Safety, Tolerability, and Pharmacokinetics of the Monoamine Oxidase B Inhibitor, HEC122505, and its Major Metabolite After Single- and Multiple- Ascending Dose, and Food Effect Study in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVES: HEC122505 is a potent and selectively monoamine oxidase B inhibitor that is safe and well-tolerated in preclinical models of Parkinson's disease. The objectives of single ascending dose and multiple dose pharmacokinetic trials of HEC122505 oral tablets were to determine the safety and tolerability of HEC122505, and to examine the food effect on the pharmacokinetic parameters of HEC122505 and its major metabolite HEC129870. METHODS: The phase I study (NCT04625361) consisted of three arms: single ascending dose study (5, 20, 50, 100, 200, 300 or 400 mg HEC122505 tablets or placebo), multiple ascending dose study (20, 50 or 100 mg HEC122505 tablets or placebo once daily), and food effect (100 mg HEC122505 tablets single dose after a high-fat, high-calorie meal). All subjects completed all trial arms and were analyzed as planned. RESULTS: Pharmacokinetic analysis showed that HEC122505 rapidly absorbed with the time to peak plasma concentration (Tmax) ranged from 0.5 to 1.75 h. In addition, maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a dose proportional manner. Food effect study showed that a high-fat, high-calorie meal had no significant effect on the pharmacokinetics of HEC122505 and its major metabolite HEC129870, suggesting that HEC122505 could be administered in both fasted and fed state in clinical trials. The subsequent multiple-dose study evaluated doses from 20 to 100 mg dose once daily for up to 8 days. HEC122505 reached steady state after approximately 5 days with a once daily dose. In these studies, all dose of HEC122505 was generally safe and well tolerated. No grade ≥ 3 drug related adverse events (AEs) occurred. CONCLUSION: HEC122505 was generally safe and well tolerated in the single ascending dose (ranging from 5 to 400 mg) and multiple ascending dose (50 to 200 mg once daily doses) studies. All the drug related adverse events (AEs) were Grade ≤ 2. There were no deaths, no subjects discontinued the trial due to AEs, and there were no other serious AEs. The safety and pharmacokinetic profile support once daily administration of HEC122505.

Safety and tolerance of combination of monoamine oxidase inhibitors and direct dopamine agonists in adults and older adults with highly resistant depression.

INTRODUCTION: Dopamine (DA) is likely to be involved in some depressive dimensions, such as anhedonia and amotivation, which account for a part of treatment-resistant forms. Monoamine oxidase inhibitors (MAOI) and direct D2 and D3 receptors agonists (D2/3r-dAG) are known to help, but we lack safety data about their combined usage. We report on safety and tolerance of the MAOI+D2r-dAG combination in a clinical series. METHOD: All patients referred to our recourse center for depression between 2013 and 2021 were screened to select those who did receive the combo. Data were extracted from clinical files. RESULTS: Sixteen patients of 60±17 years of age (8 women, 7 with age>65years, all suffered from treatment resistant depression, 7 with bipolar disorder) received the combo. There were no life-threatening adverse effects (AE). However, AE were reported by 14 patients (88%) most of which were mild and consisted of insomnia, nausea, nervousness, confusion, impulse control disorder and/or "sleep attacks". One patient presented a serious AE requiring a short hospitalization for confusion. Intolerance led to failure to introduce treatment in two patients (13%). The retrospective non-interventional design, the variety of molecules, and the modest sample size limited the scope of these results. CONCLUSION: There was no life-threatening safety issue in combining MAOI and D2/3r-dAG, especially regarding cardiovascular side effects. The systematic screening of AE might account for their frequency, but these precluded the treatment in only two patients. Comparative studies are needed to assess the efficacy of this new combination.

Serotonin syndrome: A pharmacovigilance comparative study of drugs affecting serotonin levels.

BACKGROUND: Serotonin syndrome is a rare and potentially fatal adverse drug reaction caused by serotonergic drugs and is due to an increase in serotonin concentration or activation of the 5-HT receptor in the central nervous system. We analysed adverse events in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data set to investigate the main drug classes related to reports of serotonin syndrome and the reporting risk in relation to age and sex. METHODS: We analysed data from the FAERS database to evaluate the main drug classes related to reports of the serotonin syndrome, and the reporting risk in relation to age and sex. RESULTS: We found 8,997 cases of serotonin syndrome; selective serotonin reuptake inhibitors (SSRIs) was the class of drugs with most reports, followed by opioids and other antidepressants. The highest Reporting Odds Ratios (ROR) for drug classes was for monoamine oxidase (MAO) inhibitors (45.99, 95% confidence interval (CI): 41.21-51.33) and SSRIs (32.66, 95% CI: 31.33-34.04), while the ten active substances with the highest ROR were moclobemide, isocarboxazid, oxitriptane, tranylcypromine, melitracen, phenelzine, linezolid, amoxapine, reboxetine and tryptophan; with values of ROR ranging from 44.19 (95% CI: 25.38-76.94) of tryptophan to 388.36 (95% CI: 314.58-479.46) of moclobemide. The ROR for the most commonly involved drugs was higher in the group of older adults (65 > years old), and higher in males. CONCLUSION: Prescribers need to be vigilant about drugs that can raise serotonin concentration or influence serotonergic neurotransmission, also when using drugs with less well-known risk for serotonin syndrome, like linezolid and triptans.

Safety and effectiveness of rasagiline in patients with Parkinson's disease in Japan: a post-marketing surveillance study.

BACKGROUND: Rasagiline is a monoamine oxidase B inhibitor for the treatment of Parkinson's disease (PD). This study assessed the safety and effectiveness of rasagiline in patients with PD in routine clinical practice in Japan. RESEARCH DESIGN AND METHODS: This multicenter, prospective, observational study (148 sites) enrolled patients (1 November 2018-31 October 2020) with PD. Patients received rasagiline orally 1 mg once daily; maximum observation period was 24 months. The incidence of adverse drug reactions (ADRs) was evaluated; effectiveness was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III total score. RESULTS: The safety analysis set comprised 961 patients (mean age, 72.50 years; 53.80% female; mean duration of PD, 6.82 years). Mean treatment duration was 14.74 months, with 42.25% receiving rasagiline for ≥ 19 months; 189 (19.67%) had ≥ 1 ADR. Common ADRs were dyskinesia (4.06%), orthostatic hypotension (2.29%), hallucination (1.87%), visual hallucination, nausea, fall (1.56% each), dizziness (1.35%), and somnolence (1.25%). Mean (standard deviation) UPDRS Part III total score was 28.5 (14.35) at baseline and 25.5 (14.98) at the final assessment. CONCLUSIONS: No new concerns in safety and effectiveness regarding rasagiline in Japanese patients with PD were raised. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03727139; Japan Pharmaceutical Information Center Clinical Trials Information: JapicCTI-184181.

Safety comparisons among monoamine oxidase inhibitors against Parkinson's disease using FDA adverse event reporting system.

Monoamine oxidase B (MAO-B) inhibitors are used to control Parkinson's disease (PD). Selegiline, rasagiline, and safinamide are widely used as MAO-B inhibitors worldwide. Although these drugs inhibit MAO-B, there are pharmacological and chemical differences, such as the inhibitory activity, the non-dopaminergic properties in safinamide, and the amphetamine-like structure in selegiline. MAO-B inhibitors may differ in adverse events (AEs). However, differences in actual practical clinics are not fully investigated. A retrospective study was conducted using FAERS, the largest database of spontaneous adverse events. AE signals for MAO-B inhibitors, including selegiline, rasagiline, and safinamide, were detected using the reporting odds ratio method and compared. Hypocomplementemia, hepatic cyst, hepatic function abnormal, liver disorder and cholangitis were detected for selegiline as drug-specific signals. The amphetamine effect was not confirmed for any of the three MAO-B inhibitors. The tyramine reaction was detected as an AE signal only for rasagiline. Moreover, the REM sleep behavior disorder was not detected as an AE signal for safinamide, suggesting that non-dopaminergic effects might be beneficial. Considering the differences in AEs for MAO-B inhibitors will assist with the appropriate PD medication.

Rethinking, reducing, and refining the classical oral tyramine challenge test of monoamine oxidase (MAO) inhibitors.

The oral tyramine challenge evaluates the safety of novel monoamine oxidase (MAO) inhibitors when taken with tyramine-containing food or drinks. In its current design, it comprises an extensive series of tyramine escalation steps until a blood pressure threshold is met. Due to the high variation in tyramine bioavailability, and thereby in blood pressure effect, this classical design has various limitations, including safety concerns. Based on data from a previously performed tyramine challenge study, the present study explored a reduced new design that escalates up to 400 mg, and evaluates the dose to a tyramine peak plasma concentration of ≥10 ng/mL, instead of a dose up to 800 mg, and to a blood pressure change of ≥30 mm Hg. Tested by trial simulation, the new design proves more efficient than the classical design in terms of better identifying tyramine sensitivity of test and reference treatments and reducing false-positive and false-negative rates in estimating tyramine sensitivity by more than 10-fold. Since it escalates over a lower tyramine dose range, the new design reduces risk to subjects associated with tyramine-induced blood pressure excursions, is less demanding for study participants, and is more efficient. By its focus on tyramine bioavailability as the primary concern for novel MAO inhibitors, the new tyramine challenge study provides better answers in a simplified and safer design compared with the classical design in trial simulation, warranting its use in future clinical studies.

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.

Attenuation of COX-2 enzyme by modulating H2O2-mediated NF-κB signaling pathway by monoamine oxidase inhibitor (MAOI): a further study on the reprofiling of MAOI in acute inflammation.

OBJECTIVE: This study aims to investigate the anti-inflammatory mechanism of monoamine oxidase inhibitor (MAOI) in carrageenan (CARR) induced inflammation models to reprofile their use. We also aimed to explore the role of monoamine oxidase (MAO)-mediated H2O2-NF-κB-COX-2 pathway in acute inflammation. METHODS: In vitro anti-inflammatory activity and hydrogen peroxide (H2O2) scavenging activity were performed according to the established procedure. Inflammation was induced using CARR in BALB/c mice at the foot paw and peritoneal cavity. Hourly measurement of paw swelling was performed. The level of nitric oxide (NO), myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and nuclear factor κB (NF-κB) was determined using enzyme-linked immunosorbent assay (ELISA). Peritoneal fluid was collected to investigate total count, differential count of leukocytes, and capillary permeability. RESULTS: In vitro anti-inflammatory evaluations revealed the potential role of MAOI to inhibit heat-induced protein denaturation and human red cell membrane destabilization. H2O2 inhibition activity of MAOI also proved their powerful role as an H2O2 scavenger. Treatment with MAOI in CARR-induced mice significantly reduced paw edema, leukocyte extravasation, and total and differential leukocyte count. The result of ELISA showed MAOI effectively reduce the level of COX-2, PGE2 and NF-κB in inflamed tissue. CONCLUSIONS: In short, this study demonstrates that inhibition of H2O2 by MAOI alleviates CARR-induced paw edema possibly by inhibiting the H2O2-mediated NF-κB-COX-2 pathway. The present investigation identifies MAOI might reprofile for the treatment of acute inflammation also, the MAO enzyme may use as a novel therapeutic target to design and develop new class of anti-inflammatory agents.

[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.

Effectiveness and safety of monoamine oxidase inhibitor treatment for bipolar depression versus unipolar depression: An exploratory case cohort study.

OBJECTIVE: Patients with bipolar disorder spend most of their clinical lifetime in the depressive phase of their illness. However, antidepressants are discouraged in the treatment of bipolar depression due to concerns over manic induction and drug ineffectiveness. Some reports suggest that monoamine oxidase inhibitors (MAOIs) may be safe and effective compared to other antidepressants in treating bipolar depression. The present study compared the safety and effectiveness of MAOI therapy in patients with bipolar versus unipolar depression. METHODS: Data were collected from approximately 2500 clinical research charts of patients treated with MAOI therapy at a university mood disorder clinic between 1983 and 2015. A mixed-effects model was created with patient entered as the random effect. The model included the primary diagnosis (i.e., either unipolar or bipolar depression) and other clinical covariates as fixed-effect predictors. RESULTS: Patients with bipolar depression demonstrated lower post-treatment clinical global impressions/severity scores versus patients with unipolar depression (p = 0.04). Neither group demonstrated a full syndromal manic or hypomanic episode. A higher proportion of patients with bipolar depression reported myoclonic tics and tremors, which may have resulted from concomitant lithium use. Amongst the covariates, only the number of prior antidepressant trials predicted poorer outcomes from MAOI therapy. CONCLUSION: MAOIs may be more effective-and as safe-for patients with bipolar depression versus unipolar depression. Future studies should explore this possible advantage using a larger sample size.

Safety of Ketamine Augmentation to Monoamine Oxidase Inhibitors in Treatment-Resistant Depression: A Systematic Literature Review and Case Series.

Objective: Ketamine is increasingly prescribed for treatment-resistant depression (TRD), often as add-on to regular antidepressants. Augmentation of ketamine to monoamine oxidase inhibitors (MAOIs) is advised against, as this practice might increase blood pressure or cause serotonin syndrome. Despite the potential relevance for patients, little is known about actual side effects of combined use. We summarize literature on the safety and add results of our case series.Evidence Review: PubMed and Embase were searched from inception to July 2021 for English-language articles describing concomitant use of ketamine and MAOIs. The search strategy included terms for "ketamine" AND "monoamine oxidase inhibitor" including generic and brand names. Additionally, we describe the safety of twice weekly oral esketamine administration over the course of 5 weeks to 9 months in 8 TRD patients using MAOIs.Findings: After deduplication, we screened 138 articles and assessed 43 full texts. Twelve studies were included with a total of 39 patients receiving ketamine and MAOIs. Blood pressure and heart rate increased in multiple cases, though this was deemed clinically insignificant in all but 1 patient. No signs of hypertensive crisis or serotonin syndrome were observed. In our case series, we observed minor elevations in blood pressure and heart rate and no serious adverse events.Conclusions and Relevance: The results suggest that combined use of MAOIs and esketamine is less prone to severe side effects than presumed. The investigated sample size was small, and prescribed doses of MAOIs were relatively low. Further research is required before definite conclusions about the safety of this combination can be drawn.

Treatment History Characteristics Associated With Use of Isocarboxazid: A Nationwide Register-Based Study.

PURPOSE/BACKGROUND: The monoamine oxidase inhibitor isocarboxazid (Marplan) is occasionally used in the treatment of depression, but there is only little knowledge on the nature of the use of isocarboxazid in clinical practice. We aimed to identify treatment history characteristics associated with this use. METHODS/PROCEDURES: Via the nationwide Danish registers, we identified all adult incident users of isocarboxazid in the period from 2001 to 2018, as well as up to 5 matched controls using another antidepressant (matched on date of redeemed prescription, age, sex, and region of residence). The 5-year treatment history of the isocarboxazid users and the controls was assessed via the Danish registers. The association between treatment history characteristics and isocarboxazid use was examined by multivariate conditional logistic regression. FINDINGS/RESULTS: We identified 1455 isocarboxazid users and 7045 controls using another antidepressant. The following characteristics were associated with statistically significant increased likelihood of receiving isocarboxazid treatment: Prior treatment with a selective serotonin reuptake inhibitor (odds ratio [OR], 1.80 with 95% confidence interval [CI], 1.46-2.23), a serotonin-norepinephrine reuptake inhibitor (OR, 4.90; 95% CI, 4.08-5.89), a noradrenergic and specific serotonergic antidepressant (OR, 1.56; 95% CI, 1.30-1.88), a tricyclic antidepressant (OR, 5.05; 95% CI, 4.19-6.08), other antidepressants (OR, 4.74; 95% CI, 3.74-6.01), lithium (OR, 6.70; 95% CI, 5.08-8.83), an antipsychotic (OR, 1.43; 95% CI, 1.19-1.73), and each diagnosis of depression received in relation to psychiatric hospital treatment (OR, 1.31; 95% CI, 1.23-1.39). Forty percent of those initiating isocarboxazid had received treatment with drugs from 5 or more different psychopharmacological classes in the 5 preceding years. IMPLICATIONS/CONCLUSIONS: These findings suggest that isocarboxazid is typically used for treatment-resistant depression, consistent with guideline recommendations.

[Antidepressive agents and hypertension: A case/no-case study in French pharmacovigilance database]. / Antidépresseurs et hypertension artérielle : étude cas /non-cas dans la base nationale de pharmacovigilance.

INTRODUCTION: Drug-induced hypertension was described with several pharmacological classes. The association between hypertension and antidepressant drugs (AD) is controversial. The objective of this study was to evaluate the link between hypertension and ADs. MATERIALS AND METHODS: A retrospective disproportionality analysis from observations consecutively reported to the French pharmacovigilance database between 1985 and 2020 was performed. The relationship between the suspected ADs and the occurrence of hypertension was assessed by calculating the reporting odds ratio (ROR) in a case/non-case design. A negative (paracetamol) and a positive (celecoxib) control were used to validated this disproportionality method. RESULTS: We compared 6725 cases (including 464 AD-related cases) to 789,483 non-cases (including 56,440 AD-related cases). The reporting of hypertension was significantly associated with serotonin/norepinephrine reuptake inhibitors (SNRI) (ROR 1.43, 95 % CI 1.26-1.64) and monoamine oxidase inhibitors (MAOI) (ROR 6.41, 95 % CI 4.25-9.67) but not with other ADs classes. Concerning ADs analyzed independently of their AD class, a significant signal was observed with many SNRIs (duloxetin, milnacipran and venlafaxin) and with all MAOIs (moclobemide, iproniazide) (ROR between 2.04 and 17.93) but not with others ADs. The ROR value of positive (celecoxib) and negative (paracetamol) controls were ROR=1.53; IC95 %=1.04-2.26 and ROR=0.72; IC95 %=0.65-0.80, respectively. CONCLUSION: We found a significant association between development or worsening of hypertension and SNRIs and MAOIs but not with others ADs, in this study performed in real conditions of life. It is therefore advisable to remain cautious when prescribing ADs and to check systematically for hypertension.

Serotonin toxicity of serotonergic psychedelics.

RATIONALE: In recent years, psychedelic substances with serotonergic mechanisms have accumulated substantial evidence that they may provide therapeutic benefits for people suffering with psychiatric symptoms. Psychiatric disorders targeted by these psychedelic-assisted therapies are managed with serotonergic drugs like selective serotonin reuptake inhibitors (SSRIs) as the current standard of care, so it is important to evaluate the potential risks of drug-drug interactions and serotonin toxicity (ST) between these agents. OBJECTIVES: A critical evaluation of the scientific literature is necessary to delineate the risks of ST when combining psychedelics with available serotonergic pharmacotherapy options. This review article describes signs and symptoms of ST, characterizes mechanisms of ST risk, summarizes what is known about serotonergic psychedelic drug interactions, and outlines potential management strategies. RESULTS: True ST typically occurs with a serotonergic drug overdose or in combinations in which a drug that can increase intrasynaptic serotonin is combined with a monoamine oxidase inhibitor (MAOI). Serotonergic psychotropics that do not contain MAOIs are low risk in combination with psychedelics that also do not contain MAOIs. Signs and symptoms warranting immediate medical attention include myoclonus, extreme and fluctuating vital signs, agitation or comatose mental state, muscle rigidity, pronounced hyperthermia (fever), and/or seizure activity. CONCLUSIONS: Serotonin-related adverse reactions exist along a spectrum with serotonin syndrome being the most severe manifestations of ST. Due to varying serotonergic mechanisms of psychedelics and psychotropics, with varying propensities to increase intrasynaptic serotonin, some combinations may present a significant risk for serotonin toxicity (ST) while others are likely benign.

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.

Long-term Effectiveness of Adjuvant Treatment With Catechol-O-Methyltransferase or Monoamine Oxidase B Inhibitors Compared With Dopamine Agonists Among Patients With Parkinson Disease Uncontrolled by Levodopa Therapy: The PD MED Randomized Clinical Trial.

Importance: Many people with Parkinson disease (PD) develop motor complications that are uncontrolled by levodopa dose adjustment. Among these patients, it is uncertain which drug class is more effective as adjuvant therapy. Objective: To compare the long-term effects on patient-rated quality of life of adding a dopamine agonist vs a dopamine reuptake inhibitor (DRI), either a monoamine oxidase type B (MAO-B) inhibitor or a catechol-O-methyltransferase (COMT) inhibitor, to levodopa therapy for the treatment of patients with motor complications of PD. Design, Setting, and Participants: This pragmatic semifactorial (2 × 1) randomized clinical trial recruited from 64 neurology and geriatric clinics (62 in the United Kingdom, 1 in the Czech Republic, and 1 in Russia) between February 23, 2001, and December 15, 2009. A total of 500 patients with idiopathic PD who developed uncontrolled motor complications and did not have dementia were randomly assigned on a 1:1:1 basis using a computerized minimization program. Data were analyzed between 2017 and 2020. Interventions: Open-label dopamine agonist, MAO-B inhibitor, or COMT inhibitor. Main Outcomes and Measures: Primary outcomes were scores on the 39-item Parkinson's Disease Questionnaire (PDQ-39) mobility domain and cost-effectiveness. Outcomes were assessed before study entry, at 6 and 12 months after randomization, and annually thereafter. Repeated-measures and log rank analyses were used in an intention-to-treat approach. Results: Among 500 participants, the mean (SD) age was 73.0 (8.2) years; 314 participants (62.8%) were men. Over a median of 4.5 years (range, 0-13.3 years) of follow-up, the participants in the dopamine agonist group had a mean PDQ-39 mobility score that was 2.4 points (95% CI, -1.3 to 6.0 points) better than that of the combined MAO-B and COMT groups; however, this difference was not significant (P=.20). With regard to DRIs, participants in the MAO-B group had mean PDQ-39 mobility scores that were 4.2 points (95% CI, 0.4-7.9 points; P=.03) better than those of the COMT group and EuroQol 5-dimension 3-level (EQ-5D-3L) utility scores that were 0.05 points (95% CI, 0.003-0.09 points; P=.04) better than the COMT group. Nonsignificant improvements were found in the PDQ-39 summary index (mean difference, 2.2 points; 95% CI, -0.2 to 4.5 points; P=.07) along with nonsignificant reductions in dementia (rate ratio [RR], 0.70; 95% CI, 0.47-1.03; P = .07) and mortality (RR, 0.76; 95% CI, 0.56-1.03; P=.07). When dopamine agonists were compared with MAO-B inhibitors only, the outcomes were similar. Conclusions and Relevance: In this study, patient-rated quality of life was inferior when COMT inhibitors were used as adjuvant treatment compared with MAO-B inhibitors or dopamine agonists among people with PD who experienced motor complications that were uncontrolled by levodopa therapy. The MAO-B inhibitors produced equivalent disease control, suggesting that these agents may be underused as adjuvant therapy. Trial Registration: isrctn.org Identifier: ISRCTN69812316; EU Clinical Trials Register Identifier: 2005-001813-16.

The trace amine theory of spontaneous hypertension as induced by classic monoamine oxidase inhibitors.

The classic monoamine oxidase inhibitors (MAOIs) tranylcypromine (TCP) and phenelzine (PLZ) are powerful antidepressants that come with an equally powerful stigma, and are thus rarely prescribed-despite their well-established effectiveness. Some of these preconceptions appear to stem from unclarity, as the etiology of a rare but important side effect, 'spontaneous hypertension' (SH)-a significant increase in blood pressure absent dietary tyramine ingestion-remains improperly elucidated. This paper aims at uprooting some of the stigma surrounding MAOIs by advancing the trace amine (TA) theory as the causative underpinning of SH. This theory posits that SH results from the considerable influx of TAs observed following TCP- or PLZ-administration. TAs are known, albeit at greatly supraphysiological levels, to raise blood pressure on account of their propensity to exert potent indirect sympathomimetic effects; additionally, some research posits that TAs may induce vasoconstrictive effects partly or wholly separate therefrom, which would then constitute a second hypertensive mechanism. TAs are endogenous to the human body in low quantities. Both TCP and PLZ cause marked elevations of 2-phenylethylamine (PEA), meta- and para-tyramine (m-/p-TYR), octopamine (OA), and tryptamine (TRYP), following both acute and (sub)chronic administration. This paper holds that TYR plays a pivotal role in causing SH, due to its strong pressor effect. Cautious treatment of SH is advised, given its typically self-limiting nature. The risk of hypotensive overshoots must be taken into account. For severe cases, this paper urges reconsideration, following suitable confirmation trials, of antipsychotics (notably risperidone) as these agents may reduce striatal p-TYR levels.

Monoamine Oxidase Inhibitors (MAOIs) in Psychiatric Practice: How to Use them Safely and Effectively.

Monoamine oxidase inhibitors (MAOIs) were among the first licensed pharmacological treatments for patients with depression but over time have fallen out of mainstream clinical use. This has led to a loss of clinician training opportunities and reduced availability of MAOIs for prescribing. This article provides a concise and practical overview of how to use MAOIs safely and effectively in psychiatric practice. We consider the history of MAOIs, why they are not used more frequently, their mechanisms of action, availability, indications and efficacy, general tolerability, withdrawal symptoms, and safety considerations (including hypertensive reactions and serotonin syndrome). Practical advice is given in terms of dietary restrictions, interactions with other medications (both prescribed and non-prescribed), and how prescribers can stop and switch MAOIs, both within the drug class and outside of it. We also provide advice on choice of MAOI and treatment sequencing. Lastly, we consider emerging directions and potential additional indications.