Efficacy and Safety of Iloperidone in Bipolar Mania: A Double-Blind, Placebo-Controlled Study.

Objective: To determine if iloperidone, a second-generation antipsychotic, reduces symptoms of bipolar mania.Methods: This phase 3, randomized, double-blind, placebo-controlled study was conducted in adults with bipolar mania at 27 US and international sites between April 2021 and September 2022. Participants were randomized 1:1 to iloperidone (up to 24 mg/d given twice daily) or placebo for 4 weeks. The primary efficacy endpoint was change from baseline to week 4 in Young Mania Rating Scale (YMRS) total score versus placebo. Secondary efficacy endpoints included change from baseline in the Clinical Global Impressions-Severity and Clinical Global Impression of Change scales.Results: Altogether, 414 participants were randomized and administered at least 1 dose of study medication (iloperidone, n = 206; placebo, n = 208). Overall, 139 (67.1%) iloperidone patients and 153 (72.9%) placebo patients completed the study. Iloperidone demonstrated significant improvement versus placebo at week 4 for the primary and secondary endpoints. Differences in the least-squares mean (95% CI; P value) of change from baseline for YMRS total scores were -4.0 (-5.70 to -2.25; adjusted P = .000008). The most encountered adverse events with iloperidone were tachycardia, dizziness, dry mouth, alanine aminotransferase increased, nasal congestion, increased weight, and somnolence. The incidence of akathisia and extrapyramidal symptom-related treatment-emergent adverse events was low.Conclusions: Iloperidone is effective in treating patients with bipolar mania. The tolerability and safety profile of iloperidone in bipolar mania is consistent with previous clinical studies of patients with schizophrenia, and no new safety concerns were identified.Trial Registration: ClinicalTrials.gov identifier: NCT04819776; EudraCT: 2020-000405-83.

Adjunctive agents to antipsychotics in schizophrenia: a systematic umbrella review and recommendations for amino acids, hormonal therapies and anti-inflammatory drugs.

QUESTION: This umbrella review and guidelines aimed to provide evidence to support the rational choice of selected adjunctive therapies for schizophrenia. STUDY SELECTION AND ANALYSIS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and World Federation of Societies of Biological Psychiatry (WFSBP)-grading recommendations, 63 randomised control trials (RCTs) (of which 4219 unique participants have completed the RCTs) and 29 meta-analyses were analysed. FINDINGS: Provisional recommendations (WFSBP-grade 1) could be made for two molecules in augmentation to antipsychotics: (1) N-acetyl-cysteine (NAC, 1200-3600 mg/day, for >12 consecutive weeks) in improving negative symptoms, general psychopathology (positive and negative syndrome scale for schizophrenia (PANSS) general psychopathology factor (G)-G subscale), with the RCTs with the longer duration showing the most robust findings; (2) polyunsaturated fatty acids (3000 mg/day of eicosapentaenoic acid, for >12 weeks) in improving general psychopathology. Weaker recommendations (ie, WFSBP-grade 2) could be drawn for sarcosine (2 g/day) and minocycline (200-300 mg/day) for improving negative symptoms in chronic schizophrenia (not early schizophrenia), and NAC for improving positive symptoms and cognition. Weak recommendations are not ready for clinical practice. There is provisional evidence that oestrogens and raloxifene are effective in some patients, but further research is needed to determine their benefit/risk ratio. CONCLUSIONS: The results of this umbrella review should be interpreted with caution as the number of RCTs included in the meta-analyses was generally small and the effect sizes were weak or medium. For NAC, two RCTs with low risk of bias have provided conflicting results and the WFSBP-grade recommendation included also the results of meta-analyses. These drugs could be provisionally prescribed for patients for whom no other treatments have been effective, but they should be discontinued if they prove ineffective.

Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions.

Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

Neuropsychiatric Function Improvement in Pediatric Patients with Phenylketonuria.

OBJECTIVE: To evaluate effects of sapropterin dihydrochloride on blood phenylalanine (Phe) and symptoms of neuropsychiatric impairment in children and adolescents with phenylketonuria (PKU). STUDY DESIGN: PKU subjects 8-17 years of age (n = 86) were randomized to double-blind treatment with sapropterin (n = 43) or placebo (n = 43) for 13 weeks, then all received open-label sapropterin therapy for an additional 13 weeks. Blood Phe and symptoms of inattention, hyperactivity/impulsivity (Attention-Deficit/Hyperactivity Disorder Rating Scale IV [ADHD RS-IV]), executive functioning (Behavior Rating Inventory of Executive Function), depression (Hamilton Rating Scale for Depression), and anxiety (Hamilton Rating Scale for Anxiety) were assessed. RESULTS: Following the 13-week randomization phase, the sapropterin and placebo groups had mean changes in blood Phe of -20.9% and +2.9%, respectively. Corresponding least square mean differences in ADHD RS-IV scores were significantly greater for the sapropterin vs the placebo group: Total (-3.2 points, P = .02), Inattention subscale (-1.8 points, P = .04), and Hyperactivity/Impulsivity subscale (-1.6 points, P = .02). Forest plots favored sapropterin treatment over placebo for all ADHD RS-IV and Behavior Rating Inventory of Executive Function indices. There were no significant differences in reported problems with attention or executive function between the 2 groups at baseline or at week 26 following the 13-week open-label treatment period. Anxiety and depression scores did not differ significantly between cohorts at any time. Sapropterin was well tolerated, with a favorable safety profile. CONCLUSIONS: Sapropterin reduced blood Phe and was associated with significant improvement in parent-reported symptoms of inattention, hyperactivity/impulsivity, and executive functioning in children and adolescents with PKU. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01114737. Registered 27 April 2010, https://clinicaltrials.gov/ct2/show/NCT01114737.

Comparing the pharmacology and pharmacokinetics of antipsychotics: Choosing an antipsychotic and dosing a long-acting injectable.

In this paper, we will discuss the pharmacologic properties of antipsychotics, including those that are the same in structure and those that differentiate one from another. We will bring to you how differential pharmacologic properties can explain differential efficacy and differential tolerability. We will review how to use plasma drug levels and long-acting injectables to enhance compliance early in the illness, and to manage both forms of treatment resistance (pharmacokinetic and pharmacodynamic failures). Through inadequate pharmacokinetic processes (poor absorption, rapid metabolism, enzymatic polymorphisms, etc.), antipsychotic plasma levels do not reach sufficient concentration. Pharmacodynamic treatment failure (receptor binding and sensitivity, post-receptor effects, etc.) is the inability to provide a significant effect on psychotic symptoms despite therapeutic plasma levels. Long-Acting Injectable (LAI) antipsychotics employ technology that can provide a useful treatment tool in the armamentarium of a modern psychopharmacologist. The pharmacologic properties of antipsychotics differentiate one from another and can help explain differences in efficacy and tolerability. Utilizing plasma drug levels can enhance understanding of treatment failures and lead to specific patient management strategies for best outcomes. This kind of personalized approach to antipsychotic dosage would mean a big shift in the treatment of psychiatric patients.

Screening for Bipolar I Disorder and the Rapid Mood Screener: Results of a Nationwide Health Care Provider Survey.

Objective: Effective screening for bipolar I disorder can lead to enhanced assessment, improved diagnosis, and better patient outcomes. The Rapid Mood Screener (RMS), a new bipolar I disorder screening tool, was evaluated in a nationwide survey of health care providers (HCPs).Methods: Eligible HCPs were asked to describe their opinions/current use of screening tools, assess the RMS, and evaluate the RMS versus the Mood Disorder Questionnaire (MDQ). Results were stratified by primary care and psychiatric specialty. Findings were reported using descriptive statistics; statistical significance was reported at the 95% confidence level.Results: Among respondents (N = 200), 82% used a tool to screen for major depressive disorder (MDD), while 32% used a tool for bipolar disorder. Most HCPs were aware of the MDQ (85%), but only 29% reported current use. According to HCPs, the RMS was significantly better than the MDQ on all screening tool attributes (eg, sensitivity/specificity, brevity, practicality, easy scoring; P < .05 for all). Significantly more HCPs reported that they would use the RMS versus the MDQ (81% vs 19%, P < .05); 76% reported that they would screen new patients with depressive symptoms, and 68% indicated they would rescreen patients with a depression diagnosis. Most HCPs (84%) said the RMS would have a positive impact on their practice, with 46% saying they would screen more patients for bipolar disorder.Discussion: In our survey, the RMS was favorably evaluated by HCPs. A large percentage of respondents preferred the RMS over the MDQ and indicated that it would likely have a positive impact on clinicians' screening behavior.

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.

The Efficacy of Lumateperone in Patients With Bipolar Depression With Mixed Features.

Objective: A post hoc analysis of a phase 3, randomized, double-blind, placebo-controlled outpatient study investigated efficacy of lumateperone 42 mg in patients with bipolar I or bipolar II disorder and experiencing a major depressive episode (MDE) stratified by the presence of mixed features.Methods: Adults (18-75 years) with bipolar I or bipolar II disorder experiencing an MDE, defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria, were randomized 1:1 to 6-week oral lumateperone 42 mg/d or placebo (conducted November 2017-March 2019). Montgomery-Asberg Depression Rating Scale (MADRS) total score, Clinical Global Impression Scale-Bipolar Version-Severity (CGI-BP-S) total score, and Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) were analyzed in patients (N = 376) categorized as having mixed features (Young Mania Rating Scale [YMRS] score ≥ 4 and ≤ 12, 41.5%) or not having mixed features (YMRS < 4, 58.5%) at baseline. Treatment-emergent adverse events (TEAEs) including mania/hypomania were assessed.Results: At day 43, lumateperone significantly improved MADRS and CGI-BP-S total scores change from baseline compared with placebo for patients with mixed features (MADRS least squares mean difference [LSMD] = -4.4, P < .01; CGI-BP-S LSMD = -0.7, P < .05) and without mixed features (MADRS LSMD = -4.2, P < .001, CGI-BP-S LSMD = -1.0, P < .001). Q-LES-Q-SF percent score significantly improved at day 43 with lumateperone vs placebo in patients with mixed features (LSMD = 5.9, P < .05), with numerical improvements in patients without mixed features (LSMD = 2.6, P = .27). TEAEs of mania/hypomania were rare.Conclusions: Lumateperone 42 mg significantly improved symptoms of depression and disease severity in patients with an MDE associated with bipolar I or bipolar II disorder, with or without mixed features.Trial Registration: ClinicalTrials.gov identifier: NCT03249376.

Rapid onset brain plasticity at novel pharmacologic targets hypothetically drives innovations for rapid onset antidepressant actions.

Numerous new agents with rapid onset antidepressant effects are entering clinical trials and clinical practice. Studies focus on either first-line treatment of major depressive disorder or on patients whose major depressive disorder is resistant to prior antidepressant drugs. Novel agents target three very different central nervous system sites: as antagonists of N-methyl-d-aspartate (NMDA) glutamate receptors, as positive allosteric modulators (PAMs) of gamma amino butyric acid (GABA) A neurosteroid and benzodiazepine receptor sites, and as psychedelic agonists of serotonin 2A/2C receptors. Onset of antidepressant action is rapid, sometimes after only one dose whereas traditional agents for depression take several days to weeks to have an antidepressant effect. Although the direct molecular targets of these three classes of agents with rapid antidepressant onset are quite diverse and not clearly related to each other, analysis of the downstream effects of all these agents show that all are "plastogens," namely agents that trigger rapid onset of neuroplasticity that correlates with their rapid onset of antidepressant clinical action. The GABA A PAMs and some of the NMDA antagonists induce neuroplasticity without notable changes in mental status and can be designated "neuroplastogens." Some NMDA antagonists cause mental dissociation, and the psychedelics cause psychotomimetic/hallucinatory experiences and can be designated "psychoplastogens." A great debate exists whether psychoplastogens are effective because of their ability to acutely alter mental state, or whether these acute mental states are unwanted behavioral toxicity. The promise of numerous novel agents with rapid acting antidepressant action and neuroplasticity is set to transform the treatment of major depressive disorder.

Esmethadone-HCl (REL-1017): a promising rapid antidepressant.

This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of the pharmacological class of uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists that have shown efficacy for major depressive disorder (MDD) and other diseases and disorders, such as Alzheimer's dementia and pseudobulbar affect. The other drugs in the novel class of NMDAR antagonists with therapeutic uses that are discussed for comparative purposes in this review are esketamine, ketamine, dextromethorphan, and memantine. We present in silico, in vitro, in vivo, and clinical data for esmethadone and other uncompetitive NMDAR antagonists that may advance our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants may advance our understanding of the neurobiology of MDD and other neuropsychiatric diseases and disorders.

Do We Need a New Nomenclature for Atypical Antipsychotics? A Survey of Health Care Professionals and Patients.

Objective: The current nomenclature for atypical antipsychotics does not indicate that they are used to treat nonpsychotic conditions (eg, bipolar disorder, major depressive disorder), which could have negative implications for both health care providers (HCPs) and patients. The objective of this study was to evaluate how the atypical antipsychotic class name affects HCPs who treat bipolar disorder and patients who receive the diagnosis.Methods: Nationwide surveys of primary care and psychiatric HCPs (n = 200) and patients with bipolar disorder (n = 200) were conducted to assess perspectives regarding current atypical antipsychotic nomenclature. HCP opinion about a change in class name was also evaluated. The self-administered electronic surveys were completed by HCPs from May 22, 2020, to June 1, 2020, and by patients from August 25, 2020, to September 7, 2020.Results: Compared with the mood stabilizer class name, the atypical antipsychotic name elicited stronger negative feelings from both HCPs and patients. Most HCPs avoided bringing up the atypical antipsychotic name with patients (72%), often due to fear of negative reactions. Despite being approved for bipolar mania and depression, only 48% and 39% of HCPs indicated that atypical antipsychotics were appropriate for these disorders, respectively. If an appropriate alternative for the term atypical antipsychotic was available for bipolar disorder, 71% of HCPs said they were likely to change their class-related behaviors. Most patients had never heard of the atypical antipsychotic class name (69%). Significantly more patients had negative reactions (eg, worry, fear, confusion) to the idea of their HCP prescribing an atypical antipsychotic versus a mood stabilizer (25% vs 6%). Compared with mood stabilizers, patients were less likely to take an atypical antipsychotic immediately as prescribed.Conclusions: Significantly more HCPs and patients had negative reactions to atypical antipsychotic nomenclature compared with mood stabilizer nomenclature for treating bipolar disorder. The broad descriptive atypical antipsychotic class name may not support the standard of care for the treatment of bipolar disorder.

Neuropsychiatric Consequences of COVID-19 Pandemic: A Synthetic Review from a Global Perspective.

Some research suggests that distress, secondary to isolation and fear following COVID-19 infection, can negatively affect the long-term more than the COVID-19 infection itself. This narrative review aims to provide a global view on the neuropsychiatric consequences of COVID-19 that can be ascribed to several factors, ranging from the direct effect of infection, to the body's responses against the infection, or to the psychological sequelae of social isolation, unemployment, and fear for one's health and livelihood. Current findings show that the more severe the respiratory infection, the more likely are central nervous system (CNS) complications regarding the infection itself. The immune reactions to the infection may result in symptoms similar to chronic fatigue as well as neurocognitive deficits, which last long after the infection is gone. An increase in symptoms of depression, anxiety, and trauma-related stress may also follow upon economic fears and isolation from friends and family. The consequences of the pandemic are not limited to adults; children learning remotely and away from classmates and routine activities may develop adjustment disorders, acute stress disorder, and a variety of manifestations of grief. A summary of case reports suggests that COVID-19-related stress, economic recession, and political unrest increase the risk of suicidal behaviors and acts of violence. However, it is unknown whether manifestations of mental disorders result from social causes or whether CNS complications may be responsible.

Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling.

This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects.

Muscarinic acetylcholine receptors for psychotic disorders: bench-side to clinic.

Modern interest in muscarinic acetylcholine receptor (mAChR) activators for schizophrenia began in the 1990s when xanomeline, an M1/M4-preferring mAChR agonist developed for cognitive symptoms of Alzheimer's disease (AD), had unexpected antipsychotic activity. However, strategies to address tolerability concerns associated with activation of peripheral mAChRs were not available at that time. The discovery of specific targeted ligands and combination treatments to reduce peripheral mAChR engagement have advanced the potential of mAChR activators as effective treatments for psychotic disorders. This review provides perspectives on the background of the identification of mAChRs as potential antipsychotics, advances in the preclinical understanding of mAChRs as targets, and the current state of mAChR activators under active clinical development for schizophrenia.

Pharmacological Comparative Characterization of REL-1017 (Esmethadone-HCl) and Other NMDAR Channel Blockers in Human Heterodimeric N-Methyl-D-Aspartate Receptors.

Excessive Ca2+ currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of drugs in clinical use for major depressive disorder (MDD) and other neuropsychiatric diseases. The pharmacological characterization of uncompetitive NMDAR blockers in clinical use may improve our understanding of NMDAR function in physiology and pathology. REL-1017 (esmethadone-HCl), a novel uncompetitive NMDAR channel blocker in Phase 3 trials for the treatment of MDD, was characterized together with dextromethorphan, memantine, (±)-ketamine, and MK-801 in cell lines over-expressing NMDAR subtypes using fluorometric imaging plate reader (FLIPR), automated patch-clamp, and manual patch-clamp electrophysiology. In the absence of Mg2+, NMDAR subtypes NR1-2D were most sensitive to low, sub-µM glutamate concentrations in FLIPR experiments. FLIPR Ca2+ determination demonstrated low µM affinity of REL-1017 at NMDARs with minimal subtype preference. In automated and manual patch-clamp electrophysiological experiments, REL-1017 exhibited preference for the NR1-2D NMDAR subtype in the presence of 1 mM Mg2+ and 1 µM L-glutamate. Tau off and trapping characteristics were similar for (±)-ketamine and REL-1017. Results of radioligand binding assays in rat cortical neurons correlated with the estimated affinities obtained in FLIPR assays and in automated and manual patch-clamp assays. In silico studies of NMDARs in closed and open conformation indicate that REL-1017 has a higher preference for docking and undocking the open-channel conformation compared to ketamine. In conclusion, the pharmacological characteristics of REL-1017 at NMDARs, including relatively low affinity at the NMDAR, NR1-2D subtype preference in the presence of 1 mM Mg2+, tau off and degree of trapping similar to (±)-ketamine, and preferential docking and undocking of the open NMDAR, could all be important variables for understanding the rapid-onset antidepressant effects of REL-1017 without psychotomimetic side effects.

Emerging drugs for the treatment of major depressive disorder.

INTRODUCTION: Major depressive disorder (MDD) continues to be one of the highest contributors to disease burden and years lived with disability in the world. Current existing treatments have been associated with intolerable side effects, long onset of action and suboptimal remission rates. Newer agents are being developed that will be reviewed here, such as glutamate and gamma-aminobutyric acid (GABA) and the reinvigorated testing of psychedelic drugs. This review will summarize the target mechanisms of the newer ADTs currently in development and available on the market. AREAS COVERED: It briefly covers the existing agents for MDD and treatment-resistant depression (TRD) and the need for new agents with higher efficacy. Therapeutic agents currently in Phase II or later clinical trials are listed and discussed, based on a thorough review of the US National Institutes of Health clinicaltrials.gov index and a search of the Informa Pharmaprojects database. Compounds of interest are grouped into scientific rationale and include atypical antipsychotics, GABA positive allosteric modulators, glutamatergic agents, opioids, orexin 2 receptor antagonists, and psychedelics. EXPERT OPINION: New therapeutic agents currently in development are promising, with a more rapid onset of action and the ability to augment and treat TRD.

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.

Psilocybin in neuropsychiatry: a review of its pharmacology, safety, and efficacy.

Psilocybin is a tryptamine alkaloid found in some mushrooms, especially those of the genus Psilocybe. Psilocybin has four metabolites including the pharmacologically active primary metabolite psilocin, which readily enters the systemic circulation. The psychoactive effects of psilocin are believed to arise due to the partial agonist effects at the 5HT2A receptor. Psilocin also binds to various other receptor subtypes although the actions of psilocin at other receptors are not fully explored. Psilocybin administered at doses sufficient to cause hallucinogenic experiences has been trialed for addictive disorders, anxiety and depression. This review investigates studies of psilocybin and psilocin and assesses the potential for use of psilocybin and a treatment agent in neuropsychiatry. The potential for harm is also assessed, which may limit the use of psilocybin as a pharmacotherapy. Careful evaluation of the number needed to harm vs the number needed to treat will ultimately justify the potential clinical use of psilocybin. This field needs a responsible pathway forward.