Lithium augmentation of ketamine increases insulin signaling and antidepressant-like active stress coping in a rodent model of treatment-resistant depression.

Lithium, a mood stabilizer and common adjunctive treatment for refractory depression, shares overlapping mechanisms of action with ketamine and enhances the duration of ketamine's antidepressant actions in rodent models at sub-therapeutic doses. Yet, in a recent clinical trial, lithium co-treatment with ketamine failed to improve antidepressant outcomes in subjects previously shown to respond to ketamine alone. The potential for lithium augmentation to improve antidepressant outcomes in ketamine nonresponders, however, has not been explored. The current study examined the behavioral, molecular and metabolic actions of lithium and ketamine co-treatment in a rodent model of antidepressant resistance. Male Wistar rats were administered adrenocorticotropic hormone (ACTH; 100 µg/day, i.p. over 14 days) and subsequently treated with ketamine (10 mg/kg; 2 days; n = 12), lithium (37 mg/kg; 2 days; n = 12), ketamine + lithium (10 mg/kg + 37 mg/kg; 2 days; n = 12), or vehicle saline (0.9%; n = 12). Rats were subjected to open field (6 min) and forced swim tests (6 min). Peripheral blood and brain prefrontal cortical (PFC) tissue was collected one hour following stress exposure. Western blotting was used to determine the effects of treatment on extracellular signal-regulated kinase (ERK); mammalian target of rapamycin (mTOR), phospho kinase B (Akt), and glycogen synthase kinase-3ß (GSK3ß) protein levels in the infralimbic (IL) and prelimbic (PL) subregions of the PFC. Prefrontal oxygen consumption rate (OCR) and extracellular acidification rates (ECAR) were also determined in anterior PFC tissue at rest and following stimulation with brain-derived neurotrophic factor (BDNF) and tumor necrosis factor α (TNFα). Blood plasma levels of mTOR and insulin were determined using enzyme-linked immunosorbent assays (ELISAs). Overall, rats receiving ketamine+lithium displayed a robust antidepressant response to the combined treatment as demonstrated through significant reductions in immobility time (p < 0.05) and latency to immobility (p < 0.01). These animals also had higher expression of plasma mTOR (p < 0.01) and insulin (p < 0.001). Tissue bioenergetics analyses revealed that combined ketamine+lithium treatment did not significantly alter the respiratory response to BDNF or TNFα. Animals receiving both ketamine and lithium had significantly higher phosphorylation (p)-to-total expression ratios of mTOR (p < 0.001) and Akt (p < 0.01), and lower ERK in the IL compared to control animals. In contrast, pmTOR/mTOR levels were reduced in the PL of ketamine+lithium treated animals, while pERK/ERK expression levels were elevated. Taken together, these data demonstrate that lithium augmentation of ketamine in antidepressant nonresponsive animals improves antidepressant-like behavioral responses under stress, together with peripheral insulin efflux and region-specific PFC insulin signaling.

An exploratory study of clinical and physiological correlates of problematic social media use in adolescents.

Prior validation studies of the Bergen Social Media Addiction Scale (BSMAS) demonstrate its utility for identifying problematic social media use in adolescents. There are knowledge gaps regarding the potential clinical and physiological underpinnings of problematic social media use in adolescents. This cross-sectional, single-visit study examined a sample of depressed (n = 30) and healthy (n = 30) adolescents who underwent clinical assessments of depressive symptom severity, bullying, cyberbullying, self-esteem, salivary measures of stress (cortisol and α-amylase) to identify correlates with adolescent and parental reports of the BSMAS. LASSO-penalized multiple linear regression models were implemented. With respect to the adolescent BSMAS scores in all subjects, the risk of problematic social media increased as depressive symptom severity increased. Depressed female adolescents appeared to have a greater risk. Based on parental BSMAS scores, depression status, depressive symptom severity, cyberbullying score, and salivary cortisol significantly predicted problematic social media use. For the depressed sample, the risk of problematic social media use increased as salivary cortisol increased. No significant predictors of problematic social media usage emerged in the healthy control sample. These preliminary results provide novel insights into clinical and physiological characteristics of problematic social media use in adolescents.

Altered markers of stress in depressed adolescents after acute social media use.

Social media use (SMU) is an inherent element in the daily life and neurodevelopment of adolescents, but broad concerns exist regarding the untoward effects of social media on adolescents. We conducted a prospective, cross-sectional study that sought to examine the acute effects of SMU on clinical measures and biomarkers of stress in healthy and depressed adolescents. After at least 24 h of abstinence from social media, depressed adolescents (n = 30) and healthy control adolescents (n = 30) underwent baseline clinical assessment of their prior SMU, depressive symptom severity, self-esteem, and exposure to bullying. Participants provided salivary samples that were analyzed for α-amylase and cortisol levels. After 20 min of unsupervised SMU, saliva analyses and clinical assessments were repeated. After 20 min of SMU, salivary cortisol and α-amylase levels were significantly higher in adolescents with depression but not in healthy control adolescents. Furthermore, small but statistically significant changes in depressive symptom severity occurred in all participants. These changes in depressive symptoms were not clinically meaningful. SMU did not significantly change self-esteem measures among participants. Adolescents with depression appeared to have more physiological reactivity after SMU compared with healthy adolescents. Further research should characterize SMU as a clinical dimension and risk factor among adolescents with depression and other psychiatric disorders.