We present a case with decreased metabolic activity of CYP2D6, a cytochrome P450 enzyme catalyzing the metabolism of nortriptyline (NT). Conventional dosage regimen led to toxic plasma concentration of NT and adverse effects such as dry mouth, constipation, and dizziness in this case with genotype CYP2D6*5/*10B. This case suggests the clinical usefulness of pharmacogenetic testing in individualized dosage adjustments of NT.
Antidepressive Agents, Tricyclic/*adverse effects/pharmacokinetics ; Cytochrome P-450 CYP2D6/*genetics/metabolism ; Depression/*drug therapy/genetics ; Genotype ; Humans ; Male ; Middle Aged ; Nortriptyline/*adverse effects/pharmacokinetics

OBJECTIVETo assess the association of BDNF gene Val66Met polymorphism with efficacy of antidepressant treatment and plasma BDNF level.

METHODSTwo hundred and forty-nine ethnic Han Chinese patients with depression(study group), who have met the diagnostic criteria of DSM-IV, were prescribed with venlafaxine or paroxetine. Two hundred and two healthy individuals were recruited as the control group. General demographic information such as gender, age, educational status, occupation, and marriage status were collected. HAMD-17 was adopted as the primary rating tool to evaluate the severity of depression on the baseline and at the end of 1st, 2nd, 4th, 6th week of treatment. PCR-restriction fragment length polymorphism was applied to determine the Val66Met polymorphism of the BDNF gene in the two groups. Plasma BDNF concentration was measured with ELISA before and after 6 weeks of treatment.

RESULTSNo significant differences have been found in HAMD scores and reduction of HAMD scores on the baseline and at the end of 1 st, 2nd, 4th, 6th weeks of treatment for each genotype. Nor were significant differences found in the Val66Met genotypes and allelic frequency between patients who achieved remission or not after 6 weeks' treatment as well as the healthy volunteers. The plasma BDNF level in depression patients was lower than that in healthy controls. The BDNF level has increased significantly after 6 weeks' treatment with both venlafaxine and paroxetine, but was still lower than the healthy controls. The BDNF level in the patients achieved remission who were treated with venlafaxine was similar to the normal controls, while those treated with paroxetine was still lower than normal controls. The BDNF level in patients who have not achieved remission was lower than normal controls. The BDNF level was not associated with the Val66Met polymorphism on the baseline and the end of 6th week.

CONCLUSIONNo association has been found between the efficacy of venlafaxine or paroxetine and the BDNF Val66Met polymorphism. The BDNF level of patients with depression is significantly lower than healthy controls on the baseline, and can be enhanced with the treatment. Particularly, the BDNF level in patients who achieved remission after the treatment of venlafaxine can rise to normal. The level of BDNF has certain value in the forecasting of efficacy in the anti-depression therapy. BDNF level is not associated with the Val66Met polymorphism of the BDNF gene.

Adolescent ; Adult ; Aged ; Antidepressive Agents ; therapeutic use ; Brain-Derived Neurotrophic Factor ; blood ; genetics ; Depression ; blood ; drug therapy ; genetics ; Female ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic

As regulating the function of the liver and spleen of the famous traditional formula, Sini San is widely used in the treatment of various diseases caused by liver depression and Qi stagnation, and its efficacy is significant clinically. Recently it is discovered that Sini San is effective in the treatment of nervous system diseases such as depression. Furthermore, there is a lot of literature about the effect of Sini San on the molecular mechanism of antidepressant. However, the anti-depression mechanism of Sini San is not very clear, in our present study, based on the auxiliary mechanism elucidation system for Chinese medicine and network pharmacology system to construct the chemical ingredients of the target interactions and disease-related protein of the interaction network. Results show that there are 263 chemical ingredients and 19 corresponding targets of depression in Sini San network. Sini San can anti-depressant effect through G-protein coupled receptor protein signaling pathway, cAMP system, neurological system process and neurotransmitter secretion, inflammatory response, neuroendocrine, metal ion transport and so on. These studies provided valuable clues for the mechanism and treatment of anti-depressant.
Animals ; Antidepressive Agents ; administration & dosage ; chemistry ; Databases, Factual ; Depression ; drug therapy ; genetics ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; Gene Regulatory Networks ; drug effects ; Humans ; Signal Transduction

OBJECTIVETo screen microRNAs with specific expression of in hippocampus of rats with chronic stress induced depression model, and observe the effect of traditional Chinese medicine Chaihu Shugan San on the expression of microRNA in hippocampus.

METHODSD rats were randomly divided into 3 groups: the normal control group, the model control group and the Chaihu Shugan San group. The depression model was replicated by unpredictable chronic mild stress combined with separation. Behavioral changes of the rats were observed by Open-field test and sucrose solution consumption test, and the expression of microRNAs in hippocampus was assayed by microRNA micro-array.

RESULTCompared with the normal control group, there were 13 specific miRNAs in hippocampus in the model control group with the expression difference of more than 2 times. Among them, down-regulating miRNAs included miR298, miR-130b, miR-135a, miR-323, miR-503, miR-15b, miR-532, and miR-125a, and the up-regulation miRNAs included miR7a, miR-212, miR-124, miR-139, and miR-182. Among the 13 specific miRNAs, miR-125a and miR-182 recovered to normal after intervention with Chaihu Shugan San in the Chaihu Shugan San group.

CONCLUSIONThis study preliminarily found that 13 specific miRNAs in hippocampus are related to depression. Among them, miR-125a and miR-182 recover to normal after intervention with Chaihu Shugan San, which may be the target points of the antidepressant effect of Chaihu Shugan San. We shall further analyze the target genes and their mechanisms.

Animals ; Antidepressive Agents ; administration & dosage ; Behavior, Animal ; drug effects ; Depression ; drug therapy ; genetics ; metabolism ; psychology ; Disease Models, Animal ; Gene Expression ; drug effects ; Hippocampus ; drug effects ; metabolism ; Humans ; Male ; MicroRNAs ; genetics ; metabolism ; Plant Extracts ; administration & dosage ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo explore the effects and anti-depression mechanisms of Kaixin Jieyu Decoction (, KJD).

METHODSThe rat vascular depression (VD) model was established by ligation of bilateral common carotid arteries (LBCCA) combined with chronic unpredictable mild stress (CUMS). Forty Wistar rats were randomly divided into sham, VD model, VD + high-dose KJD [15.4 g/(kg·d) of crude drug], VD + medium-dose KJD [7.7 g/(kg·d) of crude drug], and VD + fluoxetine [2.4 mg/(kg·d)] groups (n=8 in each group), and the treatments lasted for 21 days. Changes of behavior and hippocampus pathology were observed. The level of glial fibrillary acidic protein (GFAP) protein and mRNA in hippocampus was detected respectively by immunohistochemistry and real-time polymerase chain reaction.

RESULTSCompared with the sham group, rats in model group showed a variety of behavioral obstacles, including a significant reduction in sucrose consumption percentage, horizontal and vertical activity scores in open-field tests (P<0.05 or P<0.01), pathological damage like neuronal degeneration, necrosis, and a significant decrease of GFAP protein and mRNA in hippocampus (P<0.01); compared with the model group, rats in the high-dose KJD group, medium-dose KJD group and fluoxetine group obtained notable higher behavioral scores, and pathological injury lessened in hippocampus with a increased expression of GFAP protein and mRNA P<0.05 or P<0.01); compared with the medium-dose KJD group and fluoxetine group, GFAP mRNA in high-dose KJD group expressed higer (P<0.05).

CONCLUSIONLBCCA combined with CUMS may cause depression-like behavioral changes resulting in the VD model of rats whose depression state can be ameliorated by KJD, and the mechanism of cerebral protection is related possibly with promoting expression of GFAP in hippocampus.

Animals ; Behavior, Animal ; Depression ; drug therapy ; genetics ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Electrophoresis, Agar Gel ; Glial Fibrillary Acidic Protein ; genetics ; metabolism ; Hippocampus ; drug effects ; metabolism ; pathology ; Immunohistochemistry ; Male ; RNA, Messenger ; genetics ; metabolism ; Rats, Wistar ; Transition Temperature

OBJECTIVETo observe the effect of Polygala tenuifolia Willd YZ-50 on the mRNA expression of brain-derived neurotrophic factor (BNDF) and its receptor TrkB in rats with chronic stress depression.es.

METHODSNormal male Wistar rats were divided in to control group, model group, desipramine (20 mg/kg) group, and low and high-dose (2.8 and 5.6 g/kg) YZ-50 groups. The total RNA was extracted from the rats with chronic stress depression, and the mRNA expression of BDNF and TrkB was detected by RT-PCR.

RESULTSCompared with the model group, YZ-50 at both low and high doses significantly increased the mRNA expression of BDNF and TrkB in the hippocampus of rats with chronic stress depression, and the effect was more obvious in the high-dose group (P<0.01).

CONCLUSIONYZ-50 can up-regulate the expression of BDNF and TrkB mRNA to promote the recovery of the neurons from chronic stress-induced damages and produces anti-depressant effect.

Animals ; Brain-Derived Neurotrophic Factor ; genetics ; metabolism ; Depression ; drug therapy ; etiology ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; Male ; Polygala ; chemistry ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Wistar ; Receptor, trkB ; genetics ; metabolism ; Stress, Physiological ; physiology ; Up-Regulation ; drug effects

In 2012, the preparation process and quality standard for Guizhi Fuling capsule were improved. To compare the effects and differences of capsules before (2011) and after(2012-2014) the improvement, evaluation models for intrinsic dysmenorrhea, pelvic inflammation and hysteromyoma were applied in rats. Models were induced by oxytocin, liqiud bacteria mixture and estrogen loading, respectively. The capsules (12 batchs/year, 48 bathcs in all), sampled randomly in 2011-2014, the effects were assessed using the three models. In anti-dysmenorrhea models, remarked reduction of writhing frequency, ET-1 and PGF2α content in uterus could be detected, as well as extension of writhing latency. In pelvic inflammation rats, depression of TNF-α and raise of IL-2 were induced by earh batch of capsules. In hysteromyoma model, uterine weight and smooth muscle proliferation, including E2 and P level in plasma, were lowered obviously by all batchs of capsules. Secondly, Guizhi Fuling capsules produced in 2012-2014 revealed better effectiveness than the ones manufactured in 2011. Moreover, pharmacodynamics indexes of the samples made in 2011 differed significantly between groups, which could not be observed in the ones ot 2012-2014. After tne preparation process and quality standard improvement, the effectiveness and homogeneity of Guizhi Fuling capsules were enhanced.
Animals ; Capsules ; administration & dosage ; chemistry ; standards ; Depression ; drug therapy ; genetics ; metabolism ; Dinoprost ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; standards ; Dysmenorrhea ; drug therapy ; genetics ; metabolism ; Female ; Humans ; Interleukin-2 ; genetics ; metabolism ; Pelvic Inflammatory Disease ; drug therapy ; genetics ; metabolism ; Quality Improvement ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; genetics ; metabolism

Sini Powder (SP), a traditional Chinese herbal formula, has long been used to treat depression in patients, although the underlying mechanisms remain to be elucidated. In the present study, we found that rats treated with SP extract for 7 days showed a significant increase in swimming time and reduction in immobility time in forced swimming test in a dose-dependent manner, without changes in locomotion. These effects could be attributed to SP's modulation of the hypothalamus-pituitary-adrenal axis, because a single pretreatment of SP extract could rescue increased serum corticosterone and plasma adrenocorticotropin levels induced by acute elevated platform stress. A single pretreatment of SP extract could also elevate the mRNA expression of hippocampal glucocorticoid receptors. In conclusion, our results suggest that SP extract may act as an anti-stress medication to produce antidepressant-like effects.
Adrenocorticotropic Hormone ; blood ; Animals ; Antidepressive Agents ; administration & dosage ; Corticosterone ; blood ; Depression ; drug therapy ; genetics ; metabolism ; physiopathology ; Drugs, Chinese Herbal ; administration & dosage ; Hippocampus ; drug effects ; Humans ; Male ; Pituitary-Adrenal System ; drug effects ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Glucocorticoid ; genetics ; metabolism

The serotonin transporter (SERT) is the target site for serotonin reuptake inhibitors, which are the most widely used agents for treating various psychiatric diseases including depression. The SERT is a member of a large family of homologous integral membrane proteins. This transporter takes up 5-HT in a process that is coupled to the transmembrane movement of Na+, Cl-, and K+. The SERT may operate in at least two modes, an alternating access carrier or a channel. The function of SERT is acutely regulated by various protein kinases and phosphatases. The SERT gene is located on chromosome 17 and has several polymorphisms including 5-HTTLPR and intron 2 VNTR. Most studies involving the association between 5-HTTLPR and the response to SSRI in depression reported that l/l genotype showed better response and fewer side effects. But, it is too early to draw definite conclusion of the effects of 5-HTTLPR on anti-depressant treatment. Therefore, it is necessary to perform further studies reflecting various ethnicities and genetics of subjects as well as the environmental interactions. This review discusses recent advances in defining the structure, the action mechanism, the location, and the regulation of SERT. Furthermore, it discusses the function of SERT polymorphisms and its implications on the anti-depressant therapies.
Chromosomes, Human, Pair 17 ; Depression ; Drug Therapy* ; Genetics ; Genotype ; Humans ; Introns ; Membrane Proteins ; Phosphoric Monoester Hydrolases ; Protein Kinases ; Serotonin Plasma Membrane Transport Proteins* ; Serotonin Uptake Inhibitors ; Serotonin*

The rats were exposed to chronic unpredictable mild stress(CUMS) and kept in separate cages for inducing depressive disorder, which was judged by behavioral indicators. The number and morphology of neurons in hippocampal CA3 area and prefrontal cortex were observed by hematoxylin-eosin(HE) staining. The levels of brain-derived neurotrophic factor(BDNF), 5-hydroxytryptamine(5-HT), 5-hydroxyindoleacetic acid(5-HIAA), dopamine(DA), norepinephrine(NE), glutamic acid(GLU), interleukin-1β(IL-1β), interleukin-18(IL-18), and tumor necrosis factor-α(TNF-α) were detected by enzyme-linked immunosorbent assay(ELISA). Real-time polymerase chain reaction(RT-PCR) and Western blot were conducted to determine the mRNA and protein expression levels of related molecules in NLRP3 pathway. The results showed that compared with the model group, acidic polysaccharides from Poria at the low-, medium-, and high-doses(0.1, 0.3 and 0.5 g·kg~(-1)·d~(-1)) all improved the depression-like behavior of rats, increased the number of neurons and the levels of BDNF, 5-HT, 5-HIAA, DA, and NE in the hippocampus, and reduced GLU and serum IL-1β, IL-18, and TNF-α levels. The mRNA expression levels of ASC, caspase-1, IL-1β, and IL-18 and the protein expression levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 in each medication group were down-regulated, whereas the protein expression levels of pro-caspase-1, pro-IL-1β, and pro-IL-18 were up-regulated. All these have indicated that acidic polysaccharides from Poria exerted the antidepressant effect possibly by regulating neurotransmitters and NLRP3 inflammasome signaling pathway.
Animals ; Antidepressive Agents ; Depression/drug therapy* ; Interleukin-1beta ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Neurotransmitter Agents ; Polysaccharides/pharmacology* ; Poria ; Rats