support for a "self-medication" model of ADHD and smoking includes not only nicotine but also MAO-inhibitors as dopamine agonists contained in cigarettes and e-cigarettes.

Ayahuasca for the Treatment of Depression.

Ayahuasca, the vine of the souls in Quechua, is a psychedelic brew with a few formulations that most often include the bark of a liana in the Malpighiaceae family (Banisteriopsis caapi), with leaves from a shrub in the coffee family Rubiaceae (Psychotria viridis). Mixed with water and boiled for hours or days, it produces a brownish-colored liquid with a strong and characteristic taste. Ayahuasca contains the psychedelic tryptamine N,N-Dimethyltryptamine (DMT), and Monoamine Oxidase Inhibitors (MAOi), and in the past few years, it has been tested. In recent years its antidepressant properties have been put to the test. Evidence from open and randomized placebo-controlled clinical trials has shown encouraging results, indicating significant and rapid antidepressant effects, starting as early as 1 day after the ayahuasca intervention. In addition, we have explored the nature of these effects using multivariate measures. In this article, we will review the history, pharmacology, clinical trials, and clinical and behavioral markers associated with the antidepressant effects of ayahuasca.

Revisiting monoamine oxidase inhibitors for the treatment of depressive disorders: A systematic review and network meta-analysis.

BACKGROUND: Monoamine oxidase inhibitors (MAOIs) were the first class of modern antidepressants; however, they are under-utilized as compared to the newer antidepressants. METHODS: In this systematic review, network meta-analysis was used to investigate the comparative efficacy and acceptability of MAOIs for depressive disorders. Overall, the network meta-analysis included 52 double-blind, randomized controlled trials (RCTs) that compared 14 antidepressants or placebo. Across studies, the mean arm size was n = 58 participants from a total N = 6462 (5309 active drug; 1153 placebo). RESULTS: Except fluvoxamine, all antidepressants demonstrated superior efficacy to placebo, and none demonstrated substantially better or worse all-cause dropout rates. Phenelzine demonstrated superior evidence for efficacy compared to all other treatments, and clomipramine demonstrated superior evidence for acceptability compared to all other treatments. LIMITATIONS: The study is primarily limited by low estimate precision due to a relative paucity of studies for some of the included treatment conditions. Further evidence is required to study the relative efficacy of MAOIs against newer antidepressants. CONCLUSIONS: The results of this analysis largely support the re-evaluation of the use of MAOIs as antidepressant agents in the treatment algorithm of depression.

Sizes and ligands tuned gold nanocluster acting as a new type of monoamine oxidase B inhibitor.

Monoamine oxidase inhibitors (MAOIs) are a class of drugs that can be used in the treatment of Parkinson's disease, clinical depression, and anxiety by targeting monoamine oxidase B (MAO). However, the side effects of MAOIs drive the requirement of a new framework of enzyme inhibitors development. In this context, a new type of MAOI has been built on the framework of gold nanoclusters (AuNCs), realizing the transformation from no function of small molecules to MAOI function of ligand-modified AuNCs. The MAOI activity of fabricated AuNCs can be achieved by size control and specific ligands modification. In this work, AuNCs modified with cysteamine or 4-aminothiophenol, about 1-3 nm in size, were found to have MAOI activity (MAOI-like AuNCs) and their characterization has been extensively described. Meanwhile, the possible mechanism behind this MAOI activity has been explored and it is believed that the proper size of AuNCs with ligands containing amino groups can bind tightly with the entrance to active sites of MAO, blocking the enzyme interacting with its substrates, thereby realizing the function of MAOI. Last, the antimicrobial activity and the performance of the MAOI-like AuNCs in the human blood sample were explored and suggested that MAOI-like AuNCs do not possess strong antimicrobial activity and have no visualized side effect on blood cells, although the by-product peroxide of MAO reaction may reshape the white blood cells. The research in this work may shed some light on the development of a new type of enzyme inhibitor based on the framework of nanomaterials.

Antinociceptive Effects of the Antidepressant Phenelzine are Mediated by Context-Dependent Inhibition of Neuronal Responses in the Dorsal Horn.

The putative strong anti-nociceptive properties of the antidepressant phenelzine (PLZ) have not been widely explored as a treatment for pain. Antinociceptive effects of PLZ were identified in the formalin model of tonic pain (Mifflin et al., 2016) and in allodynia associated with experimental autoimmune encephalomyelitis, (EAE) a mouse model of multiple sclerosis (Potter et al., 2016). Here, we further clarify the specific types of stimuli and contexts in which PLZ modulates nociceptive sensitivity. Our findings indicate that PLZ selectively inhibits ongoing inflammatory pain while sparing transient reflexive and acute nociception. We also investigated the cellular mechanisms of action of PLZ in the dorsal horn, and as expected of a monoamine-oxidase inhibitor, PLZ increased serotonin (5HT) immunoreactivity. We next used two approaches to test the hypothesis that PLZ inhibits the activation of spinal nociresponsive neurons. First, we evaluated the formalin-evoked protein expression of the immediate early gene, c-fos. PLZ reduced Fos expression in the superficial dorsal horn. Second, we evaluated the effects of PLZ on intracellular calcium responses to superfusion of glutamate (0.3-1.0 mM) in an ex vivo lumbar spinal cord slice preparation. Superfusion with PLZ (100-300 µM) reduced 1 mM glutamate-evoked calcium responses. This was blocked by pretreatment with the 5HT1A-receptor antagonist WAY-100,635, but not the alpha-2 adrenergic antagonist idazoxan. We conclude that PLZ exerts antinociceptive effects through a 5-HT/5HT1AR-dependent inhibition of neuronal responses within nociceptive circuits of the dorsal horn.

Chronic CB1 cannabinoid receptor antagonism persistently increases dendritic spine densities in brain regions important to zebra finch vocal learning and production in an antidepressant-sensitive manner.

During typical late-postnatal CNS development, net reductions in dendritic spine densities are associated with activity-dependent learning. Prior results showed agonist exposure in young animals increased spine densities in a subset of song regions while adult exposures did not, suggesting endocannabinoid signaling regulates dendritic spine dynamics important to vocal development. Here we addressed this question using the CB1 receptor-selective antagonist SR141716A (SR) to disrupt endocannabinoid signaling both during and after vocal learning. We hypothesized antagonist exposure during vocal development, but not adulthood, would alter spine densities. Following 25days of exposure and a 25day maturation period, 3D reconstructions of Golgi-Cox stained neurons were used to measure spine densities. We found antagonist treatments during both age periods increased densities within Area X (basal ganglia) and following adult treatments within HVC (premotor cortical-like). Results suggest both inappropriate cannabinoid receptor stimulation and inhibition are capable of similar disregulatory effects during establishment of circuits important to vocal learning, with antagonism extending these effects through adulthood. Given clinical evidence of depressant effects of SR, we tested the ability of the antidepressant monoamine oxidase inhibitor (MAOI) phenelzine to mitigate SR-induced spine density increases. This was confirmed implicating interaction between monoamine and endocannabinoid systems. Finally, we evaluated acute effects of these drugs to alter ability of novel song exposure to increase spine densities in auditory NCM and other regions, finding when combined, SR and phenelzine increased densities within Area X. These results contribute to understanding relevance of dendritic spine dynamics in neuronal development, drug abuse, and depression.

Anesthetic Considerations for Patients on Antidepressant Therapy-Part I.

Millions of patients take antidepressant medications in the United States for the treatment of depression or anxiety disorders. Some antidepressants are prescribed off-label to treat problems such as chronic pain, low energy, and menstrual symptoms. Antidepressants are a broad and expansive group of medications, but the more common drug classes include tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors. A miscellaneous or "atypical" category covers other agents. Some herbal supplements that claim to have antidepressant activity will also be discussed. In Part I of this review, antidepressant pharmacology, adverse effects, and drug interactions with adrenergic agonists will be discussed. In part II, drug interactions with sedation and general anesthetics will be reviewed. Bleeding effects and serotonin syndrome implications in anesthetic practice will also be highlighted.

Modification of 5-methoxy-N,N-dimethyltryptamine-induced hyperactivity by monoamine oxidase A inhibitor harmaline in mice and the underlying serotonergic mechanisms.

BACKGROUND: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are indolealkylamine (IAA) drugs often abused together. Our recent studies have revealed the significant effects of co-administered harmaline, a monoamine oxidase inhibitor (MAOI), on 5-MeO-DMT pharmacokinetics and thermoregulation. This study was to delineate the impact of harmaline and 5-MeO-DMT on home-cage activity in mouse models, as well as the contribution of serotonin (5-HT) receptors. METHODS: Home-cage activities of individual animals were monitored automatically in the home cages following implantation of telemetry transmitters and administration of various doses of IAA drugs and 5-HT receptor antagonists. Area under the effect curve (AUEC) of mouse activity values were calculated by trapezoidal rule. RESULTS: High dose of harmaline (15mg/kg, ip) alone caused an early-phase (0-45min) hypoactivity in mice that was fully attenuated by 5-HT1A receptor antagonist WAY-100635, whereas a late-phase (45-180min) hyperactivity that was reduced by 5-HT2A receptor antagonist MDL-100907. 5-MeO-DMT (10 and 20mg/kg, ip) alone induced biphasic effects, an early-phase (0-45min) hypoactivity that was completely attenuated by WAY-100635, and a late-phase (45-180min) hyperactivity that was fully suppressed by MDL-100907. Interestingly, co-administration of MAOI harmaline (2-15mg/kg) with a subthreshold dose of 5-MeO-DMT (2mg/kg) induced excessive hyperactivities at late phase (45-180min) that could be abolished by either WAY-100635 or MDL-100907. CONCLUSIONS: Co-administration of MAOI with 5-MeO-DMT provokes excessive late-phase hyperactivity, which involves the activation of both 5-HT1A and 5-HT2A receptors.

Insights into CYP2B6-mediated drug-drug interactions.

Mounting evidence demonstrates that CYP2B6 plays a much larger role in human drug metabolism than was previously believed. The discovery of multiple important substrates of CYP2B6 as well as polymorphic differences has sparked increasing interest in the genetic and xenobiotic factors contributing to the expression and function of the enzyme. The expression of CYP2B6 is regulated primarily by the xenobiotic receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) in the liver. In addition to CYP2B6, these receptors also mediate the inductive expression of CYP3A4, and a number of important phase II enzymes and drug transporters. CYP2B6 has been demonstrated to play a role in the metabolism of 2%-10% of clinically used drugs including widely used antineoplastic agents cyclophosphamide and ifosfamide, anesthetics propofol and ketamine, synthetic opioids pethidine and methadone, and the antiretrovirals nevirapine and efavirenz, among others. Significant inter-individual variability in the expression and function of the human CYP2B6 gene exists and can result in altered clinical outcomes in patients receiving treatment with CYP2B6-substrate drugs. These variances arise from a number of sources including genetic polymorphism, and xenobiotic intervention. In this review, we will provide an overview of the key players in CYP2B6 expression and function and highlight recent advances made in assessing clinical ramifications of important CYP2B6-mediated drug-drug interactions.