A Pilot Study on the Effect of Cannabis Extract on Weight Loss in Diet-induced Obese Mice / 신경정신의학

Methods@#A total of 12 C57BL/6 male mice (Orient Bio), aged 6 weeks, were fed a high-fat diet for 13 weeks to construct a diet-induced obesity model. During the following 5 weeks, diet-induced obese mice were daily administered cannabis extract or sesame seed oil orally along with the high-fat diet. The body weight of each subject was measured weekly. Venous blood was drawn for biochemistry, enzyme-linked immunoassay, and oral glucose tolerance test before and after treatment. Body fat was measured by dual-energy X-ray absorptiometry, and the mesenteric adipose tissue was also measured after sacrifice. We used exact Wilcoxon’s two-sample analyses and generalized estimating equations to test the differences between the cannabis-treated group and control. @*Results@#There was significant weight loss (p=0.009) observed in the cannabis-treated mice compared to the control group after 5 weeks of treatment. High-fat diet-induced glucose intolerance in the cannabis-treated group was significantly ameliorated (p=0.032), whereas there were no profound differences between the two groups in terms of other physiological markers, including corticosterone level. @*Conclusion@#This study shows that orally administered cannabis extract had a pharmacological effect of weight loss in diet-induced obese mice. This weight loss might be attributed to an increase in energy expenditure and regulation of glucose homeostasis.

Extrapyramidal Signs and Risk of Progression from Mild Cognitive Impairment to Dementia: A Clinical Research Center for Dementia of South Korea Study

OBJECTIVE: Extrapyramidal signs (EPS) are common in patients with mild cognitive impairment (MCI). However, few studies have assessed the effect of EPS on the clinical course of MCI. We aimed to evaluate whether patients with EPS show more frequent progression from MCI to Alzheimer's disease (AD) and to other types of dementia. METHODS: Participants (n=882) with MCI were recruited, and were followed for up to 5 years. The EPS positive group was defined by the presence of at least one EPS based on a focused neurologic examination at baseline. RESULTS: A total of 234 converted to dementia during the follow-up period. The risk of progression to AD was lower in the patients with EPS after adjusting for potential confounders [hazard ratio (HR)=0.70, 95% confidence interval (CI)=0.53–0.93, p=0.01]. In contrast, the patients with EPS had a six-fold elevated risk of progression to dementia other than AD (HR=6.33, 95%CI=2.30–17.39, p < 0.001). CONCLUSION: EPS in patients with MCI is a strong risk factor for progression of MCI to non-Alzheimer dementia. The careful neurologic examination for EPS in patients with MCI can yield important clinical information for prognosis.

Serum Cytokine Levels in Major Depressive Disorder and Its Role in Antidepressant Response

OBJECTIVE: Cytokines have been reported to have key roles in major depressive disorder (MDD). However, much less is known about cytokines in MDD and antidepressant treatment due to the diversity of cytokines and the heterogeneity of depression. We investigated the levels of cytokines in patients with MDD compared with healthy subjects and their associations with antidepressant response. METHODS: We investigated the changes of several cytokines (eotaxin, sCD40L, IL-8, MCP-1alpha, TNF-alpha, INF-gamma and MIP-1alpha) by Luminex assay in 66 patients with MDD and 22 healthy controls. The antidepressant response was assessed by 17-item Hamilton Rating Scale for Depression. RESULTS: We found the levels of sCD40L (p=0.001), IL-8 (p=0.004) and MCP-1 (p=0.03) of healthy controls were significantly higher than those of depressive patients. However, the level of eotaxin and TNF-alpha were not associated with MDD. In addition, we found the level of MCP-1 was significantly changed after antidepressant treatment (p=0.01). CONCLUSION: These findings suggest the roles of cytokines in MDD are complex, and could vary according to the individual characteristics of each patient. Further studies regarding the relationship between cytokines and MDD will be required.

Association between the BDNF Val66Met Polymorphism and Chronicity of Depression

OBJECTIVE: Both clinical and biological factors influence the course of depressive disorders. This study tested for associations between the brain-derived neurotrophic factor (BDNF) gene at the Val66Met locus and the course of major depressive disorder (MDD). METHODS: Three hundred ten Korean subjects (209 patients, 101 controls) were genotyped for rs6265 at nucleotide 196 (G/A), which produces an amino acid substitution at codon 66 (Val66Met) of the gene for BDNF. Course of illness was evaluated both by chronicity of current episode (episode duration >24 months) and by the lifetime history of recurrences. RESULTS: Patients with the Met/Met BDNF genotype had a significantly higher rate of chronic depression than all others. There was a significant dose effect of the Met allele on chronicity. Compared with the Val/Val genotype, the relative risk of chronicity was 1.67 for the Val/Met genotype, and 2.58 for the Met/Met genotype. Lifetime history of recurrent episodes was not related to BDNF genotypes but was significantly associated with younger age of onset and with a history of depression in first degree relatives. CONCLUSION: BDNF genotyping may be informative for anticipating chronicity in major depression.

Association between Depression and Education Level in Alzheimer's Dementia : A CREDOS (Clinical Research Center for Dementia of South Korea) Study

OBJECTIVES: We aimed to identify the association depression with education level in patients with Alzheimer's dementia (AD). METHODS: We examined 911 patients with AD in CREDOS (Clinical Research Center for Dementia of South Korea) study and designed cross-sectional study. Each patient underwent psychiatrical, neurological and medical examination, interview for caregivers, laboratory tests, neuropsychological tests, and brain MRI. Cognitive function was measured using Korean version of Mini-Mental State Examination, Global Deterioration Scale and Clinical Dementia Rating. Psycho-Behavioral symptom was measured using Caregiver-Administered Neuropsychiatric Inventory. Daily Living was measured using Barthel Index for daily living activities and Seoul-Instrumental Activities of Daily Living. Depressive symptoms using the Korean version of the Short form on Geriatric Depression Scale were measured. Education was classified into low, intermediate, and high levels. 621 patients were performed APOE genotyping among the 911 patients. RESULTS: Out of the 911 patients, 477 were low education, 287 were intermediate education, and 147 were high education. 341 patients had depression. In logistic regression model we confirmed low education was the risk factor of depression (OR 2.26, 95% CI 1.66-3.07). CONCLUSION: This study confirmed that low education was associated with depression in Alzheimer's dementia.

An Association Study between Various Adrenergic Alpha 2 Receptor Polymorphisms and Treatment Response to Mirtazapine in Major Depression

OBJECTIVES: Genetic differences may contribute to the inter-individual differences in treatment response to antidepressants among patients suffering from major depression. This study investigated a possible association of treatment response to mirtazapine with various adrenergic alpha 2 receptor polymorphisms in major depressive patients. METHODS: A 6-week naturalistic treatment study with a blinded outcome examined 84 Korean patients with major depression. Treatment response to mirtazapine was defined as > or =50% decrease in HAM-D scores at six weeks. In this study, four genetic polymorphisms were selected ; ADRA2A MspI, ADRA2A DraI, alpha2BDel301-303, and alpha2CDel322-325. RESULTS: The Del/Del genotype of alpha2CDel322-325 exhibited a significant association with response to mirtazapine through multiple logistic regression. ADRA2A DraI, alpha2BDel301-303, and alpha2CDel322-325 did not showed a significant association with response to mirtazapine. CONCLUSION: Based on the finding that alpha2CDel322-325 polymorphism had an association with the mirtazapine response, we postulate that the polymorphism related to the mechanism of the antidepressant effect is important in predicting the response to antidepressants.

An Association Study between Various Adrenergic Alpha 2 Receptor Polymorphisms and Treatment Response to Mirtazapine in Major Depression

OBJECTIVES: Genetic differences may contribute to the inter-individual differences in treatment response to antidepressants among patients suffering from major depression. This study investigated a possible association of treatment response to mirtazapine with various adrenergic alpha 2 receptor polymorphisms in major depressive patients. METHODS: A 6-week naturalistic treatment study with a blinded outcome examined 84 Korean patients with major depression. Treatment response to mirtazapine was defined as > or =50% decrease in HAM-D scores at six weeks. In this study, four genetic polymorphisms were selected ; ADRA2A MspI, ADRA2A DraI, alpha2BDel301-303, and alpha2CDel322-325. RESULTS: The Del/Del genotype of alpha2CDel322-325 exhibited a significant association with response to mirtazapine through multiple logistic regression. ADRA2A DraI, alpha2BDel301-303, and alpha2CDel322-325 did not showed a significant association with response to mirtazapine. CONCLUSION: Based on the finding that alpha2CDel322-325 polymorphism had an association with the mirtazapine response, we postulate that the polymorphism related to the mechanism of the antidepressant effect is important in predicting the response to antidepressants.

CREB-Phosphorylation as a Predictor of Therapeutic Response to Antidepressants

OBJECTIVES: CREB (c-AMP response element binding protein) is known as a key mediator of the therapeutic response to antidepressants. We investigated the change of CREB-phosphorylation (pCREB) at the early point of the fluoxetine treatment to find out it can be a predictor for antidepressant response. METHODS: We evaluated the pCREB of T - lymphocyte nuclear extracts from 18 depressed patients at 0 and 1th week during fluoxetine treatment (20 mg/day). Responders were defined as the > or = 50% reduction of HAM-D score in 4 weeks. We compared the changes of pCREB at 0 and 1th week between responders and non-responders. RESULTS: The responders showed a significant increase of pCREB at week 1 compared with week 0. The HAM-D difference between week 0 and 4 was positively correlated with the change of pCREB response. CONCLUSION: These results suggest that the early change of pCREB in peripheral lymphocyte can predict the later response of antidepressant. The correlation showed pCREB directly reflects a response status to the antidepressant fluoxetine and clinical improvement.

CREB-Phosphorylation as a Predictor of Therapeutic Response to Antidepressants

OBJECTIVES: CREB (c-AMP response element binding protein) is known as a key mediator of the therapeutic response to antidepressants. We investigated the change of CREB-phosphorylation (pCREB) at the early point of the fluoxetine treatment to find out it can be a predictor for antidepressant response. METHODS: We evaluated the pCREB of T - lymphocyte nuclear extracts from 18 depressed patients at 0 and 1th week during fluoxetine treatment (20 mg/day). Responders were defined as the > or = 50% reduction of HAM-D score in 4 weeks. We compared the changes of pCREB at 0 and 1th week between responders and non-responders. RESULTS: The responders showed a significant increase of pCREB at week 1 compared with week 0. The HAM-D difference between week 0 and 4 was positively correlated with the change of pCREB response. CONCLUSION: These results suggest that the early change of pCREB in peripheral lymphocyte can predict the later response of antidepressant. The correlation showed pCREB directly reflects a response status to the antidepressant fluoxetine and clinical improvement.

Serotonin Transporter Gene Polymorphisms and Chronic Illness of Depression

Clinical course of depression is variable. The serotonin transporter gene is one of the most studied genes for depression. We examined the association of serotonin transporter gene polymorphisms with chronicity and recurrent tendency of depression in Korean subjects. This cross-sectional study involved 252 patients with major depression. Patients were genotyped for s/l polymorphisms in 5-HTT promoter region (5-HTTLPR), s/l variation in second intron of the 5-HTT gene (5-HTT VNTR intron2). Chronicity was associated with 5-HTTLPR. Patients with l/l had higher rate of chronicity than the other patients (l/l vs s/l or s/s; odds ratio, 4.45; 95% confidence interval, 1.59-12.46; P=0.005; logistic regression analysis). Recurrent tendency was not associated with 5-HTTLPR. Chronicity and recurrent tendency were not associated with 5-HTT VNTR intron2. These results suggest that chronic depression is associated with 5-HTTLPR.

Comparative Study of Serum Brain-Derived Neurotrophic Factor in Acute and Chronic Depression / 대한정신약물학회지

OBJECTIVE: The aim of this study was to compare the serum brain-derived neurotrophic factor (BDNF) in acute depression with that in chronic depression. METHODS: Eighty subjects who met criteria for major depressive disorder (MDD) were recruited. Patients experiencing at least their fourth episode or an episode of at least 24 months in duration were defined as chronically depressed (n=21). Other patients were classified as acutely depressed (n=59). Antidepressant medications were administered for 6 weeks. Serum BDNF and Hamilton rating scale for depression (HAM-D) scores were measure before and after the administration of medication. RESULTS: We found significant differences in serum BDNF between the two groups. Serum BDNF was significantly higher among those with chronic depression than among those with acute depression both at baseline and after medication. CONCLUSION: This study suggested that serum BDNF might constitute a potential biological marker for chronic depression.

An Association Study between Various Monoamine Transporter Gene Polymorphisms and Treatment Response to Mirtazapine in Major Depression / 대한정신약물학회지

OBJECTIVE: Genetic differences may contribute to the inter-individual differences in treatment response to antidepressants among patients suffering from major depression. This study investigated a possible association of various monoamine transporter genetic polymorphisms with treatment response to mirtazapine in major depressive patients in elderly. METHODS: In this study, three genetic polymorphisms were selected: serotonin transporter 5- HTTLPR, serotonin transporter 5-HTT intron 2 VNTR, and norepinephrine transporter NET (G1287A). The patients with major depression diagnosed by DSM-IV were recruited to a 6 week naturalistic mirtazapine treatment study in Samsung Medical Center. Treatment response to mirtazapine was defined as > or =50% decrease in HAMD-17 scores at 6 weeks, and the genotypes in the patients were determined using the polymerase chain reaction. RESULTS: Our results showed that ss allele carriers were included more in responder group (ss allele in responder vs. non responder group; 69.4% vs. 40.0%). In addition, l-allele (sl/ll) carriers were included less in responder group (sl/ll allele in responder vs. non responder group; 30.6% vs. 60.0%). Multiple logistic regression analyses showed the 5-HTTLPR polymorphism as an predictor of the mirtazapine response (5HTTLPR ss allele carrier vs. l-allele (sl/ll) carrier; odds ratio: 3.81; 95% confidence interval [CI], 1.32-11.0; p=0.013). However, 5-HTT intron 2 VNTR l/s (p=0.33 by multiple logistic regression; [OR], 0.53; 95% [CI], 0.15-1.88), and NET (G1287A) G/A (p=0.68 by multiple logistic regression; [OR], 1.25; 95% [CI], 0.44-3.53) showed no statistical significant influences on response rate. CONCLUSION: In conclusion, 5HTTLPR polymorphism may predict treatment response to mirtazapine in major depressive patients in elderly.

Serum S100B Levels and Major Depressive Disorder: Its Characteristics and Role in Antidepressant Response

OBJECTIVE: S100B is a neurotrophic factor that is involved in neuroplasticity. Neuroplasticity is disrupted in depression; however, treatment with antidepressants can restore neuroplasticity. S100B has previously been used as a biological marker for neuropathology and neuroplasticity; therefore, in this study, we compared serum S100B levels in depressive patients to those of normal controls. In addition, we compared the serum S100B levels of antidepressant responders to those of nonresponders. METHODS: Thirty five normal controls and 59 depressive patients were enrolled in this study. Depressive patients entered a 6 week clinical trial that included treatment with antidepressants. The serum S100B levels and clinical assessments, which included Hamilton depression rating scores, were measured at baseline and after 6 weeks of treatment with antidepressants. The difference in the serum S100B levels between depressive patients and normal controls and between antidepressant responders and nonresponders was then compared. RESULTS: There were no significant differences in the serum S100B levels of normal controls and depressive patients. In addition, 30 of the depressive patients responded to antidepressant treatment while 29 did not. Finally, the responders had significantly higher baseline serum S100B levels than the nonresponders. CONCLUSION: The results of this study suggest that the baseline serum S100B level is associated with the subsequent response to antidepressants. In addition, the high baseline serum S100B level that was observed in depressive patients may enhance neuroplasticity, which results in a favorable therapeutic response to antidepressants.

CREB Expression in Peripheral Lymphocyte and Antidepressant Response / 대한정신약물학회지

OBJECTIVE: The molecules related with the intracellular signal transduction system are one of the main targets for the mode of mechanisms of antidepressant treatment in depressive patients. In vivo and in vitro studies have provided the evidence that the transcription factor, CREB (c-AMP response element binding protein) is the key mediator of the therapeutic response to antidepressants. We investigated the relationship between the treatment response to fluoxetine for 6 weeks and the change of CREB immunoreactivity in peripheral T lymphocyte. METHODS: CREB-expression and phosphorylation were quantified via western blot, and binding activity between transcription factor and CRE-oligonucleotide via electrophoretic mobility shift assay (EMSA) in nuclear extracts from 14 normal controls and 31 depressed patients at 0 and 6th week during fluoxetine treatment (20 mg/day). Responder was defined as the > or =50% of reduction or < or =7 of HAM-D score. We compared the changes of CREB during 6 weeks of fluoxetine treatment between drug responders and non-responders using SPSS11.0. RESULTS: After six weeks of treatment with fluoxetine, the drug responders showed a significant increase in CREB (p=0.024 by t-test) and p-CREB (p=0.045 by Mann-Whitney U test) compared with the non-responders. The change of CREB immunoreactivity was positively correlated with the change of p-CREB (r=0.770, p=0.000 by Spearman's rho), and the change of p-CREB was also positively correlated with CRE-DNA binding (r=0.753, p=0.000 by Spearman's rho). CONCLUSION: These results suggest that CREB response in peripheral lymphocyte may reflect and mediate the response to antidepressant treatment in depressed patients.

Association between the Genetic Polymorphisms of the Biogenic Amine Transporters and the Antidepressant Responsiveness in Korean Depressed Patients / 대한정신약물학회지

OBJECTIVE: Serotonin transporter (5-HTT) is a key synaptic regulator of serotonergic neurotransmission and a major site of action of most antidepressants. The functional polymorphism of 5-HTT gene is reported to be associated with antidepressant responsiveness. Norepinephrine transporter (NET) and dopamine transporter (DAT) are also the targets for antidepressant drugs, and these biogenic amine transporters share a similar structure and mode of action as 5-HTT. We investigated the association between genetic polymorphisms of biogenic amine transporters and antidepressant response. METHODS: We genotyped 203 patients with major depressive disorder and 147 normal controls, using polymerase chain reaction (PCR) of genomic DNA with primers flanking the second intron and promoter regions of 5-HTT gene, and the 3' untranslated region of DAT. NET-1 (Thr99Ile) and NET-8 (1287 G/A) polymorphism were characterized by amplification and restriction fragment length polymorphisms (RFLP) analysis. RESULTS: VNTR polymorphism in the 3' untranslated region of DAT (p=0.020) was associated with a diagnosis of depression, but was influenced by age effect. We found that NET-8 polymorphism (p=0.015) in NET gene had significant associations with antidepressant response, as did the allelic variations of the promoter (p<0.0001) and intron2 (p=0.023) region in 5-HTT gene. The choice of drug had no effect on drug responsiveness. CONCLUSIONS: These results suggest that allelic variations of 5-HTT and NET genes affect the antidepressant responsiveness.

Serotonin Transporter Gene Polymorphsims and Its Phenotypic Characteristics Expressed in Platelet 3H-Serotonin Uptake Study in Korean Depressed Patients / 신경정신의학

OBJECTIVES: Serotonin transporter (5-HTT) is a key synaptic regulator of serotonergic neurotransmission and a major site of action of serotonin selective reuptake inhibitors (SSRIs) such as fluoxetine or paroxetine. Two PCR-fomatted polymorphisms at this locus have been described, the first of which is a repeat sequence polymorphism located in the promoter region (5-HTT gene-linked polymorphic region, 5-HTTLPR), and the second is a variable number tandem repeat located in intron2 (STin2). 5-HTTLPR insertion/deletion polymorphism with long (l) and short (s) forms affects the transcriptional efficiency of 5-HTT transporter expression. We examined the pharmacodynamic characteristic of 5-HTT gene polymorphism in the patients with major depression, which was expressed in the peripheral platelet. METHODS: 5-HTT gene polymophisms and pharmacodynamic characteristics of 5-HTT in the platelet was measured in 41 patients with major depression defined by DSM IV criteria and 35 healthy normal volunteers. 5-HTT gene polymophisms were analyzed with the primers flanking the regulatory region and the second intron from genomic DNA. Pharmacodynamic characteristics of 5-HTT in the platelet was measured with [3H]-serotonin uptake study. The uptake of [3H]-serotonin was quantified with Vmax and Km value. RESULTS: We found that the Vmax value of 5-HTT in peripheral platelet was higher in the patients with s/s genotype (2.17 pmol/10(4) platelets/min, 1.53-3.90 pmol/10(4) platelets/min) than with s/l (1.73 pmol/10(4) platelets/min, 0.83-3.40 pmol/10(4) platelets/min) or l/l (1.0(4) pmol/10(4) platelets/min, 0.88-1.31 pmol/10(4) platelets/min) genotype of 5-HTTLPR. Normal subjects with s/s genotype also had significantly higher Vmax value than those with s/l or l/l genotype. However, STin2 genotype showed no significant association with Vmax or Km in both groups. CONCLUSIONS: These results suggest that allelic variation of 5-HTT gene affects the phenotypic expression of 5-HTT in human platelet, and may be linked with phenotypic heterogeneity in the antidepressant responsiveness in depressed patients. This is another different finding based on ethnic variation with respect to pharmacodynamic characteristics of 5-HTT gene polymorphism.

CAG Repeats of KCNN3 Gene in the Patients with Schizophrenia / 신경정신의학

OBJECTS:We investigated a possible association between the polymorphic trinucleotide repeat(TNR) expansion in neuronal potassium channel gene KCNN3 and schizophrenia. METHODS: CAG/CTG repeat distribution in KCNN3, CTG18.1 and ERDA1 was examined and the copy number of ligation product in repeat expansion detection(RED) was measured in Korean patients with schizophrenia(n=245) and ethnically matched healthy controls(n=116). RESULTS: Longer alleles in the KCNN3 gene were over-represented in patients. The frequency of alleles with CAG repeats longer than 19 copy in the KCNN3 gene was higher in the patients with schizophrenia as compared to controls(73.3% vs. 65.1%;p=0.029, Fisher's exact test). And this difference was more prominent in schizophrenic patients with familial background(p=0.03, Fisher's exact test). We found no difference in the frequency of longer alleles between negative and positive subtypes of schizophrenia. Ligation product size in RED and alleles with CAG repeat number in the CTG18.1 gene was not increased in the patients. The copy number of ligation product in RED was highly correlated with CAG/CTG copies of ERDA1 in the patient group(r=0.45, p<0.001) as well as in the control group(r=0.44, p<0.001). However, CAG repeat length in the KCNN3 gene was not correlated with ERDA1 score. CONCLUSIONS: Our results support the hypothesis that the longer allele of KCNN3 may be considered as a candidate gene for schizophrenia, especially in the case with familial background. And the RED assay results was affected by the CAG copy number of ERDA1.

CAG Repeat Expansions in the Patients with Mood Disorder / 신경정신의학

OBJECTIVES: The genetic facotrs have been suggested for the etiology of mood disorders but the mode of inheritance is complex. Increased severity and an earlier onset of the bipolar and major depressive disorder over generations within families(Anticipation) were reported. In order to test the hypothesis that trinucleotide repeat expansions underlie the genetic basis of Bipolar and major depressive disorders, we have analyzed the extent of CAG reapeats in genomic DNA from mood disorder patients. METHODS: 55 bipolar disorder, 67 major depressive disorder patients were recruited according to the DSM-III-R criteria. 89 normal controls were recruited from the medical personnel, students and the visitors to the health services center who had no history of psychiatric illness and show normal profile of MMPI. The genomic DNA of patients and controls was analyzed by use of the(CTG) 17 oligonucleotide and the repeat expansion detection(RED) method. The Mann-Whitney U test was used to compare the distribution of the number of CAG repeats among the groups. RESULTS: when the bipolar disorder, major depressive disorder patients were compared with the control group, no significant differences were observed. CONCLUSION: Our results do not support the hypothesis that expanding CAG repeats are causing the observed genetic anticipation in bipolar disorders and major depressive disorders.

Serotonin Transporter Gene Polymorphism and Major Depression / 신경정신의학

OBJECTIVE: Serotonin transporter(5-hydroxytryptamine transporter, 5-HTT) plays a critical role in the termination of serotonergic neurotransmission into the presynaptic neuron and represents an initial site of uptake inhibiting antidepressants, including tricyclic antidepressants and selective serotonin reuptake inhibitors. We investigated the possible association between the 5-HTT gene and major depression, and examined whether there are genotypic characteristics in 5-HTT gene that result in treatment nonresponsiveness to uptake inhibiting antidepressants. METHODS: 5-HTT gene polymorphisms are analyzed with the primers flanking the second intron and regulatory region from genomic DNA. We genotyped 142 patients with major depression and dysthymia, and 252 age and sex matched normal subjects. All individuals were Korean. RESULTS: We found no significant differences in the allele frequency(2 nd intron, p=0.941 : promoter, p=0.122) between patients and controls. However, in association studies between antidepressant responsiveness in depressive patients and allele frequencies of 5-HTT gene polymorphism in intron2 and promoter regions, there was shown significant differences in both(p<0.0001, p=0.0028, respectively by Fisher exact test). CONCLUSIONS: These results suggest that there is no major effect of 5-HTT gene polymorphisms on the susceptibility to major depressions, while antidepressant nonresponding is related with genotypic alteration in 5-HTT gene.