Schizophrenia is a complex neuropsychiatric disorder characterized by dysfunctions in multiple neurotransmission systems, with glutamatergic hypofunction, particularly involving NMDA receptors, playing a central role. Experimental models using NMDA receptor antagonists, such as ketamine, effectively reproduce behavioral alterations observed in schizophrenia, including locomotor hyperactivity. Nitric oxide (NO) signaling, closely associated with NMDA receptor activation, has also been implicated in the disorder, suggesting that nitrergic dysfunction contributes to its pathophysiology. The NO donor sodium nitroprusside (SNP) has shown potential in modulating schizophrenia-like phenotypes; however, its effects on neuroactive amino acids remain poorly understood. This study aimed to investigate the effects of SNP on behavioral and amino acid alterations induced by ketamine in an animal model of schizophrenia. Male Wistar rats were administered ketamine to induce a schizophrenia-like phenotype, followed by treatment with SNP. Locomotor activity was evaluated using the open-field test, and concentrations of several neuroactive amino acids related functionally and/or metabolically were quantified in whole brain using high-performance liquid chromatography (HPLC) with fluorimetric detection. Ketamine administration induced significant locomotor hyperactivity, which was attenuated by SNP treatment. Moreover, ketamine and SNP differentially affected the concentrations of several neuroactive amino acids in brain. Notably, ketamine increased the concentrations of L-serine, glutamine and glycine while SNP increased the concentrations of aspartate, L-serine and arginine. L-serine, glutamine and glycine increases produced by administration of ketamine were not present when SNP was combined with ketamine. These findings highlight the complex interactions among amino acids in schizophrenia-like pathology.

OBJECTIVE:Brain default mode network (DMN) function is altered in schizophrenia (SZ). Considering the roles of nitrergic and glutamatergic transmission in SZ neurobiology, supplementation with nitric oxide (NO) donors such as sodium nitroprusside (SNP) has been proposed as a means of reducing symptoms, but results have been mixed and potential mechanisms remain unclear. In this context, we sought to investigate the effects of SNP on DMN functional connectivity (FC) assessed by functional magnetic resonance imaging (fMRI) in SZ patients and healthy controls. METHODS:In an open-label trial, participants were divided into three treatment groups to receive intravenous SNP (0.25 µg/kg/min over 12 minutes): SZ patients on clozapine (CLZ) (n=13), SZ patients on non-CLZ antipsychotics (n=13), and controls (n=14). fMRI data was collected continuously before, during, and after SNP infusion. Symptom changes were evaluated with the Brief Psychiatric Rating Scale (BPRS). RESULTS:Considering only patient groups at baseline, there was no difference in connectivity. When comparing all patient groups to controls, patients exhibited increased activity in DMN subregions and increased FC in the left supramarginal gyrus. During SNP infusion, FC was increased in the left angular gyrus; immediately following infusion, FC increased in the bilateral medial temporal gyri and left supramarginal gyrus of patients compared to controls. There were no significant differences between patient groups at any time point, nor changes in symptoms. CONCLUSION:Although our results are preliminary, this work demonstrated for the first time that SNP modulates brain connectivity in healthy controls and patients with SZ. Future research is warranted to confirm these findings.

Most amino acids contain a chiral center and thus, can exist as L- and D-isomers. For many years, it was thought that only the L-isomers were present in mammals. However, in recent decades it has been demonstrated that D-isomers are also present. Three of these amino acids, namely D-serine, D-aspartate, and D-alanine, have been proposed to play a role in the etiology of schizophrenia via interactions with glutamate receptors. D-Serine and D-alanine act at the glycine modulatory site on the NMDA receptor, while D-aspartate acts at the glutamate site on the same receptor. D-aspartate also acts on the mGlu5 receptor and can stimulate glutamate release presynaptically. Preclinical studies have reported that manipulations to reduce brain levels of D-serine, D-aspartate, or D-alanine lead to schizophrenia-relevant behaviors, and clinical studies have reported reduced levels of these D-amino acids in the brain tissue (postmortem) and/or body fluids from schizophrenia patients compared to those noted in controls, although there are some contradictory findings. The possible use of these amino acids and/or the manipulation of their relevant enzymes in the treatment of schizophrenia are described. D-Cysteine has been identified recently in human brain tissue, with the highest values in white matter; demonstration of its involvement in brain development has led to speculation that it could be involved in the etiology of schizophrenia, identifying it as a potential therapy in combination with antipsychotics. Future directions and potential problems that should be considered in studies on D-amino acids and their relevant enzymes in schizophrenia are discussed.

Schizophrenia is a complex heterogenous disorder thought to be caused by interactions between genetic and environmental factors. The theories developed to explain the etiology of schizophrenia have focused largely on the dysfunction of neurotransmitters such as dopamine, serotonin and glutamate with their receptors, although research in the past several decades has indicated strongly that other factors are also involved and that the role of neuroglial cells in psychotic disorders including schizophrenia should be given more attention. Although glia were originally thought to be present in the brain only to support neurons in a physical, metabolic and nutritional capacity, it has become apparent that these cells have a variety of important physiological roles and that abnormalities in their function may make significant contributions to the symptoms of schizophrenia. In the present paper, we review the interactions of brain microglia, astrocytes and oligodendroglia with aspects such as transmitter dysregulation, neuro-inflammation, oxidative stress, synaptic function, the gut microbiome, myelination and the blood–brain barrier that appear to affect the cause, development and treatment of schizophrenia. We also review crosstalk between microglia, astrocytes and oligodendrocytes and the effects of antipsychotics on neuroglia. Problems associated with studies on specific biomarkers for glia in schizophrenia are discussed.

A large body of research supports the role of stress in several psychiatric disorders in which anxiety is a prominent symptom. Other research has indicated that the gut microbiome-immune system- brain axis is involved in a large number of disorders and that this axis is affected by various stressors. The focus of the current review is on the following stress-related disorders: generalized anxiety disorder, panic disorder, social anxiety disorder, post-traumatic stress disorder and obsessivecompulsive disorder. Descriptions of systems interacting in the gut-brain axis, microbiome-derived molecules and of pro- and prebiotics are given. Preclinical and clinical studies on the relationship of the gut microbiome to the psychiatric disorders mentioned above are reviewed. Many studies support the role of the gut microbiome in the production of symptoms in these disorders and suggest the potential for pro- and prebiotics for their treatment, but there are also contradictory findings and concerns about the limitations of some of the research that has been done. Matters to be considered in future research include longer-term studies with factors such as sex of the subjects, drug use, comorbidity, ethnicity/ race, environmental effects, diet, and exercise taken into account; appropriate compositions of pro- and prebiotics; the translatability of studies on animal models to clinical situations; and the effects on the gut microbiome of drugs currently used to treat these disorders. Despite these challenges, this is a very active area of research that holds promise for more effective, precision treatment of these stressrelated disorders in the future.

Psychosis, defined as a set of symptoms that results in a distorted sense of reality, is observed in several psychiatric disorders in addition to schizophrenia. This paper reviews the literature relevant to the underlying neurobiology of psychosis. The dopamine hypothesis has been a major influence in the study of the neurochemistry of psychosis and in development of antipsychotic drugs. However, it became clear early on that other factors must be involved in the dysfunction involved in psychosis. In the current review, it is reported how several of these factors, namely dysregulation of neurotransmitters [dopamine, serotonin, glutamate, and γ-aminobutyric acid (GABA)], neuroinflammation, glia (microglia, astrocytes, and oligodendrocytes), the hypothalamic–pituitary–adrenal axis, the gut microbiome, oxidative stress, and mitochondrial dysfunction contribute to psychosis and interact with one another. Research on psychosis has increased knowledge of the complexity of psychotic disorders. Potential new pharmacotherapies, including combinations of drugs (with pre- and probiotics in some cases) affecting several of the factors mentioned above, have been suggested. Similarly, several putative biomarkers, particularly those related to the immune system, have been proposed. Future research on both pharmacotherapy and biomarkers will require better-designed studies conducted on an all stages of psychotic disorders and must consider confounders such as sex differences and comorbidity.

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.

Familial hemiplegic migraine type-1 (FHM-1) is a form of migraine with aura caused by mutations in the P/Q-type (Cav2.1) voltage-gated calcium channel. Pregabalin, used clinically in the treatment of chronic pain and epilepsy, inhibits P/Q-type calcium channel activity and recent studies suggest that it may have potential for the treatment of migraine. Spreading Depolarization (SD) is a neurophysiological phenomenon that can occur during migraine with aura by propagating a wave of silenced neuronal function through cortex and sometimes subcortical brain structures. Here, utilizing an optogenetic stimulation technique optimized to allow for non-invasive initiation of cortical SD, we demonstrate that chronic pregabalin administration [12 mg/kg/day (s.c.)] in vivo increased the threshold for cortical spreading depolarization in transgenic mice harboring the clinically-relevant Ca v 2.1 S218L mutation (S218L). In addition, chronic pregabalin treatment limited subcortical propagation of recurrent spreading depolarization events to the striatum and hippocampus in both wild-type and S218L mice. To examine contributing underlying mechanisms of action of chronic pregabalin, we performed whole-cell patch-clamp electrophysiology in CA1 neurons in ex vivo brain slices from mice treated with chronic pregabalin vs vehicle. In WT mice, chronic pregabalin produced a decrease in spontaneous excitatory postsynaptic current (sEPSC) amplitude with no effect on frequency. In contrast, in S218L mice chronic pregabalin produced an increase in sEPSC amplitude and decreased frequency. These electrophysiological findings suggest that in FHM-1 mice chronic pregabalin acts through both pre- and post-synaptic mechanisms in CA1 hippocampal neurons to elicit FHM-1 genotype-specific inhibitory action. The results highlight the potential of chronic pregabalin to limit recurrent SD to subcortical brain structures during pathophysiological events in both the genetically-normal and FHM-1 brain. The work further provides insights into FHM-1 pathophysiology and the potential for chronic pregabalin treatment to prevent SD in migraineurs.

INTRODUCTION:Ayahuasca is a psychedelic brew originally used by Amazonian indigenous groups and in religious rituals. Pre-clinical and observational studies have demonstrated its possible potential as an antidepressant, and open- and placebo-controlled clinical trials corroborated these results. For it to become an approved treatment for depression, its safety and tolerability need to be assessed and documented. AREAS COVERED:We have gathered data regarding the occurrence of adverse events (AEs) in all reported randomized, placebo-controlled trials with healthy and clinical populations involving ayahuasca administration (n = 108 ayahuasca administrations). We systematically categorized these results, recorded their prevalence, and discussed the possible mechanisms related to their emergence. EXPERT OPINION:There were no reports of serious AEs, indicating a relative safety of ayahuasca administration in controlled settings. Most common AEs included nausea, vomiting, headaches, and transient increases in cardiovascular measurements. Ayahuasca research is still in its infancy, especially concerning the absence of large and robust clinical trials to verify its antidepressant effects. Dose standardization, legal prohibition of the possession of its alkaloids and how traditional communities will be compensated if ayahuasca becomes an approved medicine are the biggest obstacles to overcome for its future use in the therapeutic context.

Background: The substantial female hormone fluctuations associated with pregnancy and postpartum have been linked to a greater risk of developing depressive symptoms, particularly in high-risk women (HRW), i.e. those with histories of mood sensitivity to female hormone fluctuations. We have shown that glutamate (Glu) levels in the medial prefrontal cortex (MPFC) decrease during perimenopause, a period of increased risk of developing a major depressive episode. Our team has also demonstrated that percentage gray matter (%GM), another neural correlate of maternal brain health, decreases in the MPFC during pregnancy. Objective: To investigate MPFC Glu levels and %GM from late pregnancy up to 7 weeks postpartum in HRW and healthy pregnant women (HPW). Methods: Single-voxel spectra were acquired from the MPFC of 41 HPW and 22 HRW using 3- Tesla in vivo proton magnetic resonance spectroscopy at five different time points. Results: We observed a statistically significant interaction between time and group for the metabolite Glu, with Glu levels being lower for HRW during pregnancy and early postpartum (p<0.05). MPFC %GM was initially lower during pregnancy and then significantly increased over time in both groups (p<0.01). Conclusion: This investigation suggests that the vulnerability towards PPD is associated with unique fluctuations of MPFC Glu levels during pregnancy and early postpartum period. Our results also suggest that the decline in MPFC %GM associated with pregnancy seems to progressively recover over time. Further investigations are needed to determine the specific role that female hormones play on the physiological changes in %GM during pregnancy and postpartum.

Ayahuasca is a psychoactive brew traditionally used in indigenous and religious rituals and ceremonies in South America for its therapeutic, psychedelic, and entheogenic effects. It is usually prepared by lengthy boiling of the leaves of the bush Psychotria viridis and the mashed stalks of the vine Banisteriopsis caapi in water. The former contains the classical psychedelic N,N-dimethyltryptamine (DMT), which is thought to be the main psychoactive alkaloid present in the brew. The latter serves as a source for β-carbolines, known for their monoamine oxidase-inhibiting (MAOI) properties. Recent preliminary research has provided encouraging results investigating ayahuasca's therapeutic potential, especially regarding its antidepressant effects. On a molecular level, pre-clinical and clinical evidence points to a complex pharmacological profile conveyed by the brew, including modulation of serotoninergic, glutamatergic, dopaminergic, and endocannabinoid systems. Its substances also interact with the vesicular monoamine transporter (VMAT), trace amine-associated receptor 1 (TAAR1), and sigma-1 receptors. Furthermore, ayahuasca's components also seem to modulate levels of inflammatory and neurotrophic factors beneficially. On a biological level, this translates into neuroprotective and neuroplastic effects. Here we review the current knowledge regarding these molecular interactions and how they relate to the possible antidepressant effects ayahuasca seems to produce.

Background: Hikikomori, a severe and often prolonged social withdrawal observed primarily in young people, was first described in Japan, but cases have now been reported in many other countries. Methods: A review paper on hikikomori has been prepared following the literature searches in 3 databases. Search terms related to hikikomori included epidemiology, globalization, diagnosis, treatment, comorbidity, and COVID-19. Conclusions: Hikikomori was first reported in Japan and has been described in detail by researchers there, but there are now reports in many countries of hikikomori-like cases. It occurs primarily in young people, often men in their late teens and early twenties who isolate themselves, sometimes confining themselves to their homes for months or even years. It has been proposed that hikikomori has increased in recent years in part because of advances in information technology that result in decreased socialization. Hikikomori was originally considered a non-psychotic phenomenon, but comorbidity with psychiatric disorders is often present and should be considered during diagnosis. Considerable efforts have been made in recent years to establish reliable, widely applicable guidelines for the diagnosis and treatment of hikikomori. There is very little information with regard to neurobiology, although involvement of the immune system, oxidative stress, and the social brain network has been proposed. It is widely agreed that hikikomori must be treated in a multi-dimensional fashion, with family support very important. Lessons learned from these treatment approaches are relevant to the potential increased risk of social withdrawal arising from COVID-19 pandemic lockdowns.

Although results are still preliminary, ketamine and classical hallucinogens have shown promise in recent years as novel, fast-acting antidepressants, especially for the treatment of unipolar treatment-resistant depression (TRD). Depression also seems to be related to abnormal levels of peripheral inflammatory and neurotrophic biomarkers, which may one day help to diagnose of this disorder. In this context, this systematic review of clinical trials evaluated the current evidence that relates the antidepressant effects of ketamine and classical hallucinogens on TRD with changes in inflammatory and neurotrophic biomarkers. Twelve studies were found (n = 587), 2 with oral ayahuasca (1 mL/kg) and 10 with ketamine (mostly intravenous 0.5 mg/kg) administration. Results for all biomarkers assessed were contradictory and thus inconclusive. Randomized controlled trials with bigger samples and higher statistical power are warranted to clarify if peripheral biomarkers can confidently be used to indicate and measure ketamine’s and classical hallucinogens’ antidepressant effect. The PROSPERO ID for this study is CRD42021249089.

Major depressive disorder (MDD) is a prominent cause of disability worldwide. Current antidepressant drugs produce full remission in only about one-third of MDD patients and there are no biomarkers to guide physicians in selecting the best treatment for individuals. There is an urgency to learn more about the etiology of MDD and to identify new targets that will lead to improved therapy and hopefully aid in predicting and preventing MDD. There has been extensive interest in the roles of the immune system and the gut microbiome in MDD and in how these systems interact. Gut microbes can contribute to the nature of immune responses, and a chronic inflammatory state may lead to increased responsiveness to stress and to development of MDD. The gut microbiome-immune system-brain axis is bidirectional, is sensitive to stress and is important in development of stress-related disorders such as MDD. Communication between the gut and brain involves the enteric nervous system (ENS), the autonomic nervous system (ANS), neuroendocrine signaling systems and the immune system, and all of these can interact with the gut microbiota. Preclinical studies and preliminary clinical investigations have reported improved mood with administration of probiotics and prebiotics, but large, carefully controlled clinical trials are now necessary to evaluate their effectiveness in treating MDD. The roles that several gut microbe-derived molecules such as neurotransmitters, short chain fatty acids and tryptophan play in MDD are reviewed briefly. Challenges and potential future directions associated with studying this important axis as it relates to MDD are discussed.

Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.

BACKGROUND:Neuroactive steroids (NASs) exert multiple biological effects on development and inflammation. The effects of NASs on disease progression in multiple sclerosis (MS) are uncertain, prompting analyses of NAS profiles during the transition from clinically isolated syndrome (CIS) to relapsing-remitting (RR) MS.METHODS:Subjects with CIS or RRMS and healthy controls (HCs) were recruited; demographic and clinical data as well as disability scores measured by the Expanded Disability Status Scale (EDSS) were recorded. Matched plasma NAS and amino acid (AA) concentrations were measured.RESULTS:HC (n = 17), CIS (n = 31), and RRMS (n = 33) groups showed similar ages and sex distribution although disability scores were higher in the RRMS group. The conversion rate of CIS to RRMS group was 51.6% (n = 16) during a mean follow-up period of 1.85 years. The RRMS group showed significantly higher mean allopregnanolone, aspartate, and taurine concentrations with lower epiallopregnanolone concentrations than CIS patients, and higher L-serine-O-phosphate and lower alanine, arginine, and glutamine concentrations than the HC group. Among CIS and RRMS groups, multivariate hierarchical regressions revealed that higher concentrations of plasma tetrahydrodeoxycorticosterone (THDOC) may predict disability worsening.CONCLUSIONS:RRMS and CIS patients exhibited differing concentrations of both NASs and AAs in plasma while both THDOC and pregnanolone might serve as biomarkers of disability worsening.

Autoimmune encephalitis often produces signs and symptoms that appear to be at the interface between neurology and psychiatry. Since psychiatric symptoms are often prominent, patients are often first seen in a psychiatric setting. Therefore it is important that psychiatrists, as well as neurologists, be able to recognize autoimmune encephalitis, a task that is often difficult. Early diagnosis of autoimmune encephalitis is crucial as this will usually result in a better outcome for the patient. This chapter provides an introduction to various autoimmune encephalitides and describes their pathophysiology and the possible associated neuropsychiatric, neuropsychological (cognitive), and neurological (sensory-motor) signs and symptoms. This chapter also reviews the possible treatments of these associated signs and symptoms.

Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and neurochemical effects in addition to inhibition of MAO, and findings on these effects have contributed to a body of evidence indicating that PLZ also has neuroprotective/neurorescue properties. These attributes are reviewed in this paper and include catabolism to the active metabolite β-phenylethylidenehydrazine (PEH) and effects of PLZ and PEH on the GABA-glutamate balance in brain, sequestration of reactive aldehydes, and inhibition of primary amine oxidase. Also discussed are the encouraging findings of the effects of PLZ in animal models of stroke, spinal cord injury, traumatic brain injury, and multiple sclerosis, as well other actions such as reduction of nitrative stress, reduction of the effects of a toxin on dopaminergic neurons, potential anticonvulsant actions, and effects on brain-derived neurotrophic factor, neural cell adhesion molecules, an anti-apoptotic factor, and brain levels of ornithine and N -acetylamino acids.