Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)–TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF–TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF–TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.

Depression is the most prevalent and among the most debilitating of psychiatric disorders. The precise neurobiology of this illness is unknown. Several lines of evidence suggest that peripheral and central inflammation plays a role in depressive symptoms, and that anti-inflammatory drugs canimprove depressive symptoms in patients with inflammation-related depression. Signaling via brain-derived neurotrophic factor (BDNF) and its receptor, tropomycin receptor kinase B (TrkB) plays a key role in the pathophysiology of depression and in the therapeutic mechanisms of antidepressants. A recent paper showed that lipopolysaccharide (LPS)-induced inflammation gave rise to depression-like phenotype by altering BDNF-TrkB signaling in the prefrontal cortex, hippocampus, and nucleus accumbens, areas thought to be involved in the antidepressant effects of TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist, ANA-12.Here we provide an overview of the tryptophan-kynurenine pathway and BDNF-TrkB signaling in the pathophysiology of inflammation-induced depression, and propose mechanistic actions for potential therapeutic agents.Additionally, the authors discuss the putative role ofTrkB agonists and antagonists as novel therapeutic drugs for inflammation-related depression.

SEVERAL LINES of evidence suggest that a dysfunction in glutamatergic neurotransmission via the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors might be involved in the pathophysiology of schizophrenia.^1-6 This hypothesis has evolved from clinical findings that phencyclidine and its congener ketamine, which block the NMDA receptor ion channel, induce a schizophrenia-like psychosis, representing negative and positive symptoms and cognitive dysfunction in healthy humans, and that phencyclidine exacerbates such symptoms in patients with chronic schizophrenia.^1,5 Although only L-amino acids generally play a physiologic role in species other than bacteria, the existence of some D-amino acids, such as D-serine in higher species, including humans, has been demonstrated.^7-9 It has previously been shown that D-serine is selectively enriched in the forebrain, with immunocytochemical localization in type II astrocytes in gray matter areas also rich in the NMDA receptor,¹⁰ suggesting that D-serine may modulate the strychnine-insensitive glycine sites of the NMDA receptor.⁹ Interestingly, therapeutic trials with D-serine have been shown to significantly improve symptoms (positive, negative, and cognitive) in patients with schizophrenia,¹¹ suggesting that D-serine may play an important role in the pathophysiology of schizophrenia.¹² Therefore, it would be of great interest to clarify the potential contribution of endogenous D-serine to the pathophysiology of schizophrenia. Along these lines, the present study was undertaken to examine whether the serum levels of D- and L-serine of patients with schizophrenia are different from those of age- and sex-matched healthy controls.