sirolimus and Depressive-Disorder--Major

Suicide is a public health crisis with limited treatment options. Ketamine has demonstrated rapid and robust improvements in suicidal ideation (SI). The parent study for the secondary pilot analyses presented here was a double-blind, cross-over trial that found pretreatment with the mechanistic target of rapamycin complex 1 (mTORC1) prolonged the antidepressant effects of ketamine. Here we examined the effect of mTORC1 inhibition on ketamine's antisuicidal effects. Twenty patients in a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo prior to IV ketamine (0.5 mg/kg). We found ketamine administration resulted in significant improvements across all measures with the largest effect at 24 h with only the Beck Scale for Suicide remaining significant at the two-week follow-up. There were no significant main effects of pretreatment. While these analyses are pilot in nature and overall severity of SI was relatively low, the antisuicidal findings (no effect of rapamycin) being in contrast to the antidepressant effects (prolonged effect with rapamycin), suggest the rapid-acting antisuicidal and antidepressant effects of ketamine may be mechanistically distinct and the trajectories of response, recovery, and relapse may be independent. These findings provide additional evidence of ketamine's antisuicidal effects and highlight the importance of future studies that continue to examine potential differences in mechanisms and trajectory of outcomes.

Topics: Antidepressive Agents; Depression; Depressive Disorder, Major; Humans; Ketamine; Mechanistic Target of Rapamycin Complex 1; Sirolimus; Suicidal Ideation

Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo 2 h prior to the intravenous administration of ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS). Rapamycin pretreatment did not alter the antidepressant effects of ketamine at the 24-h timepoint. Over the subsequent 2-weeks, we found a significant treatment by time interaction (F

Topics: Antidepressive Agents; Depressive Disorder, Major; Humans; Ketamine; Mechanistic Target of Rapamycin Complex 1; Sirolimus; Treatment Outcome

Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder (BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex (mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206 (40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania. Furthermore, selective knockdown of AKT via AAV-AKT-shRNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly, pharmacological activation of AKT signaling by SC79 (40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002 (25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin (mTOR) signaling with rapamycin (10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.. 氯胺酮是一种快速起效的抗抑郁药，已被用于治疗重度抑郁症和双相情感障碍。最近的研究表明氯胺酮可能会诱发用药患者出现躁狂症的风险。氯胺酮已用于建立躁狂症动物模型。然而，其机制仍不清楚。在该研究中，我们发现慢性锂暴露可减弱氯胺酮诱导的成年小鼠躁狂样行为和内侧前额叶皮层（mPFC）中c-Fos的表达。此外，转录组测序分析探究锂治疗对氯胺酮诱导的小鼠前额叶皮层转录组的影响，确定了磷酸肌醇3-激酶（PI3K）-蛋白激酶B（AKT）信号通路的失活参与了此过程。进一步，选择性AKT抑制剂MK2206可逆转氯胺酮诱导的躁狂样行为。通过AAV选择性敲低mPFC中的AKT也可逆转氯胺酮诱导的躁狂样行为。更重要的是，AKT激活剂SC79可使低剂量氯胺酮处理的小鼠出现躁狂样行为。同样地，PI3K抑制剂LY294002也可逆转氯胺酮诱导的小鼠躁狂样行为。但是，mTOR抑制剂雷帕霉素不能改善氯胺酮诱导的躁狂样行为。总之，我们的结果表明慢性锂治疗通过PI3K-AKT信号通路改善氯胺酮诱导的躁狂样行为。PI3K-AKT信号通路有可能发展为双相情感障碍治疗的新靶点。.

Topics: Animals; Antidepressive Agents; Depressive Disorder, Major; Ketamine; Lithium; Lithium Compounds; Male; Mammals; Mania; Mice; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; Rodent Diseases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Recent investigations have suggested that microRNAs (miRNAs or miRs) are involved in several pathways that may contribute to the pathomechanism of major depressive disorder (MDD). Sex may not only act as a demographic factor in clinical practive, but may also play a vital role in the molecular heterogeneity of MDD. Although many molecular changes correlated with MDD are found in males, the molecular mechanisms of MDD remain poorly understood. The present study performed bioinformatics analysis to investigate the pathomechanism of MDD in males. The present study identified miR‑124‑3p as one of the most dysregulated miRNAs in MDD, with decreased expression in the post‑mortem BA44 brain area of male patients with MDD. In addition, miR‑124‑3p targets DNA damage‑inducible transcript 4 (DDIT4) and specificity protein 1 (SP1), a DDIT4 transcription factor, in the validated target module of the miRWalk 2.0 database. This is concurrent with an increase in the expression level of DDIT4, which is an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway. It was also demonstrated that miR‑124‑3p expression was positively associated with mTOR signaling and this relationship was dependent on the tuberous sclerosis proteins 1/2 complex. Taken together, these results provided a novel insight on miR‑124‑3p involvement in the biological alterations of male patients with MDD and suggested that this miRNA may also serve as a male‑specific target for antidepressant treatment.

Topics: Autopsy; Computational Biology; Depressive Disorder, Major; Gene Expression Regulation; Humans; Male; MicroRNAs; Signal Transduction; Sirolimus; Sp1 Transcription Factor; TOR Serine-Threonine Kinases; Transcription Factors

Topics: Animals; Antibiotics, Antineoplastic; Depressive Disorder, Major; Drug Delivery Systems; Humans; Neoplasms; Neurodegenerative Diseases; Sirolimus; TOR Serine-Threonine Kinases

Current treatments for major depressive disorder (MDD) have a time lag and are ineffective for a large number of patients. Development of novel pharmacological therapies requires a comprehensive understanding of the molecular events that contribute to MDD pathophysiology. Recent evidence points toward aberrant activity of synaptic proteins as a critical contributing factor. In the present studies, we used viral-mediated gene transfer to target a key mediator of activity-dependent synaptic protein synthesis downstream of mechanistic target of rapamycin complex 1 (mTORC1) known as p70 S6 kinase 1 (S6K1). Targeted delivery of two mutants of S6K1, constitutively active or dominant-negative, to the medial prefrontal cortex (mPFC) of rats allowed control of the mTORC1/S6K1 translational pathway. Our results demonstrate that increased expression of S6K1 in the mPFC produces antidepressant effects in the forced swim test without altering locomotor activity. Moreover, expression of active S6K1 in the mPFC blocked the anhedonia caused by chronic stress, resulting in a state of stress resilience. This antidepressant response was associated with increased neuronal complexity caused by enhanced S6K1 activity. Conversely, expression of dominant-negative S6K1 in the mPFC resulted in prodepressive behavior in the forced swim test and was sufficient to cause anhedonia in the absence of chronic stress exposure. Together, these data demonstrate a critical role for S6K1 activity in depressive behaviors, and suggest that pathways downstream of mTORC1 may underlie the pathophysiology and treatment of MDD.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Depressive Disorder, Major; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Ketamine; Male; Maze Learning; Neurons; Phenotype; Phosphorylation; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; Swimming

Topics: Adolescent; Animals; Antidepressive Agents; Depressive Disorder, Major; Drug Resistance; Female; Humans; Ketamine; Middle Aged; Phosphorylation; Rats; Receptors, N-Methyl-D-Aspartate; Sirolimus; Treatment Outcome