MRP1 polymorphisms associated with citalopram response in patients with major depression.

Multidrug resistance protein 1 (MRP1, ABCC1) transports antidepressive agents in the endothelial cells of the blood-brain barrier. Therefore, polymorphisms in the MRP1 gene may affect the treatment response of antidepressants. This study was aimed to identify the association between genetic variations in MRP1/ABCC1 and the therapeutic response to the antidepressant citalopram. One hundred and twenty-three patients who had been treated with citalopram monotherapy to control their major depressive disorder were recruited, and genotype data from 64 patients who had completed their 8-week follow-up were evaluated together with those from 100 controls. Nine MRP1 single nucleotide polymorphisms (SNPs) showing more than 5% allele frequency in the Korean population were analyzed. The c.4002G>A, a synonymous SNP in exon 28, showed a strong association with the remission state at 8 weeks (P = 0.005, odds ratio [OR], 4.7, 95% confidence interval [CI], 1.5 approximately 14.7). The c.4002G>A forms a linkage disequilibrium block with 3 other SNPs including c.5462T>A in the 3' untranslated region. Accordingly, the haplotype showed a significant association with the remission state (P = 0.014). Subsequent molecular studies also supported the association between these MRP1 polymorphisms and the citalopram response. Thus, kinetic studies using MRP1-enriched membrane vesicles revealed that citalopram is a substrate of MRP1 (Km = 1.99 microM, Vmax = 137 pmol/min per milligram protein). In addition, individuals with c.4002G>A or c.5462T>A polymorphisms showed higher MRP1 mRNA levels in peripheral blood cells. These results suggest that MRP1 polymorphisms may be a predictive marker of citalopram treatment in major depression.

Trial of aripiprazole in the treatment of first-episode schizophrenia.

AIMS: Aripiprazole is an atypical antipsychotic indicated for the treatment of adult patients with schizophrenia. It is effective and well tolerated in patients with schizophrenia or schizoaffective disorder. The aim of the present study was to investigate therapeutic efficacy and tolerability of aripiprazole in patients with first-episode schizophrenia. METHODS: Twenty-one patients meeting the DSM-IV criteria for schizophrenia were recruited. The Positive and Negative Symptom Scale (PANSS) and the Clinical Global Impressions Scale (CGI) were completed at the beginning of the study and again after 1, 2, 4, and 8 weeks of aripiprazole treatment. Side-effects were analyzed using the Udvalg for Kliniske Undersøgelser Side-Effect Rating Scale. Weight was checked at each testing session, and prolactin levels were measured at baseline and after 8 weeks of aripiprazole treatment. RESULTS: Significant benefits were observed after the first week of treatment. After 1 week of aripiprazole treatment, subscale and total scores on the PANSS had decreased significantly. This significant decrease was maintained throughout the study period. The mean score of CGI severity was also significantly different after 2 weeks of aripiprazole administration when compared to baseline score, and the significance was maintained thereafter. Weight did not significantly change after aripiprazole administration. Although mean prolactin level was decreased at 8 weeks, the difference was not significant. CONCLUSIONS: Aripiprazole is an effective and well-tolerated antipsychotic agent in patients with first-episode schizophrenia. Further investigations with larger samples are needed.

Effects of CYP2D6 and CYP3A5 genotypes on the plasma concentrations of risperidone and 9-hydroxyrisperidone in Korean schizophrenic patients.

This study was conducted to evaluate the effects of the CYP2D6 and CYP3A5 genotypes on the steady-state plasma levels of risperidone (RIS), 9-hydroxyrisperidone (9-OH-RIS), and the active moiety (RIS plus 9-OH-RIS) in Korean schizophrenic patients. Sixty-four Korean schizophrenic patients were enrolled. CYP2D6 and CYP3A5 genotypes were determined, and the plasma levels of RIS and 9-OH-RIS were measured using high-performance liquid chromatography. The dose-normalized plasma concentrations of RIS, 9-OH-RIS, and the active moiety were compared according to the CYP2D6 and CYP3A5 genotypes. Among the patients, 57 were CYP2D6 extensive metabolizers (EMs; CYP2D6*1/*1, *1/*10, and *10/*10) and 7 were CYP2D6 poor metabolizers (PMs; CYP2D6*1/*5 and *10/*5). For the CYP3A5 genotype, 30 patients were CYP3A5*1 expressors (*1/*1 [n = 1] and *1/*3 [n = 29]) and 34 patients were CYP3A5 nonexpressors (*3/*3). The plasma levels of RIS (2.03 ng/mL per milligram for EMs vs 5.57 ng/mL per milligram for PMs, P < 0.001) and 9-OH-RIS (5.06 ng/mL per milligram for EMs vs 0.22 ng/mL per milligram for PMs, P < 0.001) were significantly different among CYP2D6 genotype groups, but the CYP2D6 EMs (7.09 ng/mL per milligram) and PMs (5.79 ng/mL per milligram) did not show no difference in the levels of the active moiety (P = 0.470). CYP3A5 nonexpressors exhibited higher plasma concentrations of both RIS and 9-OH-RIS than its expressors. In the case of 9-OH-RIS, CYP3A5 nonexpressors exhibited significantly higher concentrations than CYP3A5 expressors (5.42 vs 3.51 ng/mL per milligram, P = 0.022). In addition, concentrations of the active moiety were also significantly different between the CYP3A5 nonexpressors (8.39 ng/mL per milligram) and expressors (5.30 ng/mL per milligram, P = 0.005). In conclusion, both CYP2D6 and CYP3A5 genotypes affected plasma levels of RIS and 9-OH-RIS, whereas the active moiety levels were influenced only by the CYP3A5 genotype but not by the CYP2D6 genotype.

Association study of the serotonin transporter promoter polymorphism and mirtazapine antidepressant response in major depressive disorder.

Modulations of serotonergic and noradrenergic systems are thought to be critical to the therapeutic effect of most antidepressants, and their efficacies have been shown to depend on a functional polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR). Mirtazapine has a dual-action profile, combining the enhancement of the noradrenergic neurotransmitter system with specific actions on particular serotonergic receptor subtypes. The goal of this study was to elucidate whether the 5-HTTLPR polymorphism is associated with the mirtazapine antidepressant response in subjects with major depressive disorder (MDD). One hundred and one MDD patients were evaluated during 4 weeks of mirtazapine treatment. The severity of depression was assessed with the 21-item Hamilton Depression Rating scale, and the 5-HTTLPR genotypes in the patients were determined using the polymerase chain reaction. Our results showed that responses at the 2nd and 4th weeks were significantly better for the s/s genotype of the 5-HTTLPR polymorphism than for l-allele carriers. These results support our hypothesis that the response to noradrenergic and specific serotonergic antidepressants is significantly associated with the 5-HTTLPR polymorphism.

Association between the tryptophan hydroxylase-1 gene A218C polymorphism and citalopram antidepressant response in a Korean population.

Tryptophan hydroxylase-1 (TPH1) is the rate-limiting enzyme in serotonin biosynthesis, and selective serotonin reuptake inhibitors (SSRIs) exert their activity enhancing the general serotonergic tone. Citalopram is the most selective SSRI, with little or no affinity for a variety of receptor types. The goal of this study was to investigate whether the A218C polymorphism of the TPH1 gene is associated with the citalopram antidepressant response in subjects with major depressive disorder (MDD). All of the patients were evaluated using the 21-item Hamilton Depression Rating Scale before beginning and after 8 weeks of citalopram treatment. Genotyping was performed with the polymerase chain reaction. The remission rate to citalopram treatment was worse in MDD subjects with the TPH1 A/A and A/C genotypes than in those with the TPH1 C/C genotype. Our results suggest that the A218C polymorphism of the TPH1 gene serves as a modulator of antidepressant activity, especially in terms of treatment remission.

Relationship between G-protein beta-3 subunit C825T polymorphism and mirtazapine responses in Korean patients with major depression.

AIMS: This study aimed to determine the relationship between the C825T polymorphism in the G-protein beta 3 subunit (GNB3) gene and the response to mirtazapine in a Korean population with major depressive disorder (MDD). METHOD: Mirtazapine was administered for 8 weeks to the 101 MDD patients who completed this study. All subjects were examined using the Structured Clinical Interview for DSM-IV, and the severity of depression was assessed using the 21-item Hamilton Depression Rating (HAMD-21) scale. RESULTS: There was a significant main effect of time on the decrease in the HAMD-21 score during the 8-week study period. However, a main effect of or an interaction of genotype with time on the decrease in the HAMD-21 score during the 8-week study period was not found. ANOVA revealed no significant effects of the GNB3 C825T polymorphism on the decrease in the HAMD-21 score at each time period. CONCLUSION: Although the C825T polymorphism of the GNB3 gene may affect the pathogenesis of MDD, our results do not support the hypothesis that this polymorphism is involved in the therapeutic response to mirtazapine in Korean patients with MDD.

Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder.

The brain-derived neurotrophic factor (BDNF) gene is a candidate gene for influencing the clinical response to treatment with antidepressants. The purpose of this study was to determine the relationship between the Val66Met polymorphism in the BNDF gene and the response to citalopram in a Korean population with major depressive disorder (MDD). Citalopram was administered for 8 weeks to the 83 patients who completed this study. We found that the genotype, allele, and allele-carrier distributions for the Val66Met polymorphism differed significantly between responders (Rp) and nonresponders (Non-Rp). The frequency of M-allele carriers (VM+MM) was higher in Rp than in Non-Rp (chi(2)=8.926, p=0.003, OR=4.375, 95%CI=1.609-11.892), as was the M-allele frequency (chi(2)=6.879, p=0.009, OR=2.500, 95%CI=1.249-5.005). There were also significant differences in the core (p=0.012) and activity (p=0.008) scores. Patients carrying the M-allele had a lower score. Also, patients carrying the M-allele tended to have lower psychic anxiety (p=0.072). The percentage change in the total HAM-D score was higher for M-allele carriers (VM+MM allele) than for noncarriers (p=0.034) after 8 weeks of medication. We found that the genotype, allele, and allele-carrier distributions did not differ significantly between MDD patients and normal controls. These results suggest that the Val66Met polymorphism of BDNF is associated with citalopram efficacy, with M-allele carriers responding better to citalopram treatment. Moreover, the Val66Met polymorphism was correlated with improvements in core, activity, and psychic anxiety symptoms.

Reward dependence is related to norepinephrine transporter T-182C gene polymorphism in a Korean population.

It is well established that approximately 50% of the variance in personality traits is genetic. The goal of this study was to investigate a relationship between personality traits and the T-182C polymorphism in the norepinephrine transporter gene. The participants included 115 healthy adults with no history of psychiatric disorders and other physical illness during the past 6 months. All participants were tested with the Temperament and Character Inventory and genotyped norepinephrine transporter gene polymorphism. Differences on the Temperament and Character Inventory dimensions among three groups were examined with one-way analysis of variance. Our study suggests that the norepinephrine transporter T-182C gene polymorphism is associated with reward dependence in Koreans, but the small number of study participants and their sex and age heterogeneity limits generalization of our results. Further studies are necessary with a larger number of homogeneous participants to confirm whether the norepinephrine transporter gene is related to personality traits.

No association between the tryptophan hydroxylase gene polymorphism and major depressive disorders and antidepressant response in a Korean population.

The serotonergic neurotransmitter system has been implicated in major depressive disorder (MDD) and appears to be the target of a variety of antidepressants. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin biosynthesis, and selective serotonin re-uptake inhibitors exert their activity enhancing the general serotonergic tone. The goal of this study was to investigate whether the A218C polymorphism of the TPH gene is associated with MDD or antidepressant response. All patients were evaluated at the start and in the eighth week of using the 21-item Hamilton Depression Rating Scale. Genotyping was analyzed with polymerase chain reaction. There were no significant differences in genotypes and allele frequencies between the MDD patients (n = 93) and the control group (n = 127) and in the antidepressant response among TPH gene variants. Results suggest that the A218C polymorphism of the TPH gene does not play a major role in pathogenesis in MDD and does not serve as a modulator of antidepressant activity.

Development and validation of a screening scale for depression in Korea: the Lee and Rhee Depression Scale.

OBJECTIVE: The aim of this study was to develop a culturally sensitive instrument that addressed how individuals express and experience depression to detect this disorder in Koreans. We also assessed the validity, reliability, and diagnostic utility of this scale (Lee and Rhee Depression Scale; LRDS). METHODS: The sample consisted of 3,697 normal adults selected from 12 administrative districts (Do) and 448 Korean patients diagnosed with depression using the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). Reliability was calculated using Cronbach's α. Construct validity, discriminant validity, and concurrent validity were also measured. Receiver-operator-characteristic (ROC) analysis was employed to evaluate diagnostic efficiency. RESULTS: The LRDS was found to be a reliable instrument (Cronbach's α=0.95) consisting of six factors: negative thinking about the future, negative thinking about the self, worry and agitation, depressed mood, somatization, and loss of volition. Comparison of LRDS scores discriminated the group of patients with depression from the normal individuals in the control group. The measure showed good concurrent validity in that scores were significantly and strongly correlated with scores on established scales such as the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale (HAM-D), and the D scale of the Minnesota Multiphasic Personality Inventory-second edition (MMPI-2). Diagnostic efficiency was 77.7%, and the cut-off scores were 65 for males and 70 for females. CONCLUSION: To our knowledge, this is the first study to develop a depression-screening scale on the basis of Korean patients' complaints about the disorder. As a culturally sensitive tool, the LRDS will be useful in clinical and research settings in Korea.

Association of the adrenergic alpha 2a receptor--1291C/G polymorphism with weight change and treatment response to mirtazapine in patients with major depressive disorder.

BACKGROUND: Adrenergic alpha2a receptors (ADRA2A) are expressed in the central nervous system and peripheral tissues. The primary mechanism of action of mirtazapine is the antagonism of central presynaptic alpha2 receptors. Mirtazapine is reportedly associated with weight gain. Our objective was to determine whether the ADRA2A -1291C/G polymorphism is associated with weight gain and treatment response to mirtazapine in patients with major depressive disorder (MDD). METHODS: The ADRA2A -1291C/G polymorphism was analyzed in 314 MDD patients and 162 control subjects. All patients were evaluated using the 21-item Hamilton Depression Rating Scale at the beginning of the study and at 1, 2, 4, and 8 weeks of mirtazapine treatment. RESULTS: No relationship was observed between the ADRA2A -1291C/G polymorphism and MDD. No significant difference was found between responder and non-responder groups when comparing the ADRA2A genotype distribution with treatment response to mirtazapine. Repeated measures ANOVA with the last observation carry-forward test indicated that after adjusting for baseline body weight, age, and gender, the subjects with the C/C genotype exhibited a greater mean body weight gain than the subjects with the C/G or G/G genotype after 8 weeks of mirtazapine treatment (p=0.052). CONCLUSIONS: The ADRA2A -1291C/G polymorphism does not appear to be a predictor of treatment response to mirtazapine. This polymorphism was weakly associated with weight change after 8 weeks of mirtazapine treatment. Further investigation is required to determine whether other polymorphisms of this gene influence treatment response and weight change in patients receiving mirtazapine.

Association of glucocorticoid receptor polymorphisms with the susceptibility to major depressive disorder and treatment responses in Korean depressive patients.

OBJECTIVE: Major depressive disorder (MDD) is closely related to stress reactions and serotonin probably underpins the pathophysiology of MDD. Alterations of the hypothalamic-pituitary-adrenal axis at the gene level have reciprocal consequences on serotonin neurotransmission. Glucocorticoid receptor (GR) polymorphisms affect glucocorticoid sensitivity, which is associated with cortisol feedback effects. Therefore, we hypothesised that GR polymorphisms are associated with the susceptibility to MDD and predict the treatment response. METHOD: Ninety-six subjects with a minimum score of 17 on the 21-item Hamilton Depression Scale (HAMD) at baseline were enrolled into the present study. The genotypes of GR (N363S, ER22/23EK, Bcl1, and TthIII1 polymorphisms) were analysed. The HAMD score was again measured after 1, 2, 4 and 8 weeks of antidepressant treatment to detect whether the therapeutic effects differed with the GR genotype. RESULTS: Our subjects carried no N363S or ER22/23EK genetic polymorphisms and three types of Bcl1 and TthIII1 genetic polymorphisms. The C/C genotype and C allele at Bcl1 polymorphism were more frequent in MDD patients than in normal controls (p < 0.01 and p = 0.01, respectively). The genotype distributions did not differ significantly between responders and non-responders. CONCLUSION: These results suggest that GR polymorphism cannot predict the therapeutic response after antidepressant administration. However, GR polymorphism (Bcl1) might play a role in the pathophysiology of MDD. Future studies should check this finding in larger populations with different characteristics.

The neural substrates of affective face recognition in patients with Hwa-Byung and healthy individuals in Korea.

Hwa-Byung (HB) is a Korean culture-bound psychiatric syndrome caused by the suppression of anger. HB patients have various psychological and somatic symptoms, such as chest discomfort, a sensation of heat, and the sensation of having an epigastric mass. In this study, we measured brain activity in HB patients and healthy individuals in response to affective facial stimuli. Using functional magnetic resonance imaging (fMRI), the current study measured neural responses to neutral, sad, and angry facial stimuli in 12 healthy individuals and 12 patients with HB. In response to all types of facial stimuli, HB patients showed increased activations in the lingual gyrus and fusiform gyrus compared with healthy persons, but they showed relatively lower activation in the thalamus. We also found that patients with HB showed lower activity in response to the neutral condition in the right ACC than healthy controls. The current study indicates that the suppression of affect results in aberrant function of the brain regions of the visual pathway, and functional impairment in the ACC may contribute to the pathophysiology of HB.

Effect of serotonin receptor 2A gene polymorphism on mirtazapine response in major depression.

The 5-HTR2A gene is a candidate gene for influencing the clinical response to treatment with antidepressants. The purpose of this study was to determine the relationship between the -1438A/G polymorphism of the 5-HTR2A gene and the response to mirtazapine in a Korean population with major depressive disorder. Mirtazapine was administered for eight weeks to the 101 patients who completed the study, during which we evaluated the clinical outcome using repeated-measures ANCOVA. A main effect of genotype or an effect of genotype-time interactions on the decrease in HAMD score during the eight-week follow-up was not found, which suggests that the 5-HTR2A -1438A/G polymorphism does not affect the clinical outcome to mirtazapine administration. However, significant effects of genotype and allele carriers on the decrease in the sleep score over the eight weeks were found (genotype: F = 4.093, p = 0.017; allele: F = 4.371, p = 0.037), whereas no effect of genotype-time interactions on the decrease in the HAMD score over the eight-week follow-up was found. These observations suggest that the -1438A/G polymorphism on the sleep improvement at each time period revealed significant differences in the sleep scores after two weeks of mirtazapine administration. The sleep scores were lower for carriers of the A+ allele than of the A- allele after two weeks of mirtazapine administration (p = 0.041), which means that the -1438GG genotype is associated with less improvement in sleep, and suggests that the effect of mirtazapine on improving the sleep quality differs with the 5-HTR2A -1438A/G polymorphism within two weeks of mirtazapine treatment. In conclusion, although the -1438A/G polymorphism affects the sleep improvement resulting from the administration of mirtazapine to Korean patients with major depressive disorder, our results do not support the hypothesis that this polymorphism of the 5-HTR2A gene is involved in the therapeutic response to mirtazapine.

Serotonin receptor 2A gene polymorphism (-1438A/G) and short-term treatment response to citalopram.

The 5-HTR2A gene is a candidate gene for influencing the clinical response to antidepressant treatment. The purpose of this study was to determine the relationship between the -1438A/G polymorphism in the 5-HTR2A gene and the response to citalopram in a Korean population with major depressive disorder (MDD). Citalopram was administered for 4 weeks to the 71 patients who completed this study. We found significant differences in genotype, allele, and carrier distribution between the normal group and MDD patients (genotypes: chi(2) = 6.473, d.f. = 2, p = 0.039; alleles: chi(2) = 5.589, d.f. = 1, p = 0.018; OR = 0.618, 95% CI = 0.414-0.922; allele carriers: chi(2) = 5.383, d.f. = 1, p = 0.020; OR = 0.473, 95% CI = 0.249-0.879). The frequency of the -1438G allele was much higher in MDD patients than in the normal group (allele carriers: chi(2) = 5.383, d.f. = 1, p = 0.020; OR = 0.473, 95% CI = 0.249-0.879). There were also significant differences in response to citalopram according to the -1438A/G variation of 5-HTR2A in MDD patients. The group of remitters carried a higher frequency of the GG allele than of the AA and AG alleles. More of nonremitters carried the A allele than were without it (genotype: chi(2) = 8.016, p = 0.018; allele carrier: chi(2) = 4.512, p = 0.034; OR = 0.324, 95% CI = 0.112-0.936). The response to citalopram differed with the -1438A/G polymorphism genotype and allele carriers. The -1438G/-1438G genotype appeared to be associated with a better response to citalopram, with especially the G allele being related to core depressive symptoms and psychic anxiety improvement (p<0.05). These results suggest that the G allele of the -1438A/G polymorphism in the 5-HTR2A gene is associated with MDD, and that patients with -1438G/-1438G have a better response to citalopram treatment than patients with -1438A/-1438A or -1438A/-1438G.

Influence of the serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a prevalent anxiety disorder marked by behavioral, physiologic, and hormonal alterations. The etiology of PTSD is unknown, although exposure to a traumatic event constitutes a necessary, but not sufficient, factor. Serotonergic dysfunction has been implicated in PTSD. The present study examined the possible association between the serotonin-transporter-linked polymorphic region (SERTPR) and PTSD. The genotype and allele frequencies of the SERTPR were analyzed in 100 PTSD patients and 197 unrelated healthy controls using a case-control design. The frequency of the s/s genotype was significantly higher in PTSD patients than in normal controls. These findings suggest that the SERTPR s/s genotype is one of the genetic factors for the susceptibility to PTSD. Further investigations are required into the influence of gene polymorphisms on the biological mechanisms of PTSD, its clinical expression, and its response to treatment.