OPEN Foundation

C. Li

Dose-Related Effects of Adjunctive Ketamine in Taiwanese Patients with Treatment-Resistant Depression

May 11, 2017 / Depression, Ketamine, Papers, Psychiatry, Psychology, Publications / By / , , , , , ,

Abstract

The antidepressant effects of ketamine are thought to depend on brain-derived neurotrophic factor (BDNF) genotype and dose. The purpose of this study was to characterize the dose-related antidepressant effects of ketamine in patients with treatment-resistant depression drawn from a Chinese population predominately possessing lower activity BDNF genotypes (Val/Met, Met/Met). We conducted a double-blind, randomized, parallel-group, placebo-controlled trial of a single ketamine infusion (saline, 0.2 mg/kg, 0.5 mg/kg). Patients (N=71; BDNF genotype: Val/Val (N=12, 17%), Val/Met (N=40, 56.3%), and Met/Met (N=19, 26.8%)) received mood ratings before infusion, after infusion, and for the subsequent 14 days. Plasma ketamine levels and BDNF genotypes were assessed. This study found a significant dose-related ketamine effect on scores on the Hamilton Depression Rating Scale (HAMD). The responder analysis (>50% reduction from baseline HAMD on at least 2 days between days 2 and 5) also revealed a significant dose-related effect (saline: 12.5%, 0.2 mg/kg: 39.1%; 0.5 mg/kg: 45.8%). This is the first report to our knowledge to demonstrate the dose-related efficacy of R/S-ketamine for treatment-resistant depression and the first to characterize ketamine effects in a genotyped Chinese population in which most (83%) patients possessed at least one copy of the lower functioning Met allele of the BDNF gene.
Su, T. P., Chen, M. H., Li, C. T., Lin, W. C., Hong, C. J., Gueorguieva, R., … & Krystal, J. H. (2017). Dose-Related Effects of Adjunctive Ketamine in Taiwanese Patients with Treatment-Resistant Depression. Neuropsychopharmacology. 10.1038/npp.2017.94
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Anticancer activities of harmine by inducing a pro-death autophagy and apoptosis in human gastric cancer cells

February 28, 2017 / Ayahuasca, Medicine, Other subjects, Papers, Publications / By / , , , , ,

Abstract

BACKGROUND:
Harmine, a β-carboline alkaloid from Peganum harmala, has multiple anti-tumor activities, especially for its folk therapy for digestive system neoplasm. However, the underlying mechanism of harmine on gastric cancer remains unclear.
PURPOSE:
To illuminate the potential anti-tumor activity and mechanism of harmine against gastric cancer cells.
METHODS/STUDY DESIGNS:
The anti-proliferative activity of harmine in vitro was evaluated by MTT assay. The autophagic activity induced by harmine was assessed using GFP-LC3 transfection. FITC/PI double staining was applied for the apoptosis inspection. The mitochondrial membrane potential was detected by JC-1 fluorescence probe. The potential mechanisms for proteins level in autophagy and apoptosis were analyzed by Western blot.
RESULTS:
Harmine exhibited potent effects on both autophagy and apoptosis. Treatment with harmine could enhance dots of GFP-LC3 in cells. Meanwhile, the process had connection with Beclin-1, LC3-II, and p62 by the inhibition of Akt/mTOR/p70S6K signaling. However, high concentration of harmine led to apoptosis characterized by the propidium/Annexin V-positive cell pollution, cell shrunk and the collapse of mitochondrial membrane potential. The regulation of Bcl-2, Bax and the gathering of cleaved-PARP, cleaved-caspase 3 and cleaved-caspase 9 contributed to the induction of apoptosis. In addition, 10μM LY294002 (a specific inhibitor of PI3K/Akt) combination with 40μM harmine significantly increased the cytotoxicity to the gastric cancer cells and up-regulated both the apoptosis-related protein (cleaved-PARP, cleaved-caspase-3) and autophagy-related protein (Beclin-1, LC3-II, and p62). Adding the inhibitor of autophagy, 3-MA or BafA1, increased the viability of harmine-exposured gastric cancer cells, which confirmed the role of autophagy played in the gastric cancer cell death induced by harmine.
CONCLUSION:
Harmine might be a potent inducer of apoptosis and autophagy, which offered evidences to therapy of harmine in gastric carcinoma in the folk medicine.
Li, C., Wang, Y., Wang, C., Yi, X., Li, M., & He, X. (2017). Anticancer activities of harmine by inducing a pro-death autophagy and apoptosis in human gastric cancer cells. Phytomedicine, 28, 10-18. 10.1016/j.phymed.2017.02.008
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The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: A randomized controlled study

January 29, 2016 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Background

Low-dose ketamine has been found to have robust and rapid antidepressant effects. A hypoactive prefrontal cortex (PFC) and a hyperactive amygdala have been suggested to be associated with treatment-resistant depression (TRD). However, it is unclear whether the rapid antidepressant mechanisms of ketamine on TRD involve changes in glutamatergic neurotransmission in the PFC and the amygdala.
Methods

A group of 48 TRD patients were recruited and equally randomized into three groups (A: 0.5 kg/mg-ketamine; B: 0.2 kg/mg-ketamine; and C: normal saline [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][NS]). Standardized uptake values (SUV) of glucose metabolism measured by 18F-FDG positron-emission-tomography before and immediately after a 40-min ketamine or NS infusion were used for subsequent region-of-interest (ROI) analyses (a priori regions: PFC and amygdala) and whole-brain voxel-wise analyses and were correlated with antidepressant responses, as defined by the Hamilton depression rating scale score. The 18F-FDG signals were used as a proxy measure of glutamate neurotransmission.
Results

The ROI analysis indicated that Group A and Group B, but not Group C, had increases in the SUV of the PFC (group-by-time interaction: F = 7.373, P = 0.002), whereas decreases in the SUV of the amygdala were observed in all three groups (main effect of time, P  < 0.001). The voxel-wise analysis further confirmed a significant group effect on the PFC (corrected for family-wise errors, P  < 0.05; post hoc analysis: Group A<Group C, Group B<Group C). The SUV differences in the PFC predicted the antidepressant responses at 40 and 240 min post-treatment. The PFC changes did not differ between those with and without side effects.

Conclusion

Ketamine’s rapid antidepressant effects involved the facilitation of glutamatergic neurotransmission in the PFC.

Li, C. T., Chen, M. H., Lin, W. C., Hong, C. J., Yang, B. H., Liu, R. S., … & Su, T. P. (2016). The effects of low‐dose ketamine on the prefrontal cortex and amygdala in treatment‐resistant depression: A randomized controlled study. Human Brain Mapping. http://dx.doi.org/10.1002/hbm.23085
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30 April - Q&A with Rick Strassman

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