BDNF receptor TrkB as the mediator of the antidepressant drug action.

Brain-derived neurotrophic factor (BDNF) signaling through its receptor TrkB has for a long time been recognized as a critical mediator of the antidepressant drug action, but BDNF signaling has been considered to be activated indirectly through the action of typical and rapid-acting antidepressants through monoamine transporters and glutamate NMDA receptors, respectively. However, recent findings demonstrate that both typical and the fast-acting antidepressants directly bind to TrkB and thereby allosterically potentiate BDNF signaling, suggesting that TrkB is the direct target for antidepressant drugs. Increased TrkB signaling particularly in the parvalbumin-expressing interneurons orchestrates iPlasticity, a state of juvenile-like enhanced plasticity in the adult brain. iPlasticity sensitizes neuronal networks to environmental influences, enabling rewiring of networks miswired by adverse experiences. These findings have dramatically changed the position of TrkB in the antidepressant effects and they propose a new end-to-end model of the antidepressant drug action. This model emphasizes the enabling role of antidepressant treatment and the active participation of the patient in the process of recovery from mood disorders.

3,4-Methylenedioxy methamphetamine, synthetic cathinones and psychedelics: From recreational to novel psychotherapeutic drugs.

The utility of classical drugs used to treat psychiatric disorders (e.g., antidepressants, anxiolytics) is often limited by issues of lack of efficacy, delayed onset of action or side effects. Psychoactive substances have a long history of being used as tools to alter consciousness and as a gateway to approach the unknown and the divinities. These substances were initially obtained from plants and animals and more recently by chemical synthesis, and its consumption evolved toward a more recreational use, leading to drug abuse-related disorders, trafficking, and subsequent banning by the authorities. However, these substances, by modulation of certain neurochemical pathways, have been proven to have a beneficial effect on some psychiatric disorders. This evidence obtained under medically controlled conditions and often associated with psychotherapy, makes these substances an alternative to conventional medicines, to which in many cases the patient does not respond properly. Such disorders include post-traumatic stress disease and treatment-resistant depression, for which classical drugs such as MDMA, ketamine, psilocybin and LSD, among others, have already been clinically tested, reporting successful outcomes. The irruption of new psychoactive substances (NPS), especially during the last decade and despite their recreational and illicit uses, has enlarged the library of substances with potential utility on these disorders. In fact, many of them were synthetized with therapeutic purposes and were withdrawn for concrete reasons (e.g., adverse effects, improper pharmacological profile). In this review we focus on the basis, existing evidence and possible use of synthetic cathinones and psychedelics (specially tryptamines) for the treatment of mental illnesses and the properties that should be found in NPS to obtain new therapeutic compounds.

Antiobesity, Antihyperglycemic, and Antidepressive Potentiality of Rice Fermented Food Through Modulation of Intestinal Microbiota.

The present study has been aimed at evaluating the antiobesity, antihyperglycemic, and antidepressive potentials of Asparagus racemosus starter-based rice fermented foods. High-throughput NGS technology has revealed a number of bacterial genera in the prepared fermented rice, such as Lactobacillus (29.44%), Brevundimonas (16.21%), Stenotrophomonas (6.18%), Pseudomonas (3.11%), Bacillus (2.88%), and others (<2%). Eight-week administration of rice fermented food has increased food intake, whole-body weight, organ weight, different fat masses, serum lipid profiles, and histology of liver and adipose tissues in HFD-induced obese mice. In addition, upregulation of fatty acid oxidation and downregulation of adipocytogenesis- and lypogenesis-related genes along with the expression of their regulatory nuclear factors such as PPARα, PPARγ, PPARδ, and SREBP-1c have also been noted. Moreover, fermented food decreases fasting blood glucose level and improves glucose and insulin tolerance as well as the expression of GLUT4 receptor. Antiobesity and antihyperglycemic effects are also supported by the changes in insulin, leptin, and adiponectin hormone levels. The real-time polymerase chain reaction (RT-PCR) and denaturing gradient gel electrophoresis (DGGE) analyses have clearly demonstrated the intense colonization of Bacteroides, Lactobacillus, and Bifidobacterium, as well as the suppressed growth rate of γ- and δ-Proteobacteria and Firmicutes in the gut after fermented food intake. In the intestine, the latter group of microorganisms possibly modulate short-chain fatty acid (SCFA) levels such as acetate, butyrate, and propionate more than twofold. The impairment of memory-learning and anxiety-like obesity-associated cognitive phenotypes is mitigated significantly (p < 0.01) by fermented food as well. Thus, the formulated fermented food could be used as a natural therapeutic to alleviate obesity and its associated psychological and pathophysiological ailments.

Rewiring of the Serotonin System in Major Depression.

Serotonin is a key neurotransmitter that is implicated in a wide variety of behavioral and cognitive phenotypes. Originating in the raphe nuclei, 5-HT neurons project widely to innervate many brain regions implicated in the functions. During the development of the brain, as serotonin axons project and innervate brain regions, there is evidence that 5-HT plays key roles in wiring the developing brain, both by modulating 5-HT innervation and by influencing synaptic organization within corticolimbic structures. These actions are mediated by 14 different 5-HT receptors, with region- and cell-specific patterns of expression. More recently, the role of the 5-HT system in synaptic re-organization during adulthood has been suggested. The 5-HT neurons have the unusual capacity to regrow and reinnervate brain regions following insults such as brain injury, chronic stress, or altered development that result in disconnection of the 5-HT system and often cause depression, anxiety, and cognitive impairment. Chronic treatment with antidepressants that amplify 5-HT action, such as selective serotonin reuptake inhibitors (SSRIs), appears to accelerate the rewiring of the 5-HT system by mechanisms that may be critical to the behavioral and cognitive improvements induced in these models. In this review, we survey the possible 5-HT receptor mechanisms that could mediate 5-HT rewiring and assess the evidence that 5-HT-mediated brain rewiring is impacting recovery from mental illness. By amplifying 5-HT-induced rewiring processes using SSRIs and selective 5-HT agonists, more rapid and effective treatments for injury-induced mental illness or cognitive impairment may be achieved.

The Association Between Prenatal Exposure to Antidepressants and Autism: Some Research and Public Health Aspects.

Use of antidepressants (ADs) in general, and in pregnant notwithstanding, has been increasing globally in recent decades. Associations with a wide range of adverse perinatal and childhood outcomes following prenatal ADs exposure have been observed in registry-based studies, with Autism Spectrum Disorders (ASD) frequently reported. Studies using animal models, sibling analyses, and negative control approaches, have linked dysfunctional serotonin metabolism with ASD, but did not convincingly tease apart the role of maternal mental health from that of ADs. As work to decipher the nature of the AD-ASD association continues, this review raises some public health concerns pertinent to a hypothetical conclusion that this association is causal, including the need to identify specific gestation periods with higher risk, the importance of precise assessment of the ASD potential prevention that might be attributed to AD discontinuation, and the estimation of risks associated with prenatal exposure to untreated depression.