Is (R)-ketamine a potential therapeutic agent for treatment-resistant depression with less detrimental side effects? A review of molecular mechanisms underlying ketamine and its enantiomers.

Approximately one-third of individuals with major depressive disorder are resistant to conventional antidepressants (i.e., monoamine-based therapies), and, even among respondents, a proper therapeutic effect may require weeks of treatment. Ketamine, a racemic mixture of the two enantiomers, (R)-ketamine and (S)-ketamine, is an N-methyl-d-aspartate receptor (NMDAR) antagonist and has been shown to have rapid-acting antidepressant properties in patients with treatment-resistant depression (TRD). Although (R)-ketamine has a lower affinity for NMDAR, it presents greater potency and longer-lasting antidepressant properties, with no major side effects, than racemic ketamine or (S)-ketamine in preclinical findings. Thereby, ketamine and its enantiomers have not only an antagonistic effect on NMDAR but also a strong synaptogenic-modulatory effect, which is impaired in TRD pathophysiology. In this review, we summarize the current evidence regarding the modulation of neurotransmission, neuroplasticity, and neural network activity as putative mechanisms of these rapid-acting antidepressants, highlighting differences on intracellular signaling pathways of synaptic proteins such as mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK) and brain-derived neurotrophic factor (BDNF). In addition, we discuss probable mechanisms involved in the side effects of ketamine and its enantiomers.

Evaluation of stress biomarkers and electrolytes in saliva of patients undergoing fixed orthodontic treatment.

BACKGROUND: The aim of this study was to test the hypothesis that treatment with orthodontic appliances evokes significant functional limitations and emotional stress, which can be detected by salivary biomarkers. METHODS: Twenty subjects (10 men and 10 women) who underwent orthodontic treatment were included in this prospective study. Saliva was sampled for detection of alpha-amylase activity and cortisol levels at three different times: before bracket placement (T0), 24 hours after archwire placement (T1), and 30 days after archwire placement (T2). The saliva electrolytes concentrations of calcium, phosphorus, magnesium, sodium and potassium were also evaluated. Moreover, the possible functional limitations of the appliances were evaluated by a masticatory performance test and pain experience registration. All variables were compared with those in a control group with normal occlusion. RESULTS: The orthodontic patients exhibited a significant increase in emotional stress as detected by the alpha-amylase activity at T1, the period in which patients reported the higher values of pain and exhibited the lower masticatory performance indices. The basal salivary cortisol was not affect by the treatment and the main change detected in electrolyte concentration was a sodium reduction, when these patients were compared to controls. CONCLUSIONS: The present data indicate that orthodontic patients are under emotional stress only during the period of higher pain experience, which could also disrupt the masticatory performance. However, these alterations were not correlated with a single measurement of stress-related biomarkers in saliva, suggesting that these solitary endocrine measurements are not adequate to predict the temporary pain and masticatory limitation experimented by patients undergoing orthodontic treatment.