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Treatment-resistant depression is a pleomorphic phenomenon occurring in 30% of patients with depression. The chance to achieve remission decreases with every subsequent episode. It constitutes a significant part of the global disease burden, causes increased morbidity and mortality, and is associated with poor quality of life. It involves multiple difficult-to-treat episodes, with increasing resistance over time. The concept of staging captures the process of changes causing increasing treatment resistance and global worsening of functioning in all areas of life. Ketamine is a novel rapid-acting antidepressant with neuroplastic potential. Here, we argue that ketamine use as an add-on treatment of resistant major depressive disorder, based on its unique pharmacological properties, can reverse this process, give hope to patients, and prevent therapeutic nihilism. [ABSTRACT FROM AUTHOR]

(R , S)-ketamine is an N -methyl-D-aspartate (NMDA) receptor antagonist that was originally developed as an anesthetic. Most recently, (R , S)-ketamine has been used as a rapid-acting antidepressant, and we have reported that (R , S)-ketamine can also be a prophylactic against stress in adult mice. However, most pre-clinical studies have been performed in adult mice. It is still unknown how an acute (R , S)-ketamine injection influences behavior across the lifespan (e.g., to adolescent or aged populations). Here, we administered saline or (R , S)-ketamine at varying doses to adolescent (5-week-old) and aged (24-month-old) 129S6/SvEv mice of both sexes. One hour later, behavioral despair, avoidance, locomotion, perseverative behavior, or contextual fear discrimination (CFD) was assessed. A separate cohort of mice was sacrificed 1 h following saline or (R , S)-ketamine administration. Brains were processed to quantify the marker of inflammation Cyclooxygenase 2 (Cox-2) expression to determine whether the acute effects of (R , S)-ketamine were partially mediated by changes in brain inflammation. Our findings show that (R,S)-ketamine reduced behavioral despair and perseverative behavior in adolescent female, but not male, mice and facilitated CFD in both sexes at specific doses. (R,S)-ketamine reduced Cox-2 expression specifically in ventral CA3 (vCA3) of male mice. Notably, (R , S)-ketamine was not effective in aged mice. These results underscore the need for sex- and age-specific approaches to test (R,S)-ketamine efficacy across the lifespan. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a prevalent psychiatric disease that involves malfunctions of different cell types in the brain. Accumulating studies started to reveal that microglia, the primary resident immune cells, play an important role in the development and progression of depression. Microglia respond to stress-triggered neuroinflammation, and through the release of proinflammatory cytokines and their metabolic products, microglia may modulate the function of neurons and astrocytes to regulate depression. In this review, we focused on the role of microglia in the etiology of depression. We discussed the dynamic states of microglia; the correlative and causal evidence of microglial abnormalities in depression; possible mechanisms of how microglia sense depression-related stress and modulate depression state; and how antidepressive therapies affect microglia. Understanding the role of microglia in depression may shed light on developing new treatment strategies to fight against this devastating mental illness. [ABSTRACT FROM AUTHOR]

Repurposing ketamine in the therapy of depression could well represent a breakthrough in understanding the etiology of depression. Ketamine was originally used as an anesthetic drug and later its use was extended to other therapeutic applications such as analgesia and the treatment of addiction. At the same time, the abuse of ketamine as a recreational drug has generated a concern for its psychotropic and potential long-term effects; nevertheless, its use as a fast acting antidepressant in treatment-resistant patients has boosted the interest in the mechanism of action both in psychiatry and in the wider area of neuroscience. This article provides a comprehensive overview of the actions of ketamine and intends to cover: (i) the evaluation of its clinical use in the treatment of depression and suicidal behavior; (ii) the potential use of ketamine in pediatrics; (iii) a description of its mechanism of action; (iv) the involvement of specific brain areas in producing antidepressant effects; (v) the potential interaction of ketamine with the hypothalamic-pituitary-adrenal axis; (vi) the effect of ketamine on neuronal transmission in the bed nucleus of stria terminalis and on its output; (vii) the evaluation of any gender-dependent effects of ketamine; (viii) the interaction of ketamine with the inflammatory processes involved in depression; (ix) the evaluation of the effects observed with single or repeated administration; (x) a description of any adverse or cognitive effects and its abuse potential. Finally, this review attempts to assess whether ketamine's use in depression can improve our knowledge of the etiopathology of depression and whether its therapeutic effect can be considered an actual cure for depression rather than a therapy merely aimed to control the symptoms of depression. [ABSTRACT FROM AUTHOR]

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Microglia, the resident immune cells of the brain, are highly ramified and motile and their morphology is strongly linked to their function. Microglia constantly monitor the brain parenchyma and are crucial for maintaining brain homeostasis and fine-tuning neuronal networks. Besides affecting neurons, anesthetics may have wide-ranging effects mediated by non-neuronal cells and in particular microglia. We thus examined the effect of two commonly used anesthetic agents, ketamine/xylazine and barbiturates, on microglial motility and morphology. A combination of two-photon in vivo imaging and electroencephalography (EEG) recordings in unanesthetized and anesthetized mice as well as automated analysis of ex vivo sections were used to assess morphology and dynamics of microglia. We found that administration of ketamine/xylazine and pentobarbital anesthesia resulted in quite distinct EEG profiles. Both anesthetics reduced microglial motility, but only ketamine/xylazine administration led to reduction of microglial complexity in vivo. The change of cellular dynamics in vivo was associated with a region-dependent reduction of several features of microglial cells ex vivo, such as the complexity index and the ramification length, whereas thiopental altered the size of the cytoplasm. Our results show that anesthetics have considerable effects on neuronal activity and microglial morphodynamics and that barbiturates may be a preferred anesthetic agent for the study of microglial morphology. These findings will undoubtedly raise compelling questions about the functional relevance of anesthetics on microglial cells in neuronal physiology and anesthesia-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

According to the World Health Organization (WHO), more than 700,000 people die per year due to suicide. Suicide risk factors include a previous suicide attempt and psychiatric disorders. The highest mortality rate in suicide worldwide is due to depression. Current evidence suggests that suicide etiopathogenesis is associated with neuroinflammation that activates the kynurenine pathway and causes subsequent serotonin depletion and stimulation of glutamate neurotransmission. These changes are accompanied by decreased BDNF (brain-derived neurotrophic factor) levels in the brain, which is often linked to impaired neuroplasticity and cognitive deficits. Most suicidal patients have a hyperactive hypothalamus–pituitary–adrenal (HPA) axis. Epigenetic mechanisms control the above-mentioned neurobiological changes associated with suicidal behaviour. Suicide risk could be attenuated by appropriate psychological treatment, electroconvulsive treatment, and drugs: lithium, ketamine, esketamine, clozapine. In this review, we present the etiopathogenesis of suicide behaviour and explore the mechanisms of action of anti-suicidal treatments, pinpointing similarities among them. [ABSTRACT FROM AUTHOR]